The tapeworm that turned into a tumour

Bizarre case study reports how cancerous cells came from a tapeworm infection. A tapeworm that infected a Colombian man deposited malignant cells inside his body that spread much like an aggressive cancer, researchers have reported in a bizarre, but not unprecedented, case.

“We have a situation where a foreign organism is developing as a tumour rather than developing as an organism,” says Peter Olson, a developmental parasitologist at the Natural History Museum in London. He is part of a team that describes the case in a 4 November report in the New England Journal of Medicine.

The apparently cancerous cells were first examined in 2013 by investigators at the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. They came from a 41-year-old Colombian man with HIV, who had been ill for months when he sought medical attention in January 2013. Colombian doctors found that he had a compromised immune system, had been infected by the dwarf tapeworm (Hymenolepis nana), and had small tumour-like growths in his lungs and lymph nodes. They sent tissue samples to the CDC.

Under a microscope, those samples revealed small odd-shaped cells that, like a cancer, appeared to be invading nearby healthy tissue, the CDC team found. Yet the cells tested negative for human proteins. That was a conundrum: although the US investigators knew about the man’s tapeworm infection, the invading cells did not look like they should belong to a complex, multicellular organism such as a tapeworm.

Tragically, in May 2013, the patient experienced kidney failure and died. A team led by CDC pathologist Atis Muehlenbachs examined the DNA of the invading cells and determined that they did belong to a tapeworm. And genome sequencing showed that the tapeworm cells carried particular mutations that, in human cells, are associated with tumours.

Tapeworm-derived tumours are extremely rare, says Olson, who has documented a handful of other cases in patients whose immune systems were compromised.

Olson believes that the tumorous tapeworm cells are rogue larvae that burrowed from the stomach into the lymph nodes of immunocompromised people (a healthy immune system would stop this invasion). The larvae are loaded with regenerative stem cells, so instead of turning into an adult tapeworm, they proliferate. “Those stem cells that would normally give rise to a segmented worm don’t, because they’re in the wrong place and have the wrong environmental cues,” says Olson.

Some of the cases that Olson has worked on involve the dwarf tapeworm, which is unique among the several thousand other known tapeworm species in that it can develop fully in the gut of its mammalian host. Normally, tapeworm eggs are expelled by their host and then mature in an invertebrate, before being transmitted back to a vertebrate host.

Elizabeth Murchison, a molecular geneticist at the University of Cambridge, UK, says that she finds the case astonishing. Although there is no evidence that the proliferative tapeworm cells might be transmitted between humans, Murchison (who studies tumour cells that spread between animals) wonders whether proliferative cells from other parasites could become infectious.

“This paper is tremendously important as it presents the existence of a new type of disease process, which may have previously been overlooked,” she says.

Nature doi:10.1038/nature.2015.18726  Nature  Original web page at Nature


How glucose regulation enables malignant tumor growth

A new study led by researchers at The Ohio State University Comprehensive Cancer Center. The researchers identified a critical molecule in that pathway that, if blocked, might cripple lipid production by cancer cells and slow tumor growth. This approach would be a new strategy for treating a lethal type of brain cancer called glioblastoma multiforme, as well as other malignancies. This discovery also has significant therapeutic implications on other metabolic disorders with deregulated lipid metabolism, such as atherosclerosis, obesity and diabetes.

The study discovered that activation of the epidermal growth factor receptor (EGFR), which triggers enhanced uptake of glucose, leads to a chemical change in a molecule called SCAP. This enables SCAP to transport a second molecule called SREBP, and this leads to the activation of genes that regulate the production and uptake of lipids. SREBPs are key proteins for regulating lipid metabolism. The researchers published their findings in the journal Cancer Cell Nov. 9, 2015.

“Our findings reveal the previously unrecognized, critical role of glucose in controlling lipid synthesis during tumor development,” says principal investigator Deliang Guo, PhD, assistant professor of radiation oncology at the OSUCCC — James.

“We unraveled the mechanisms behind how glucose drives tumor growth through the specific SREBP pathway. This is an important discovery for future anti-cancer drug development activities.” “For this study, Guo and his colleagues used various human cancer cell lines and a glioblastoma animal model. Technical findings include:

  • EGFR activation increases glucose uptake and promotes a posttranslational change in SCAP called N-glycosylation;
  • That N-glycosylation triggers SCAP/SREBP moving from ER to the Golgi and the subsequent activation of SREBP [and activation of genes involved in lipid production].
  • Blocking the glycosylation of SCAP suppressed the growth of glioblastoma tumors in an animal model.

“Our data explains the underlying molecular mechanism of how cancer cells respond and survive the harsh nutritional variability of the tumor microenvironment,” Guo says.  Science Daily  Original web page at Science Daily


Cancer-fighting viruses win approval

US regulators clear a viral melanoma therapy, paving the way for a promising field with a chequered past. An engineered herpesvirus that provokes an immune response against cancer has become the first treatment of its kind to be approved for use in the United States, paving the way for a long-awaited class of therapies. On 27 October, the US Food and Drug Administration (FDA) approved a genetically engineered virus called talimogene laherparepvec (T-VEC) to treat advanced melanoma. Four days earlier, advisers to the European Medicines Agency had endorsed the drug.

With dozens of ongoing clinical trials of similar ‘oncolytic’ viruses, researchers hope that the approval will generate the enthusiasm and cash needed to spur further development of the approach. “The era of the oncolytic virus is probably here,” says Stephen Russell, a cancer researcher and haematologist at the Mayo Clinic in Rochester, Minnesota. “I expect to see a great deal happening over the next few years.”

Many viruses preferentially infect cancer cells. Malignancy can suppress normal antiviral responses, and sometimes the mutations that drive tumour growth also make cells more susceptible to infection. Viral infection can thus ravage a tumour while leaving abutting healthy cells untouched, says Brad Thompson, president of the pharmaceutical-development firm Oncolytics Biotech in Calgary, Canada.

The strategy builds on a phenomenon that has been appreciated for more than a century. Physicians in the 1800s noted that their cancer patients sometimes unexpectedly went into remission after experiencing a viral infection. These case reports later inspired doctors, particularly in the 1950s and 1960s, to raid nature’s viral cupboard. Clinicians injected cancer patients with a menagerie of viruses. Sometimes the therapy destroyed the tumour, and sometimes it killed the person instead.

Unlike the wild viruses used in those mid-twentieth-century experiments, some of today’s anti-cancer viruses are painstakingly engineered. T-VEC, for example, has been altered to drastically reduce its ability to cause herpes. Researchers also inserted a gene encoding a protein that stimulates the immune system, which makes the virus even more potent against cancer.

As more researchers entered the field and initiated small clinical tests, they began to produce enticing anecdotes. Russell recalls the case of an individual with myeloma who remained sick after under­going two stem-cell transplants. A tumour on the left side of her forehead had degraded the bone underneath and was putting pressure on her brain. Yet treatment with an experimental virus sent her into complete remission (S. Russell et al. Mayo Clin. Proc. 89, 926–933; 2014). “She’s a star patient who convinced us that this oncolytic paradigm can really work,” he says.

But statistics — not anecdotes — rule over drug approvals. In 2005, regulators in China approved an oncolytic adenovirus called H101 to treat head-and-neck cancer, after evidence showed that the treatment could shrink tumours. Those trials stopped short of assessing improvements in patient survival — a measure often required for FDA approval. Since then, a medical-tourism industry has built up in China for people who cannot get the therapy in their home countries.

Then, in May this year, a team supported by biotechnology giant Amgen of Thousand Oaks, California, published promising results from a large clinical trial of T-VEC (R. H. Andtbacka et al. J. Clin. Oncol. 33, 2780–2788; 2015). The virus both shrank tumours in people with advanced melanoma and extended patient survival by a median of 4.4 months. Yet statistically, survival benefits fell just a hair’s breadth of significance. “That raised the question, ‘Well, what is statistical significance? Is this an active agent or not?’” Russell says.

He and others note that the therapy — which must be injected directly into tumours — seemed to rein in cancer elsewhere in the body as well. This is a sign that results are real and that the virus sparked an immune response as intended, Thompson says.

Administering T-VEC in combination with cancer immunotherapy could prove particularly effective, notes Stephen Hodi, an oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts. In June 2014, a small clinical trial by Amgen suggested that this combination may boost effectiveness over that of the immunotherapies alone.

And researchers continue to look for ways to improve T-VEC. In particular, they would like to be able to deliver the therapy systemically, so that the virus could target tumours in organs that are difficult to reach with an injection. This would require a technique to prevent the body from mounting an immune response to the virus prematurely, which would disable it before it could reach and kill tumour cells, says Howard Kaufman, a cancer researcher at Rutgers Cancer Institute of New Jersey.

To that end, those in the field are experimenting with a smorgasbord of viruses — from poxviruses to vesicular stomatitis virus, which does not normally infect humans but causes a blistering disease in cattle. Oncolytics Biotech is studying a virus that hitch-hikes through the body on certain blood cells, camouflaged from the immune system.

If cancer-killing viruses could be delivered to their targets through the bloodstream, rather than via injection directly into the tumour, they could be used to treat a greater range of cancers. Thompson envisions a day when physicians will be able to peruse a menu of oncolytic viruses and select the best fit. “Each virus interacts with the immune system differently,” he says. “They could have a role in pretty much all cancer therapy.”

Nature 526, 622–623 (29 October 2015) doi:10.1038/526622a  Nature  Original web page at Nature


Immunotherapy for pancreatic cancer boosts survival by more than 75 percent in mice

A new study in mice by researchers at Fred Hutchinson Cancer Research Center has found that a specialized type of immunotherapy — even when used without chemotherapy or radiation — can boost survival from pancreatic cancer, a nearly almost-lethal disease, by more than 75 percent. The findings are so promising, human clinical trials are planned within the next year.

The study, led by Drs. Sunil Hingorani and Phil Greenberg, both members of the Clinical Research Division at Fred Hutch, tested the immunotherapy on mice genetically engineered to grow pancreatic tumors very similar to those of human pancreatic cancer. The mouse model, developed by Hingorani, already has led to a first-in-humans clinical trial that is showing early promise in some patients with advanced pancreatic cancer.

Pancreatic cancer is notoriously difficult to treat, said Hingorani, because it recruits the body’s natural systems to construct both a tough physical barrier around tumors as well as an immune-cloaking device that keeps other, disease-fighting immune cells from recognizing the cancer.

Unlike any other cancer, pancreatic tumors are able to survive with a significantly decreased blood supply. As a consequence, chemotherapy, commonly administered via the bloodstream, has a difficult time getting inside. The tumors not only commonly grow quite large before patients will ever notice something is wrong, but they are very prone to metastasize, or spread to other sites in the body.

The investigators’ new study, published in Cancer Cell, breaches pancreatic cancer’s physical and immunological walls by using immunotherapy, a type of treatment that harnesses or refines the body’s own immune system, to recognize and destroy cancer cells. The researchers devised a therapy using T cells, disease-fighting immune cells, that they engineered in the lab to recognize and attack pancreatic cancer.

T-cell therapy is showing promise as a treatment for several types of blood cancers, based on early results from Fred Hutch and other research centers, but aiming these cells at solid tumors like pancreatic cancer has historically proven more difficult, Hingorani said. Part of the challenge comes from the access to tumor cells — or lack thereof. T-cell therapy is administered through the bloodstream, like chemo. It’s easy enough to see why solid tumors may present more of a challenge to treat with this kind of immunotherapy than blood cancers such as leukemia and lymphoma.

The researchers didn’t think the engineered T cells would stand a chance against pancreatic cancer on their own. But they needed somewhere to start, Greenberg said. But to their surprise, the T cells — engineered to recognize and kill cells bearing a protein called mesothelin, which is overproduced by virtually all pancreatic tumors — got into the mice’s tumors and started attacking them.

In the mouse model of the disease — which is actually slightly more aggressive than the human version, Hingorani said — animals that received T cells engineered to recognize a non-cancerous protein survived on average 54 days after their cancer became detectable. Those that received the mesothelin-directed cells lived an average of 96 days, a 78 percent bump.

Although the researchers weren’t expecting to take this first version of the T-cell therapy to clinic, that’s now their plan. Their team has already built the human version of the special T-cell protein that recognizes mesothelin. They’re planning to launch a phase 1 clinical trial to test the therapy’s safety in patients with advanced pancreatic cancer within the next year.

“As best we can tell, this would be a better therapy than anything that exists for pancreatic cancer right now,” Greenberg said. “It’s hard to be this optimistic without ever having treated a pancreatic cancer patient with this [therapy], but the biology of what we’re doing looks so remarkably true and good.   Science Daily  Original web page at Science Daily


* Why elephants rarely get cancer

Why elephants rarely get cancer is a mystery that has stumped scientists for decades. A study led by researchers at Huntsman Cancer Institute (HCI) at the University of Utah and Arizona State University, and including researchers from the Ringling Bros. Center for Elephant Conservation, may have found the answer.

According to the results, published in the Journal of the American Medical Association (JAMA), and determined over the course of several years and a unique collaboration between HCI, Primary Children’s Hospital, Utah’s Hogle Zoo, and the Ringling Bros. Center for Elephant Conservation, elephants have 38 additional modified copies (alleles) of a gene that encodes p53, a well-defined tumor suppressor, as compared to humans, who have only two. Further, elephants may have a more robust mechanism for killing damaged cells that are at risk for becoming cancerous. In isolated elephant cells, this activity is doubled compared to healthy human cells, and five times that of cells from patients with Li-Fraumeni Syndrome, who have only one working copy of p53 and more than a 90 percent lifetime cancer risk in children and adults. The results suggest extra p53 could explain elephants’ enhanced resistance to cancer.

“Nature has already figured out how to prevent cancer. It’s up to us to learn how different animals tackle the problem so we can adapt those strategies to prevent cancer in people,” says co-senior author Joshua Schiffman, M.D., pediatric oncologist at Huntsman Cancer Institute, University of Utah School of Medicine, and Primary Children’s Hospital.

According to Schiffman, elephants have long been considered a walking conundrum. Because they have 100 times as many cells as people, they should be 100 times more likely to have a cell slip into a cancerous state and trigger the disease over their long life span of 50 to 70 years. And yet it’s believed that elephants get cancer less often, a theory confirmed in this study. Analysis of a large database of elephant deaths estimates a cancer mortality rate of less than 5 percent compared to 11 to 25 percent in people.

In search of an explanation, the scientists combed through the African elephant genome and found at least 40 copies of genes that code for p53, a protein well known for its cancer-inhibiting properties. DNA analysis provides clues as to why elephants have so many copies, a substantial increase over the two found in humans. The vast majority, 38 of them, are so-called retrogenes, modified duplicates that have been churned out over evolutionary time.

Schiffman’s team collaborated with Utah’s Hogle Zoo and Ringling Bros. Center for Elephant Conservation to test whether the extra gene copies may protect elephants from cancer. They extracted white blood cells from blood drawn from the animals during routine wellness checks and subjected the cells to treatments that damage DNA, a cancer trigger. In response, the cells reacted to damage with a characteristic p53-mediated response: they committed suicide.

“It’s as if the elephants said, ‘It’s so important that we don’t get cancer, we’re going to kill this cell and start over fresh,'” says Schiffman. “If you kill the damaged cell, it’s gone, and it can’t turn into cancer. This may be more effective of an approach to cancer prevention than trying to stop a mutated cell from dividing and not being able to completely repair itself.”

With respect to cancer, patients with inherited Li-Fraumeni Syndrome are nearly the opposite of elephants. They have just one active copy of p53 and more than a 90 percent lifetime risk for cancer. Less p53 decreases the DNA damage response in patients with Li-Fraumeni Syndrome, and Schiffman’s team wondered if more p53 could protect against cancer in elephants by heightening the response to damage. To test this, the researchers did a side-by-side comparison with cells isolated from elephants (n=8), healthy humans (n=10), and from patients with Li-Fraumeni Syndrome (n=10). They found that elephant cells exposed to radiation self-destruct at twice the rate of healthy human cells and more than five times the rate of Li-Fraumeni cells (14.6%, 7.2%, and 2.7%, respectively). These findings support the idea that more p53 offers additional protection against cancer.

“By all logical reasoning, elephants should be developing a tremendous amount of cancer, and in fact, should be extinct by now due to such a high risk for cancer,” says Schiffman. “We think that making more p53 is nature’s way of keeping this species alive.” Additional studies will be needed to determine whether p53 directly protects elephants from cancer

“Twenty years ago, we founded the Ringling Bros. Center for Elephant Conservation to preserve the endangered Asian elephant for future generations. Little did we know then that they may hold the key to cancer treatment,” said Kenneth Feld, Chairman and CEO of Feld Entertainment.

“The incredible bond our staff has with these majestic animals, and the hands-on care provided at the Center for Elephant Conservation, allows us to easily provide the blood samples Dr. Schiffman needs to further his research,” said Alana Feld, executive vice president of Feld Entertainment and producer of Ringling Bros. and Barnum & Bailey. “We look forward to the day when there is a world with more elephants and less cancer.”

The elephant story represents one way that evolution may have overcome cancer. Other evidence suggests that naked mole rats and bowhead whales have evolved different approaches to the problem. Schiffman plans to use what he’s learned in elephants as a strategy for developing novel cancer-fighting therapies.

“Participating in the research is not only amazing but a win-win for humans and elephants,” said Peterson. “If elephants can hold the key to unlocking some of the mysteries of cancer, then we will see an increased awareness of the plight of elephants worldwide. What a fantastic benefit: elephants and humans living longer, better lives.”

“The animal kingdom undoubtedly holds information that could help lead to cures for many human illnesses,” said Craig Dinsmore, executive director, Utah’s Hogle Zoo. “The blood samples from our elephants at Utah’s Hogle Zoo are aiding Dr. Schiffman in his research, and we are proud to be a part of his ground-breaking work.”  Science Daily  Original web page at Science Daily


Novel compound turns off mutant cancer gene in animals with leukemia

A compound discovered and developed by a team of Georgetown Lombardi Comprehensive Cancer Center researchers that halts cancer in animals with Ewing sarcoma and prostate cancer appears to work against some forms of leukemia, too. That finding and the team’s latest work was published online Oct. 8 in Oncotarget.

The compound is YK-4-279, the first drug targeted at similar chromosomal translocations found in Ewing sarcoma, prostate cancer and in some forms of leukemia. Translocations occur when two normal genes break off from a chromosome and fuse together in a new location. This fusion produces new genes that manufacture proteins, which then push cancer cells to become more aggressive and spread. One of those proteins is EWS-FLI1. YK-4-279 appears effective in controlling the cancer promoting functions of EWS-FLI1.

“EWS-FLI1 is already known to drive a rare but deadly bone cancer called Ewing sarcoma, which occurs predominantly in children, teens and young adults,” says Aykut Üren, MD, professor of molecular oncology at Georgetown Lombardi. “It also appears to drive cancer cell growth in some prostate cancers.”

In this new study led by Üren, mice with EWS-FLI1-driven leukemia were given injections of YK-4-279 five days per week for two weeks and compared with untreated mice. By the end of the first week the mice receiving YK-4-279 had much lower numbers of leukemia cells. At the end of two weeks the treated mice were nearly normal by many measures, while the untreated mice had overwhelming numbers of cancer cells and died on average after three weeks, the researchers say. By contrast, mice receiving only two weeks of YK-4-279 lived nearly three times as long.

“The fact that treated mice did not get sick from the YK-4-279 gives us an early indication that it might be safe to use in humans, but that is a question that can’t be answered until we conduct clinical trials,” Üren explains. “We are looking for ways that would allow us to administer more of it, or even to formulate a pill.”

Üren says much more work remains for the team in order to translate this drug from a

laboratory application into clinical trials.  Science Daily  Original web page at Science Daily


Two-drug combination shows promise against one type of pancreatic cancer

One form of pancreatic cancer has a new enemy: a two-drug combination discovered by UF Health researchers that inhibits tumors and kills cancer cells in mouse models.

For the first time, researchers have shown that a certain protein becomes overabundant in pancreatic neuroendocrine tumors, allowing them to thrive. They also found that pairing a synthetic compound with an existing drug provides a more effective anticancer punch than a single drug. The findings were published recently in the Journal of the National Cancer Institute by a group that includes Rony A. François, an M.D./Ph.D. student working with Maria Zajac-Kaye, Ph.D., an associate professor in the UF College of Medicine’s department of anatomy and cell biology.

Finding new treatments is critical because less than 5 percent of patients with pancreatic neuroendocrine tumors respond to everolimus, the most commonly used pharmaceutical, François said. Neuroendocrine tumors, which form in the hormone-making islet cells, account for 3 percent to 5 percent of pancreatic malignancies and have a five-year survival rate of about 42 percent, according to the National Cancer Institute. Pancreatic neuroendocrine tumors are increasingly common, which medical experts and researches have attributed to better diagnostic imaging, an aging population and heightened awareness of the disease stemming from the 2011 death of Apple Inc. co-founder Steve Jobs.

Zajac-Kaye’s group discovered that a single protein is behind the process that allows pancreatic neuroendocrine tumors to thrive. The protein, known as focal adhesion kinase, or FAK, activates an enzyme called AKT, which helps islet cells in the pancreas to survive. But when islet cells begin turning into tumors, the FAK protein gets overproduced, researchers found. This overabundance of the protein allows tumors to resist chemotherapy and evade efforts to kill them off.

After identifying FAK’s role in tumor development, François started looking for ways to get it in check. One idea was finding something to make the antitumor drug everolimus more effective. “Once we figured out that FAK was important, we started looking for drug combinations that would increase efficacy,” he said.

Among the substances they tested was a synthetic, small-molecule compound known as PF-04554787. During lab testing, the compound “markedly inhibited” the growth of three human pancreatic cancer cell lines five days after treatment and induced the death of pancreatic cancer cells. Researchers then tested its effectiveness on human pancreatic cells that had been implanted in mouse models. Daily doses of the compound reduced tumor volume by about 50 percent after 25 days, they found.

Next, researchers paired the compound with everolimus. While everolimus can extend some patients’ lives by holding tumors in check, it does little to make them regress and is not effective for many people. François wondered if the synthetic compound would make everolimus more effective. It did, with the two-drug combination killing off pancreatic cancer cells more effectively than everolimus alone. In testing on two mouse cell lines, the drug combination reduced the viability of cancer cells by about 50 percent when compared with everolimus alone, according to the findings.

That an existing drug can be made more effective is especially encouraging because the synthetic compound that was paired with everolimus is already undergoing human clinical trials, Francois said. “This is important because we’re focused on everolimus, a drug that is already approved, non-toxic and given to patients. Anything that we can do to make it better represents a big improvement,” François said.

The findings also have potential uses for most other types of solid tumors, including those affecting the lungs and ovaries, because the same protein and enzyme are involved, François said. Next, researchers would like to study how the two-drug approach works in humans, although no clinical trials have yet been designed or scheduled.  Science Daily  Original web page at Science Daily


Blood vessel cells help tumors evade the immune system

A study by researchers at Sweden’s Karolinska Institutet is the first to suggest that cells in the tumour blood vessels contribute to a local environment that protects the cancer cells from tumour-killing immune cells. The results, which are being published in the Journal of the National Cancer Institute, can contribute to the development of better immune-based cancer therapies.

Immune-based antitumour therapies, that strengthen the body’s own ability to fight cancer, have attracted great attention in recent years and achieved interesting success rates, especially in malignant melanoma. However, many patients still do not respond to immune-based therapies.

The results from the current study imply that tumour pericytes, a cell that is part of the tumour blood vessels, critically manipulate the tumour environment, helping the cancer cells escape immune surveillance.

“Understanding the interplay between tumour pericytes, malignant cells, and the immune system might help in designing more personalised and effective therapeutic approaches,” says Principal Investigator Guillem Genové at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.

Tumours evade the immune system by a variety of mechanisms, one of them being the recruitment of so called ‘myeloid-derived suppressor cells’ (MDSC). MDSCs suppress the ability of killer T-cells to destroy cancer cells. It is known that the more MDSCs present, the worse the prognosis or therapy response of the patient. Tumours secrete signal molecules such as interleukin-6 (IL-6) that help in recruiting MDSCs, but the mechanisms behind IL-6 tumour secretion are quite unknown.

The researchers found that the higher the number of pericytes, the more “normal” the tumour environment looked like. On the contrary, diminished pericyte numbers altered the microenvironment and correlated to higher IL-6 expression from the malignant cells and more MDSCs. They also identified a subset of breast cancer patients who had fewer pericytes and increased MDSCs, correlating to a worse prognosis and more aggressive characteristics of the tumour.

“Our work suggests that ways to increase the numbers of pericytes could potentially decrease IL-6 expression. This could improve cytotoxic T-cell activity and result in better antitumour effect,” says Dr Genové. Science Daily  Original web page at Science Daily


Discovery of new code makes reprogramming of cancer cells possible

Cancer researchers dream of the day they can force tumor cells to morph back to the normal cells they once were. Now, researchers on Mayo Clinic’s Florida campus have discovered a way to potentially reprogram cancer cells back to normalcy.

The finding, published in Nature Cell Biology, represents “an unexpected new biology that provides the code, the software for turning off cancer,” says the study’s senior investigator, Panos Anastasiadis, Ph.D., chair of the Department of Cancer Biology on Mayo Clinic’s Florida campus.

That code was unraveled by the discovery that adhesion proteins — the glue that keeps cells together — interact with the microprocessor, a key player in the production of molecules called microRNAs (miRNAs). The miRNAs orchestrate whole cellular programs by simultaneously regulating expression of a group of genes. The investigators found that when normal cells come in contact with each other, a specific subset of miRNAs suppresses genes that promote cell growth. However, when adhesion is disrupted in cancer cells, these miRNAs are misregulated and cells grow out of control. The investigators showed, in laboratory experiments, that restoring the normal miRNA levels in cancer cells can reverse that aberrant cell growth.

“The study brings together two so-far unrelated research fields — cell-to-cell adhesion and miRNA biology — to resolve a long-standing problem about the role of adhesion proteins in cell behavior that was baffling scientists,” says the study’s lead author Antonis Kourtidis, Ph.D., a research associate in Dr. Anastasiadis’ lab. “Most significantly, it uncovers a new strategy for cancer therapy,” he adds.

That problem arose from conflicting reports about E-cadherin and p120 catenin — adhesion proteins that are essential for normal epithelial tissues to form, and which have long been considered to be tumor suppressors. “However, we and other researchers had found that this hypothesis didn’t seem to be true, since both E-cadherin and p120 are still present in tumor cells and required for their progression,” Dr. Anastasiadis says. “That led us to be believe that these molecules have two faces — a good one, maintaining the normal behavior of the cells, and a bad one that drives tumorigenesis.”

Their theory turned out to be true, but what was regulating this behavior was still unknown. To answer this, the researchers studied a new protein called PLEKHA7, which associates with E-cadherin and p120 only at the top, or the “apical” part of normal polarized epithelial cells. The investigators discovered that PLEKHA7 maintains the normal state of the cells, via a set of miRNAs, by tethering the microprocessor to E-cadherin and p120. In this state, E-cadherin and p120 exert their good tumor suppressor sides.

However, “when this apical adhesion complex was disrupted after loss of PLEKHA7, this set of miRNAs was misregulated, and the E-cadherin and p120 switched sides to become oncogenic,” Dr. Anastasiadis says.

“We believe that loss of the apical PLEKHA7-microprocessor complex is an early and somewhat universal event in cancer,” he adds. “In the vast majority of human tumor samples we examined, this apical structure is absent, although E-cadherin and p120 are still present. This produces the equivalent of a speeding car that has a lot of gas and no brakes (the PLEKHA7-microprocessor complex).

“By administering the affected miRNAs in cancer cells to restore their normal levels, we should be able to re-establish the brakes and restore normal cell function,” Dr. Anastasiadis says. “Initial experiments in some aggressive types of cancer are indeed very promising.  Science Daily  Original web page at Science Daily


* High use of alternative medicine in senior oncology patients

Alternative medicines are widely thought to be at least harmless and very often helpful for a wide range of discomforts and illnesses. However, although they’re marketed as “natural,” they often contain active ingredients that can react chemically and biologically with other therapies. Researchers performed a comprehensive review of all of the medications taken by senior oncology patients and found that as 26 percent were using complementary or alternative medicines (CAM), in a report published August 12th, in the Journal of Geriatric Oncology.

“Currently, few oncologists are aware of the alternative medicines their patients take,” says Ginah Nightingale, PharmD, an Assistant Professor in the Jefferson College of Pharmacy at Thomas Jefferson University. “Patients often fail to disclose the CAMs they take because they think they are safe, natural, nontoxic and not relevant to their cancer care, because they think their doctor will disapprove, or because the doctor doesn’t specifically ask.”

There are a number of CAMs that are known to interfere with certain cancer treatments. For example, St. John’s wart can make some cancer therapy less effective, according to the National Institutes of Health. Others can interfere with anesthesia during surgery for cancer. But not all interactions have been studied. Because CAMs fall under the category of health supplements, they are not regulated by the Food and Drug Administration (FDA), which means that dose and potency (and therefore reaction in the body) can vary widely between products, and between patients.

In addition, in an elderly population of cancer patients, CAMs can simply add additional medications to an already long list of drugs taken for various ailments. “Numerous pills, or what we call polypharmacy in the field, can increase the risk for medication non-adherence, potential drug-drug interactions and increase the risk for drug-disease interactions in a population that has been reported to take several medications and have several medical conditions,” says Dr. Nightingale, “The use of CAM in this subpopulation warrants substantial interest and concern on behalf of medical oncologists and allied health professionals because of the potential clinical implications associated with CAM use. Patients may be combining these agents while receiving concurrent systemic chemotherapy, radiation therapy and/or surgical interventions which have the potential to compromise the safety and efficacy of treatment interventions.

Dr. Nightingale and colleagues surveyed the senior oncology patients who came to Jefferson for consultations in the Senior Adult Oncology Multi-Disciplinary clinic. Over the course of one visit, patients were seen by professionals from five different areas crucial to maintaining a senior’s health throughout oncology treatment, including a medical oncologist, geriatrician, clinical pharmacist, social worker and dietician. As part of this assessment, the patients brought in the contents of their medicine cabinets, and the medications that were actively used were reviewed and recorded.

The research team found that 26 percent of patients were taking CAMs at some point during the continuum of their cancer care, with the highest usage among women over the age of 80 — a population that hadn’t been captured by previous studies. Among those taking complementary medicine, 68 percent were in the over-80-year-old range.

Some of the alternative medications that were commonly used in this population were alternative therapies for macular degeneration, stomach probiotics, joint health, and mega-dose vitamins or minerals. While the current study did not examine the potential adverse events caused by these medications, “we know that some can have a biochemical effect on the body and other drugs.” says Nightingale.

“It is very important to do a comprehensive screen of all of the medications that older cancer patients take, including CAMs,” says Dr. Nightingale. “Clear and transparent documentation of CAM use should be recorded in the patient’s medical record. This documentation should indicate that patient-specific communication and/or education was provided so that shared and informed decisions by the patient can be made regarding the continued use of these medications.”

“Oncology healthcare is undergoing significant transformation in the delivery of effective clinical services and is ripe for greater engagement of pharmacists to reduce drug-related problems and unnecessary medications, in order to optimize medication prescribing,” says Dr. Nightingale.  Science daily  Original web page at Science Daily


Pediatric brain tumors can be classified noninvasively at diagnosis

Medulloblastoma subgroups can be identified using imaging techniques, allowing early intervention. Medulloblastoma, the most commonly occurring malignant brain tumor in children, can be classified into four subgroups–each with a different risk profile requiring subgroup-specific therapy. Currently, subgroup determination is done after surgical removal of the tumor. Investigators at Children’s Hospital Los Angeles have now discovered that these subgroups can be determined non-invasively, using magnetic resonance spectroscopy (MRS). The paper has been published online by the journal Neuro-Oncology

“By identification of the tumor subgroup at the time of diagnosis, we will be able to begin specific therapy earlier,” said Shahab Asgharzadeh, MD, of The Saban Research Institute of Children’s Hospital Los Angeles, principal investigator on the study. Asgharzadeh is also an associate professor of Pediatrics and Pathology at the Keck School of Medicine of the University of Southern California (USC).

Treatment for medulloblastoma includes surgery, chemotherapy and radiation, with 5-year survival rates ranging from 30 to 90 percent depending upon risk profile. A recent discovery identified four subtypes of medulloblastoma (SHH, WNT, Group 3 and Group 4) with level of risk and clinical outcomes for each subtype varying significantly. Currently, classification requires surgical removal of the tumor followed by laboratory analysis of the tumor tissue. Given the clinical importance of subgroup determinations, a fast, reliable and easily accessible method could have a significant effect on the outcomes of children with this disease.

“MR spectroscopy is widely available, noninvasive and provides information on cellular metabolism, which is different in healthy and diseased tissue,” said Stefan Bluml, PhD, investigator at The Saban Research Institute of CHLA and first author of the study. Bluml is also an associate professor of Research, Radiology and Biomedical Engineering at the Viterbi School of Engineering at USC.

Using frozen tumor tissue from 30 patients diagnosed with medulloblastoma, investigators performed subgroup analysis using standard techniques. These patients also had MRS performed at the time of diagnosis. With a screening panel composed of five metabolites, investigators found that the spectra for subgroups revealed distinct metabolic features, allowing them to differentiate subgroups SHH, WNT from Groups 3 and 4.

Clinical trials are being developed to incorporate molecular subgroups into risk and treatment stratifications. The ease of obtaining MRS at the time of diagnosis should allow its incorporation into future clinical trials aimed at validating this technique to improve diagnostic classification and, ultimately, improve outcomes in children with medulloblastoma.  Science Daily  Original web page at Science Daily


Epigenetic driver of glioblastoma provides new therapeutic target

Enzyme turns off genes required for maintaining cancer stem cell properties. Cancer’s ability to grow unchecked is often attributed to cancer stem cells, a small fraction of cancer cells that have the capacity to grow and multiply indefinitely. How cancer stem cells retain this property while the bulk of a tumor’s cells do not remains largely unknown. Using human tumor samples and mouse models, researchers at University of California, San Diego School of Medicine and Moores Cancer Center discovered that cancer stem cell properties are determined by epigenetic changes — chemical modifications cells use to control which genes are turned on or off.

The study, published in the Proceedings of the National Academy of Sciences, reports that an enzyme known as Lysine-Specific Demethylase 1 (LSD1) turns off genes required to maintain cancer stem cell properties in glioblastoma, a highly aggressive form of brain cancer. This epigenetic activity helps explain how glioblastoma can resist treatment. What’s more, drugs that modify LSD1 levels could provide a new approach to treating glioblastoma

The researchers first noticed that genetically identical glioblastoma cells isolated from patients differed in their tumorigenicity, or capacity to form tumors, when transplanted to mouse models. This observation suggested that epigenetics, rather than genetics (DNA sequence), determines tumorigenicity in glioblastoma cancer stem cells.

“One of the most striking findings in our study is that there are dynamic and reversible transitions between tumorigenic and non-tumorigenic states in glioblastoma that are determined by epigenetic regulation,” said senior author Clark Chen, MD, PhD, associate professor of neurosurgery and vice-chair of research and academic development at UC San Diego School of Medicine.

Probing further, Chen’s team discovered that the epigenetic factor determining whether or not glioblastoma cells can proliferate indefinitely as cancer stem cells is their relative abundance of LSD1. LSD1 removes chemical tags known as methyl groups from DNA, turning off a number of genes required for maintaining cancer stem cell properties, including MYC, SOX2, OLIG2 and POU3F2.

“This plasticity represents a mechanism by which glioblastoma develops resistance to therapy,” Chen said. “For instance, glioblastomas can escape the killing effects of a drug targeting MYC by simply shutting it off epigenetically and turning it on after the drug is no longer present. Ultimately, strategies addressing this dynamic interplay will be needed for effective glioblastoma therapy.”

Chen and one of the study’s first authors, Jie Li, PhD, note that the epigenetic changes driving glioblastoma are similar to those that take place during normal human development. “Though most cells in our bodies contain identical DNA sequences, epigenetic changes help make a liver cell different from a brain cell,” said Li, an assistant project scientist in Chen’s lab. “Our results indicate that the same programming processes determine whether a cancer cell can grow indefinitely or not.” Science Daily  Original web page at Science Daily


* Cell structure discovery advances understanding of cancer development

University of Warwick researchers have discovered a cell structure which could help scientists understand why some cancers develop. For the first time a structure called ‘the mesh’ has been identified which helps to hold together cells. This discovery, which has been published in the online journal eLife, changes our understanding of the cell’s internal scaffolding. This also has implications for researchers’ understanding of cancer cells as the mesh is partly made of a protein which is found to change in certain cancers, such as those of the breast and bladder.

The finding was made by a team led by Dr Stephen Royle, associate professor and senior Cancer Research UK Fellow at the division of biomedical cell biology at Warwick Medical School. Dr Royle said: “As a cell biologist you dream of finding a new structure in cells but it’s so unlikely. Scientists have been looking at cells since the 17th Century and so to find something that no-one has seen before is amazing.”

Researchers at the University’s Warwick Medical School made the discovery by accident while looking at gaps between microtubules which are part of the cells’ ‘internal skeleton’. In dividing cells, these gaps are incredibly small at just 25 nanometres wide — 3,000 times thinner than a human hair.

One of Dr Royle’s PhD students was examining structures called mitotic spindles in dividing cells using a technique called tomography which is like a hospital CAT scan but on a much smaller scale. This meant that they could see the structure which they later named the mesh.

Mitotic spindles are the cell’s way of making sure that when they divide each new cell has a complete genome. Mitotic spindles are made of microtubules and the mesh holds the microtubules together, providing support. While “inter-microtubule bridges” in the mitotic spindle had been seen before, the researchers were the first to view the mesh.

Dr Royle said: “We had been looking in 2D and this gave the impression that ‘bridges’ linked microtubules together. This had been known since the 1970s. All of a sudden, tilting the fibre in 3D showed us that the bridges were not single struts at all but a web-like structure linking all the microtubules together.”

The discovery impacts on the research into cancerous cells. A cell needs to share chromosomes accurately when it divides otherwise the two new cells can end up with the wrong number of chromosomes. This is called aneuploidy and this has been linked to a range of tumours in different body organs.

The mitotic spindle is responsible for sharing the chromosomes and the researchers at the University believe that the mesh is needed to give structural support. Too little support from the mesh and the spindle will be too weak to work properly, however too much support will result in it being unable to correct mistakes. It was found that one of the proteins that make up the mesh, TACC3, is over-produced in certain cancers. When this situation was mimicked in the lab, the mesh and microtubules were altered and cells had trouble sharing chromosomes during division.

Dr Emma Smith, senior science communications officer at Cancer Research UK, said: “Problems in cell division are common in cancer — cells frequently end up with the wrong number of chromosomes. This early research provides the first glimpse of a structure that helps share out a cell’s chromosomes correctly when it divides, and it might be a crucial insight into why this process becomes faulty in cancer and whether drugs could be developed to stop it from happening.”

North West Cancer Research (NWCR) has funded the research as part of a collaborative project between the University of Warwick and the University of Liverpool, where part of the research is being carried out.

Anne Jackson, CEO at NWCR, said: “Dr Royle and Professor Ian Prior at the University of Liverpool have made significant inroads into our understanding of the way in which cancer cells behave, which could potentially better inform future cancer therapies.

“As a charity we fund only the highest standard of research, as evidenced by Dr Royle’s work.

“All our funded projects undergo a thorough peer review process, before they are considered by our scientific committee. Our specially selected scientific committee includes some of the UK’s leading professors, award-winning scientists and pioneering professionals.   Science Daily  Original web page at Science Daily


Gene therapy advance thwarts brain cancer in rats

A nanoparticle gene delivery system has been developed by scientists that destroys brain gliomas in a rat model, significantly extending the lives of the treated animals. The nanoparticles are filled with genes for an enzyme that converts a prodrug called ganciclovir into a potent destroyer of the glioma cells. The nanoparticles are filled with genes for an enzyme that converts a prodrug called ganciclovir into a potent destroyer of the glioma cells.

Glioma is one of the most lethal human cancers, with a five year survival rate of just 12%, and no reliable treatment. Advances in the understanding of the molecular processes that cause these tumors has resulted in therapies aimed at delivering specific genes into tumors — genes that make proteins to kill or suppress the growth of the tumor. Currently this approach relies heavily on using viruses to deliver the anti-tumor genes into the target cancer cells. Unfortunately, viral delivery poses significant safety risks including toxicity, activation of the patient’s immune system against the virus, and the possibility of the virus itself encouraging tumors to develop.

“Efforts to treat glioma with traditional drug and radiation therapies have not been very successful,” says Jessica Tucker, Ph.D., NIBIB Director for the Program in Gene and Drug Delivery Systems and Devices. “The ability to successfully deliver genes using these biodegradable nanoparticles, rather than potentially harmful viruses, is a significant step that reinvigorates the potential for gene therapy to treat deadly gliomas as well as other cancers.”

Jordan Green, Ph.D., of the Johns Hopkins University School of Medicine Biomedical Engineering Department and a senior author of the work, and his international team describe their findings in the February 24 issue of ACS Nano. The collaborators include colleagues from the Johns Hopkins University School of Medicine Departments of Neurosurgery, Oncology, Ophthalmology, and Pathology, as well as Tang Du Hospital in China, University of the Negevin, Israel, and the Instituto Neurologico C. Besta in Italy.

Biodegradable nanoparticles have recently shown promise as a method to deliver genes into cells. Their use for delivery avoids many of the problems associated with viral gene delivery. To demonstrate virus free delivery, the first goal of the group was to develop a nanoparticle that could efficiently carry DNA encoding a gene known as HSVtk into cells. The HSVtk gene produces an enzyme that turns the compound ganciclovir–which by itself has no effect on cancer cells — into a compound that is toxic to actively dividing brain cancer cells.

A number of polymer structures were tested for their ability to deliver DNA into two rat glioma cell lines. Among the many polymers tried, the one known as PBAE 447 was found to be the most efficient in delivering the HSVtk gene into the cultured rat glioma cells. Furthermore, when combined with ganciclovir, the HSVtk-encoding nanoparticles were 100% effective in killing both of the glioma cell lines grown in the laboratory

Next, the gene therapy system was tested in live rats with brain gliomas. Because it is important that the nanoparticles spread throughout the entire tumor, they were infused into the rat gliomas using convection-enhanced delivery (CED). The method involves injection into the tumor and the application of a pressure gradient, which efficiently disperses the nanoparticles throughout the tumors.

To test the tumor-killing ability of the system, the tumor-bearing rats were given systemic administration of ganciclovir for two days, then CED was used to infuse the HSVtk-encoding nanoparticles into the rat gliomas, and systemic ganciclovir treatment continued for eight more days. The treatment resulted in shrinkage of the tumors and a significant increase in survival when compared with control glioma-bearing animals that did not receive the combination treatment.

“The results provide the first demonstration of a successful non-viral nanomedicine method for HSVtk/ganciclovir treatment of brain cancer,” stated Green. “Next steps will include enhancing the efficiency of this nanoparticle delivery system and evaluating the technology in additional brain cancer animal models.”

In the future, the investigators envision that doctors would administer this therapy during the surgery commonly used to treat glioma in humans. They are also interested in testing the ability to deliver other cancer-killing genes and whether the nanoparticles could be successfully administered systemically — which could broaden the use of the therapy for a wide range of solid tumors and systemic cancers  Science Daily  Original web page at Science Daily


New class of compounds shrinks pancreatic cancer tumors, prevents regrowth

A chemical compound that has reduced the growth of pancreatic cancer tumors by 80 percent in treated mice has been developed by researchers. The compound, called MM41, was designed to block faulty genes. It appears to do this by targeting little knots in their DNA, called quadruplexes, which are very different from normal DNA and which are especially found in faulty genes. Scientists from UCL (University College London) have designed a chemical compound that has reduced the growth of pancreatic cancer tumors by 80 percent in treated mice.

The compound, called MM41, was designed to block faulty genes. It appears to do this by targeting little knots in their DNA, called quadruplexes, which are very different from normal DNA and which are especially found in faulty genes. The findings, published in Nature Scientific Reports, showed that MM41 had a strong inhibiting effect on two genes — k-RAS and BCL-2 — both of which are found in the majority of pancreatic cancers.

Funded by the UK charity, Pancreatic Cancer Research Fund, the UCL team, led by professor Stephen Neidle, conducted a small-scale trial, treating two groups of eight mice with pancreatic tumors with different doses of MM41 twice a week for 40 days (12 doses). A further control group received no treatment. The tumors in the group given the larger dose decreased by an average of 80 percent during the treatment period, and after 30 days, tumor regrowth stopped in all the mice. For two of the mice in this group, the tumor disappeared completely with no signs of regrowth after treatment ended for a further 239 days (the approximate equivalent to the rest of their natural life span).

Analysis of the mice tumors showed that the MM41 compound had been taken up into the nucleus of the cancer cells showing that it was able to effectively target the pancreatic cancer tumor. The team also saw no significant side effects on the mice during the study: there was no damage to other tissue or organs, and none of the mice showed any significant weight loss.

Discussing the results, Neidle explained: “This research provides a potentially very powerful alternative approach to the way that conventional drugs tackle pancreatic cancer, by targeting a very specific area of the DNA of faulty genes. One of the genes that MM41 blocks — the BCL-2 gene — is involved in regulating apoptosis, the body’s natural process which forces cells to die if they become too damaged or unhealthy to be repaired. BCL-2 is present in high amounts in many tumors and helps cancer cells to survive, but when the BCL-2 gene is blocked by MM41 in mice, the cancer cells succumb to apoptosis and die.”

Neidle stressed that although these results are exciting, MM41 is not ideal for trialling in humans and further refinements are needed. “We are now working to optimise this class of compounds, but it’s clearly worthy of further investigation for potential use in treating pancreatic cancer in people,” he said.

Pancreatic cancer is the most lethal of any common cancer. Only three in every 100 people diagnosed will live for five years or more and this survival rate has barely improved in the last 40 years. The majority of patients are diagnosed too late for surgery — currently the only potentially curative treatment — and 80 per cent of those who have surgery will see the cancer return.

Maggie Blanks, Pancreatic Cancer Research Fund’s CEO, said: “It’s because of these bleak facts that our funding strategy focuses on finding and developing alternative, effective treatments for patients as well as finding a way to diagnose pancreatic cancer at an early stage. To find a potential new way to kill pancreatic cancer tumor cells is an exciting development.”  Science Daily  Original web page at Science Daily


* Single gene turns colorectal cancer cells back into normal tissue in mice

Anti-cancer strategies generally involve killing off tumor cells. However, cancer cells may instead be coaxed to turn back into normal tissue simply by reactivating a single gene. Researchers found that restoring normal levels of a human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within only four days. Anti-cancer strategies generally involve killing off tumor cells. However, cancer cells may instead be coaxed to turn back into normal tissue simply by reactivating a single gene, according to a study that found that restoring normal levels of a human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within only 4 days. Remarkably, tumors were eliminated within 2 weeks, and signs of cancer were prevented months later.

Anti-cancer strategies generally involve killing off tumor cells. However, cancer cells may instead be coaxed to turn back into normal tissue simply by reactivating a single gene, according to a study published June 18th in the journal Cell. Researchers found that restoring normal levels of a human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within only 4 days. Remarkably, tumors were eliminated within 2 weeks, and signs of cancer were prevented months later. The findings provide proof of principle that restoring the function of a single tumor suppressor gene can cause tumor regression and suggest future avenues for developing effective cancer treatments.

Colorectal cancer is the second leading cause of cancer-related death in developed countries, accounting for nearly 700,000 deaths worldwide each year. “Treatment regimes for advanced colorectal cancer involve combination chemotherapies that are toxic and largely ineffective, yet have remained the backbone of therapy over the last decade,” says senior study author Scott Lowe of the Memorial Sloan Kettering Cancer Center.

Up to 90% of colorectal tumors contain inactivating mutations in a tumor suppressor gene called adenomatous polyposis coli (Apc). Although these mutations are thought to initiate colorectal cancer, it has not been clear whether Apc inactivation also plays a role in tumor growth and survival once cancer has already developed.

“We wanted to know whether correcting the disruption of Apc in established cancers would be enough to stop tumor growth and induce regression,” says first author Lukas Dow of Weill Cornell Medical College. This question has been challenging to address experimentally because attempts to restore function to lost or mutated genes in cancer cells often trigger excess gene activity, causing other problems in normal cells.

To overcome this challenge, Lowe and his team used a genetic technique to precisely and reversibly disrupt Apc activity in a novel mouse model of colorectal cancer. While the vast majority of existing animal models of colorectal cancer develop tumors primarily in the small intestine, the new animal model also developed tumors in the colon, similar to patients. Consistent with previous findings, Apc suppression in the animals activated the Wnt signaling pathway, which is known to control cell proliferation, migration, and survival.

When Apc was reactivated, Wnt signaling returned to normal levels, tumor cells stopped proliferating, and intestinal cells recovered normal function. Tumors regressed and disappeared or reintegrated into normal tissue within 2 weeks, and there were no signs of cancer relapse over a 6-month follow-up period. Moreover, this approach was effective in treating mice with malignant colorectal cancer tumors containing Kras and p53 mutations, which are found in about half of colorectal tumors in humans.

Although Apc reactivation is unlikely to be relevant to other types of cancer, the general experimental approach could have broad implications. “The concept of identifying tumor-specific driving mutations is a major focus of many laboratories around the world,” Dow says. “If we can define which types of mutations and changes are the critical events driving tumor growth, we will be better equipped to identify the most appropriate treatments for individual cancers.”

For their own part, Lowe and his team will next examine the consequences of Apc reactivation in tumors that progress beyond local invasion to produce distant metastases. They will also continue to investigate why Apc is so effective at suppressing colon tumor growth, with the goal of one day mimicking this effect with drug treatments.

“It is currently impractical to directly restore Apc function in patients with colorectal cancer, and past evidence suggests that completely blocking Wnt signaling would likely be severely toxic to normal intestinal cells,” Lowe says. “However, our findings suggest that small molecules aimed at modulating, but not blocking, the Wnt pathway might achieve similar effects to Apc reactivation. Further work will be critical to determine whether WNT inhibition or similar approaches would provide long-term therapeutic value in the clinic.”  Science Daily  Original we page at Science Daily


* Diagnosing cancer with lumninescent bacteria: Engineered probiotics detect tumors in liver

Engineers have devised a new way to detect cancer that has spread to the liver, by enlisting help from probiotics — beneficial bacteria similar to those found in yogurt. Using a harmless strain of E. coli that colonizes the liver, the researchers programmed the bacteria to produce a luminescent signal that can be detected with a simple urine test.

Many types of cancer, including colon and pancreatic, tend to metastasize to the liver. The earlier doctors can find these tumors, the more likely that they can successfully treat them. “There are interventions, like local surgery or local ablation, that physicians can perform if the spread of disease in the liver is confined, and because the liver can regenerate, these interventions are tolerated. New data are showing that those patients may have a higher survival rate, so there’s a particular need for detecting early metastasis in the liver,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Electrical Engineering and Computer Science at MIT.

Using a harmless strain of E. coli that colonizes the liver, the researchers programmed the bacteria to produce a luminescent signal that can be detected with a simple urine test. Bhatia and Jeff Hasty, a professor of biology at UCSD, are the senior authors of a paper describing the new approach this week in the journal Science Translational Medicine. Lead authors are MIT postdoc Tal Danino and UCSD postdoc Arthur Prindle.

Previous studies had shown that bacteria can penetrate and grow in the tumor microenvironment, where there are lots of nutrients and the body’s immune system is compromised. Because of this, scientists have been trying for many years to develop bacteria as a possible vehicle for cancer treatment.

The MIT and UCSD researchers began exploring this idea a few years ago, but soon expanded their efforts to include the concept of creating a bacterial diagnostic. To turn bacteria into diagnostic devices, the researchers engineered the cells to express the gene for a naturally occurring enzyme called lacZ that cleaves lactose into glucose and galactose. In this case, lacZ acts on a molecule injected into the mice, consisting of galactose linked to luciferin, a luminescent protein naturally produced by fireflies. Luciferin is cleaved from galactose and excreted in the urine, where it can easily be detected using a common laboratory test.

At first, the researchers were interested in developing these bacteria for injection into patients, but then decided to investigate the possibility of delivering the bacteria orally, just like the probiotic bacteria found in yogurt. To achieve that, they integrated their diagnostic circuits into a harmless strain of E. coli called Nissle 1917, which is marketed as a promoter of gastrointestinal health.

In tests with mice, the researchers found that orally delivered bacteria do not accumulate in tumors all over the body, but they do predictably zero in on liver tumors because the hepatic portal vein carries them from the digestive tract to the liver.

“We realized that if we gave a probiotic, we weren’t going to be able to get bacteria concentrations high enough to colonize the tumors all over the body, but we hypothesized that if we had tumors in the liver they would get the highest dose from an oral delivery,” says Bhatia, who is a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. This allowed the team to develop a diagnostic specialized for liver tumors. In tests in mice with colon cancer that has spread to the liver, the probiotic bacteria colonized nearly 90 percent of the metastatic tumors. In the mouse experiments, animals that were given the engineered bacteria did not exhibit any harmful side effects.

The researchers focused on the liver not only because it is a natural target for these bacteria, but also because the liver is hard to image with conventional imaging techniques like CT scanning or magnetic resonance imaging (MRI), making it difficult to diagnose metastatic tumors there. With the new system, the researchers can detect liver tumors larger than about one cubic millimeter, offering more sensitivity than existing imaging methods. This kind of diagnostic could be most useful for monitoring patients after they have had a colon tumor removed because they are at risk for recurrence in the liver, Bhatia says.

Andrea Califano, a professor of biological sciences at Columbia University, says the study is “seminal and thought-provoking in terms of clearing a new path for investigating what can be done for early detection of cancer,” adding that the therapeutic possibilities are also intriguing. “These bacteria could be engineered to cause genetic disruption of cancer cell function, deliver drugs, or reactivate the immune system,” says Califano, who was not involved in the research. The MIT team is now pursuing the idea of using probiotic bacteria to treat cancer, as well as for diagnosing it.   Science Daily  Original web page at Science Daily


New combination treatment strategy to ‘checkmate’ glioblastoma

Therapies that specifically target mutations in a person’s cancer have been much-heralded in recent years, yet cancer cells often find a way around them. To address this, researchers identified a promising combinatorial approach to treating glioblastomas, the most common form of primary brain cancer. Therapies that specifically target mutations in a person’s cancer have been much-heralded in recent years, yet cancer cells often find a way around them. To address this, researchers at University of California, San Diego School of Medicine and Moores Cancer Center identified a promising combinatorial approach to treating glioblastomas, the most common form of primary brain cancer.

The study, published May 5 by Oncotarget, demonstrates that a mouse model of glioblastoma and human glioblastoma tissue removed from patients and cultured in the lab can be effectively treated by combining three classes of anti-cancer drugs: a drug that targets a cancer mutation in the Epidermal Growth Factor Receptor (EGFR) gene, a drug that increases stress in cancer cells and a drug that damages cancer cell DNA.

“Developing therapies against glioblastoma is like a chess game. For each therapy administered, or move, by the physician, the cancer makes a counter-move,” said senior author Clark Chen, MD, PhD, associate professor of neurosurgery and vice-chair of Research and Academic Development at UC San Diego. In up to 50 percent of glioblastomas, mutations in the EGFR gene render cancer cells insensitive to growth regulation by environmental cues, allowing them to grow uncontrollably. Yet highly specific EGFR inhibitors are not particularly effective against glioblastomas with EGFR mutations.

“When glioblastoma cells are treated with EGFR inhibitors, they turn on another receptor to bypass the need for EGFR,” said Chen. “Any hope of an effective treatment requires a combination of moves strategically designed for a checkmate.” To develop such a strategy, Chen and his group turned to PLK1, a protein that regulates stress levels within glioblastoma cells and is essential for their survival. Chen and his group found that glioblastoma cells that developed resistance to EGFR inhibitors remain universally dependent on this protein.

In mouse models of glioblastoma and in explants of human glioblastoma, singular treatment with an EGFR inhibitor, a PLK1 inhibitor or the current standard of care drug (a DNA-damaging agent), each temporarily halted glioblastoma growth. But, like the human disease, the tumor eventually grew back. However, no detectable tumor recurrence was observed when a combination of all three classes of drugs was administered. The treated mice tolerated this combination regimen without showing significant side-effects.

“It is often assumed that if we find the cancer-causing mutation and inhibit the function of that mutation, we will be able to cure cancer,” said study co-author Bob S. Carter, MD, PhD, chief of neurosurgery at UC San Diego. “Our study demonstrates that the reality is far more complex. Our results provide a blueprint for how to leverage fundamental biologic concepts to tackle this challenging complexity.”

The three drugs administered to mice in this study were: BI2536, a PLK1 inhibitor; Gefitnib, an EGFR inhibitor; and TMZ, the standard-of-care chemotherapy for glioblastoma. The study authors note that while the safety or side effects of treating human patients will all three drugs is unknown, all are individually well-tolerated in humans. The clinical safety profiles of Gefitinib and TMZ are well-established for glioblastoma patients and PLK1 inhibitors have so far been well-tolerated in clinical trials (one has advanced to Phase III clinical trials for acute myeloid leukemia)  Science Daily  Original web page at Science Daily


* Cancer mutations often misidentified in the clinic

Many cancer patients in clinics across the United States might be getting inaccurate information from DNA analyses that are intended to match them with the most effective therapy. Examining normal tissue as well as tumours gives physicians a better shot at choosing effective therapies. Some institutions have already begun to sequence both normal and tumour tissue of cancer patients.  The finding, published in Science Translational Medicine on 15 April, comes as companies are increasingly focused on churning out drugs that target specific cancer-causing mutations. Demand for tumour sequencing has soared as physicians try to find the treatment best suited to combat a patient’s particular set of tumour mutations.

But many clinics sequence only the tumour DNA and do not compare those sequences to DNA taken from a patient’s normal tissue. Omitting that crucial control erodes precision in gauging which mutations are important for treating a particular cancer, says Victor Velculescu, a cancer biologist at Johns Hopkins University in Baltimore, Maryland, and lead author of the study. It can also confound clinical-trial results when investigators try to match treatment response to genetic profiles. “There is a rush to do this clinically and apply it to patient treatment without thinking about what the best control is,” says Velculescu. “You could use that information to place patients on inappropriate therapy.” Velculescu says such considerations are particularly important as US lawmakers weigh up President Barack Obama’s call for a US$215-million Precision Medicine Initiative that aims to enrol one million people in a study to combine genomic and health data.  “The reality is you can’t have precision medicine without having precision genomics,” says Velculescu. “And you can’t expect to put patients on the right therapy if you can’t correctly analyse the tumour. It’s just not going to work.”

Velculescu and his colleagues profiled tumour and normal DNA from 815 people with advanced cancers. The team tested two common methods of analysing tumour DNA: sequencing all protein-coding genes in a sample, or sequencing a smaller set of 111 genes believed to be associated with cancer. Of the samples for which all protein-coding genes were sequenced, about two-thirds of the mutations found were false positives, meaning that they were also found in the normal cells and were thus unlikely to be useful therapeutic targets. The same phenomenon was found in about one-third of the mutations uncovered by targeting the set of 111 genes.

Some institutions have already begun to sequence both normal and tumour tissue of cancer patients. Michael Berger, a cancer researcher at Memorial Sloan Kettering Cancer Center in New York, says that a programme there has so far analysed DNA from the tumours and normal tissue of more than 4,000 patients, focusing on a set of 400 genes. But Berger adds that the extra sequencing poses a significant burden: the procedure costs more money, and requires more patient education. Because mutations in normal tissue may also be found in reproductive cells, and thus can be passed on to children, patients need to consider the implications for family members and must sign a separate consent form. It has been worth the added effort for the quality and richness of the data, says Berger. But he understands that other labs — particularly those that are new to cancer sequencing — may not be ready to embrace the added burden. “Sequencing unmatched tumours is better than not sequencing at all.”

Nature doi:10.1038/nature.2015.17329  Nature  Original web page at Nature


Cancer: The Ras renaissance

Thirty years of pursuit have failed to yield a drug to take on one of the deadliest families of cancer-causing proteins. Now some researchers are taking another shot. When Stephen Fesik left the pharmaceutical industry to launch an academic drug-discovery laboratory, he drew up a wanted list of five of the most important cancer-causing proteins known to science. These proteins drive tumour growth but have proved to be a nightmare for drug developers: they are too smooth, too floppy or otherwise too finicky for drugs to bind to and block. In the parlance of the field, they are ‘undruggable’. One of the first culprits that Fesik added to his list was a protein family called Ras. For more than 30 years, it has been known that mutations in the genes that encode Ras proteins are among the most powerful cancer drivers. Ras mutations are found in some of the most aggressive and deadly cancers, including up to 25% of lung tumours and about 90% of pancreatic tumours. And for some advanced cancers, tumours with Ras mutations are associated with earlier deaths than tumours without them.

Decades of research have yet to yield a drug that can safely curb Ras activity. Past failures have driven researchers from the field and forced pharmaceutical companies to abandon advanced projects. But Fesik’s laboratory at Vanderbilt University in Nashville, Tennessee, and a handful of other teams have set their sights anew on the proteins. They are armed with improved technology and a better understanding of how Ras proteins work. Last year, the US National Cancer Institute launched the Ras Initiative, a US$10-million-a-year effort to find new ways to tackle Ras-driven cancers. And researchers are already uncovering compounds that, with tweaking, could eventually yield the first drugs to target Ras proteins.

Researchers are mindful that they still have many hurdles to jump. “You have to have a lot of respect for Ras,” says Troy Wilson, president of Wellspring Biosciences, a company in La Jolla, California, that launched in 2012 with its sights set on Ras. “It is not to be underestimated. But it’s also one of the most important oncogenes in cancer.” Advocates of this Ras renaissance say that any signs of success could provide lessons on how to target other important proteins that are deemed to be undruggable. Just because people assume Ras proteins are too difficult to target does not mean that scientists should give up, says Channing Der, a cancer researcher at the University of North Carolina at Chapel Hill. “Dogma is a moving target.”

In 1982, Der’s team was one of the first to show that mutations in human genes encoding Ras proteins can cause cancer. This finding marked the culmination of a hunt for oncogenes — genes that can drive cancer — in the human genome. They had previously only been described in viruses and animal models. The discovery laid the foundation for the modern cancer-research juggernaut, with its emphasis on tracking genetic mutations and mapping altered molecular pathways. It also prompted hopes of finding drugs that would target oncogenes and cure some cancers. The following years were filled with discovery. It became clear that humans produce three highly similar Ras proteins and that these are activated when cells need to proliferate (to replace damaged tissue, for example). Signals from outside the cell switch Ras to an ‘on’ state, in which it is bound to a molecule called GTP. Cancer-causing forms of Ras proteins have a disabled ‘off’ switch and cannot properly process the GTP. So it seemed logical to search for drugs that could interfere with GTP binding to stop mutant Ras.

But as the understanding of Ras biochemistry grew, so too did a sense of pessimism. The family’s affinity for GTP turned out to be extraordinarily high, and finding another compound that could block GTP’s access seemed impossible. Ras proteins also work by interacting with other proteins, but small-molecule drugs that are able to get inside cells are often too small to cordon off the wide surface area usually involved in protein–protein interactions. (Antibodies can make excellent drugs and can mask a large area on their targets, but most do not penetrate cell membranes.)

Ras structures offered more reasons for concern. Drug developers look at a protein’s shape to gauge the likelihood of finding a compound that will bind to a critical site. They like to see a protein with deep pockets that a drug can slip into and bind with multiple points of contact. However, Ras proteins are relatively smooth. Twenty years ago, researchers thought they had the problem solved. To function, Ras proteins need to latch on to the inside of the cell membrane through a fatty tail. That tail is added by farnesyl transferase — an enzyme that is more amenable to drug targeting than Ras proteins. So the idea was to hobble Ras activity by finding drugs that inhibit farnesyl transferase. At first, it looked like a winning strategy. Farnesyl transferase inhibitors damped down cell proliferation in mice and human cancer cells. By the early 2000s, at least six pharmaceutical companies were racing to bring the drugs to market. Many abandoned other Ras-related projects because they thought the Ras problem was solved, says chemist Herbert Waldmann of the Max Planck Institute of Molecular Physiology in Dortmund, Germany. “The whole field took a deep breath and waited,” he says.

The wait ended with one of the biggest disappointments in pharmaceutical history. One by one, the drugs failed in human clinical trials. Der, who was still studying Ras at the time, says that the episode taught him, and everyone else, an important lesson about Ras biology. The three forms of human Ras are nearly identical in terms of structure and amino-acid sequence. Researchers assumed that their functions would be similar too. Most of the tools used to study Ras proteins — cell cultures, transgenic mice and antibodies — were developed using H-Ras, which was easier to work with than the other forms. “All of us, including myself, thought why bother studying the other ones when we can just learn all about H-Ras,” says Der. “Unfortunately, a lot of money was spent on that misconception.”

It turned out that the other two forms of Ras in humans — K-Ras and N-Ras — are much more important in cancer, and the cell has a contingency plan in place to keep them working. In the absence of a farnesyl tail, another enzyme is able to tack on a different fatty tail, rendering the experimental drugs useless. The Ras field was scarred by this episode, and it took some time before researchers were willing to give the proteins another look. But about a decade later, they started coming back. “All of a sudden people turned around and said, ‘Hey, this is still one of the most important targets in oncology. Nobody has done anything in the field for ten years. Let’s do something’,” says Waldmann. This time, researchers took a fresh approach by looking for weaknesses in Ras-driven tumours.

One such weakness is ‘synthetic lethality’. When Ras proteins are in overdrive, cancer cells often become dependent on other molecular pathways for survival. Blocking these other pathways might not affect normal cells, but it kills Ras-driven tumour cells. Laboratories set about screening for the synthetic-lethal partners of mutated genes encoding Ras, with the idea that targeting them would kill cancer cells but leave normal cells unaffected. The result was a wave of papers reporting possible new targets — followed closely by another wave of reports that the synthetic-lethal results were irreproducible. Last October, William Sellers, Global Head of Oncology at the Swiss drug maker Novartis, reported at a conference that his team had tried and failed to reproduce the most prominent published Ras synthetic-lethal findings. Changes in context, such as the cell type used or specific screening conditions, could easily change the outcome of the experiment, says Julian Downward, a cancer researcher at the Francis Crick Institute in London. Researchers are still sifting through the results to find targets that hold up, but Downward is doubtful that the efforts will bear fruit. “Everyone seems to get something different from those experiments,” he says. “I suspect these are not going to be the most robust targets.”

With the disappointment of the synthetic-lethal approach fresh in their minds, several researchers have been looking to target Ras itself. “We decided you have to go to Ras directly,” says Brent Stockwell, a chemical biologist at Columbia University in New York. Improvements made during the past five years in computer modelling and in ways of screening for drug compounds offer fresh hope for targeting the smooth, unpocketed terrain of Ras proteins, Stockwell says. Researchers are now better able to predict the affinity of small molecules for proteins, for example, and have a better understanding of protein dynamics. Stockwell’s team is capitalizing on this to design small molecules that are tailored to the surface of Ras proteins — first in the computer, and then in the laboratory. “Maybe for these proteins, you’re just not going to find the right solution anywhere out there in the world,” Stockwell says. “You’ve just got to make it.”

Fesik is also building new drugs, but starting from a library of existing compounds. In his former career at Abbott Laboratories in Abbott Park, Illinois, Fesik devised ways to disrupt interactions between proteins by piecing together fragments of compounds that bind, however weakly, to the target. The result is a large, novel compound that is unlikely to be found in the standard chemical libraries used to hunt for drugs.

Fesik likens the technique, called fragment-based screening, to constructing a key to fit a lock by cutting one notch at a time. “Eventually you combine all the notches,” he says. “The compound has never been made before and yet you find it because you’re building it up slowly and tailoring it to your protein.” Fesik’s lab and his industry collaborators have found more than 130 molecules that bind weakly to K-Ras. The compounds induce a change in the protein’s structure, opening up a binding pocket in the process. The team is now trying to add on other fragments to improve the fit — in effect, the second notch in the key. Der notes that Fesik built a reputation for drugging the undruggable in industry before he left to pursue an academic career. “If anyone is going to do it, it is Fesik,” he says.

Others are looking more closely at exploiting specific mutations within K-Ras. Although there are many different cancer-associated mutations in the gene that encodes it, just three are responsible for the vast majority of Ras-driven cancers. Each of these yields an enzyme with slightly different behaviour, says Der. “If we begin to think about different mutations as having different personalities, those different personalities may open up unique vulnerabilities,” he says. “People said, ‘Nobody has done anything in the field for ten years. Let’s do something’.”

Kevan Shokat, a chemical biologist at the University of California, San Francisco, joined the Ras hunt six years ago. In 2013, he reported a compound that targets a K-Ras mutation known as G12C . The mutation, which is found in 20% of lung cancers, replaces the amino acid glycine with cysteine, which readily reacts with other molecules. Shokat’s compound exploits the reactive cysteine and binds to it irreversibly. The inhibitor will require additional tinkering before it can be used in human patients but, as the first drug candidate that truly binds directly to Ras, it has generated a tremendous amount of excitement, says Downward. “It has re-energized the whole area,” he says. Shokat says he has long thought that a mutation-specific approach might work, but he hesitated to pursue it in his laboratory until recently. Drug developers were afraid of drugs that seize upon their target and do not come off, he says, because they seemed more likely to have unanticipated reactions with other proteins in the body. But several successful drugs, such as the lymphoma and myeloma drug ibrutinib, have recently been found to bind irreversibly to their targets.

Meanwhile, pharmaceutical companies are increasingly open to the idea of developing drugs that work in subsets of patients with cancer who carry specific mutations. “There won’t be one drug that will work for every K-Ras patient,” predicts Timothy Burns, a cancer researcher at the University of Pittsburgh in Pennsylvania. Fesik says that the solutions to Ras’s puzzles, whatever they are, will probably emerge from academic institutions. He left pharma in part because he loved the pursuit of important targets, regardless of how easy or hard they are to hit. Chasing an undruggable protein can be difficult to justify in industry, where scientific interest must often take a backseat to the near-term potential for profit. “Most pharma companies don’t want to take the risk to go after these undruggable targets, and if they do, it’s temporary,” he says. Bridges are forming, however. Fesik’s laboratory has partnered with the German pharmaceutical company Boehringer Ingelheim to evaluate its first-generation Ras-binding drug. And Shokat co-founded Wellspring Biosciences to bring his inhibitor to market. The work soon won support from Janssen Biotech of Horsham, Pennsylvania. The efforts are getting government attention as well. The multimillion-dollar Ras Initiative is supporting the development of tools and basic research on Ras protein structures to aid drug discovery, says Frank McCormick, a cancer researcher at the University of California in San Francisco and co-director of the project. “We are trying to de-risk Ras as a target so that others will jump back in the ring and have another shot,” he says

For years, the pharmaceutical industry has pursued low-hanging fruit in a different category of proteins called kinases, McCormick says. Those were easier to target, and yielded many useful cancer drugs. But that wave is starting to subside, he argues, and it is time to focus on the higher-hanging fruit: tougher targets, such as Ras proteins, that are known to be crucially important. Stockwell says he hopes that the recent revival of research on Ras proteins could inspire scientists studying other intractable targets. “If there is some success there, maybe that excitement will extend to other targets,” he says. “If we really want to impact disease, there’s this vast space of additional targets that have never been mined.”

Nature 520, 278–280 (16 April 2015) doi:10.1038/520278a  Nature  Original web page at Nature 


Tumour mutations harnessed to build cancer vaccine

Personalized vaccines could provide new options to treat cancers driven by multiple genetic mutations. Vaccines made from mutated proteins found in tumours have bolstered immune responses to cancer in a small clinical trial. The results, published on 2 April in Science, are the latest from mounting efforts to generate personalized cancer therapies. In this case, three people with melanoma received vaccines designed to alert the immune system to mutated proteins found in their tumours.

It is too soon to say whether the resulting immune response will be enough to rein in tumour growth, but the trial is a crucial proof of concept, says Ton Schumacher, a cancer researcher at the Netherlands Cancer Institute in Amsterdam. We don’t really know how strong an immune response has to be to be clinically meaningful,” he says. “Nevertheless, it’s an important step.” Cancer is a genetic disease, driven by mutations that lift the brakes on cell proliferation. But the mutated proteins produced by cancerous cells can serve as a siren call to immune cells, signalling the presence of a cell that has become, in a sense, ‘foreign’. Unfortunately, many of these calls are never heard. Some tumours suppress nearby immune responses, and mutated tumour proteins may not be expressed at high enough levels to rally immune cells. Researchers have long dreamed of using those mutated proteins to generate a vaccine, says immunologist Beatriz Carreno of Washington University in St. Louis, Missouri, but lacked the technological wherewithal to do so.

The advent of cancer-genome sequencing and an improved understanding of the immune system have converged to make that approach possible. Last year, two groups, showed that such vaccines can work in mice. Carreno and her colleagues have now taken the approach into humans. The researchers sequenced the tumour genomes in samples taken from three people with melanoma and catalogued the mutated proteins in each sample. They then chose seven protein fragments per patient for use in the vaccine. White blood cells were taken from each patient and cultured in the laboratory to generate immune cells called dendritic cells. These cells were then exposed to the protein fragments, allowed to mature in the laboratory and then infused into the patients. By then, the dendritic cells had taken up the protein fragments, and were able to present them to immune cells in the body. The result: immune cells trained to target the mutated proteins produced by the tumour. Such immune cells were evident in the patients’ blood two weeks after vaccination.

Researchers have tried to develop cancer vaccines for decades, but early signs of success have tended to give way to disappointment in larger clinical trials. The same could hold true in this case, but there is cause to be optimistic, says Schumacher. Past vaccines were made with proteins that are also found in normal cells, but were simply more abundant in tumours. The immune system is trained to tolerate such proteins, so responses to the proteins remained weak even after vaccination. In this case, the proteins are not found in normal cells, and therefore should elicit a stronger response, he notes. Carreno adds that previous vaccines also generally involved only a single cancer-associated protein. Her vaccines are based on seven.

Carreno thinks that the approach could also work in other cancers that contain a lot of mutations, such as lung, colon and bladder tumours. And although the procedure is complicated, pharmaceutical companies have shown that they are willing to take on complex, personalized cancer therapies. “The pipeline for identifying mutated proteins will get more efficient with time,” Carreno says. “This therapy is no more complicated than the other therapies that are now being considered.”

Nature doi:10.1038/nature.2015.17250 Nature Original web page at Nature


Potential prognostic marker for recurrence of head and neck squamous cell carcinoma

HNSCC is the sixth most common cancer worldwide and has a high rate of recurrence and early metastatic disease, resulting in approximately 350,000 deaths each year. “Our findings suggest that MED15 may serve as a prognostic marker for HNSCC recurrence and as a therapeutic target in HNSCC patients suffering from recurrences,” said lead investigator Sven Perner, MD, PhD, of the Department of Prostate Cancer Research, Institute of Pathology, and the Department of Otorhinolaryngology at the University Hospital of Bonn (Germany). Mediator is a multiprotein complex that regulates many signaling pathways. In humans, it consists of 30 subunits including MED15, which has been implicated in breast and prostate cancer, with particular attention being given to its link to transforming growth factor-β (TGF-β) signaling. “The evidence that multiple aberrant pathways account for the progression of HNSCC calls for a much deeper understanding of the effect of molecules involved in these signaling pathways upon HNSCC progression,” noted Dr. Perner.

To investigate the role of MED15 in HNSCC, the researchers analyzed tissues from 113 patients with primary tumors, 30 recurrent tumor tissues, 85 lymph node metastases, and 20 control samples of normal squamous epithelial tissue. Using immunohistochemical staining, expression scores were calculated by multiplying staining intensity by the index of immunoreactive cells and categorized as no expression (<0.07), low expression (≥0.07<0.2), or overexpression (≥0.2). They found that MED15 was overexpressed in 35% of primary tumors, 30% of lymph node metastases, and 70% of recurrences, in contrast to no or low expression in control samples. To determine the extent to which MED15 levels correlated with mortality, the investigators performed immunohistochemical analysis of primary tumor tissues from the 108 patients who developed recurrent tumors. They found that the mortality rate (defined as death within 1 to 12 years after first diagnosis) increased from 58% overall to 78% in the subset of patients whose tumors showed MED15 overexpression, with a significant association found between MED15 overexpression and high mortality.

Further investigation revealed that the mortality rate of patients with tumors in the oropharynx or oral cavity was significantly higher than that of patients with tumors in the hypopharynx or larynx. Likewise, the expression of MED15 was found to be higher in oral cavity/oropharyngeal tumors compared with tumors from the hypopharynx or larynx. The study also investigated whether MED15 levels were associated with any of the risk factors for HNSCC, such as tobacco use, alcohol consumption, or chronic oncogenic human papillomavirus infections. Only heavy alcohol consumption was found to be significantly associated with MED15 overexpression, shedding light on the possible mechanism of action of alcohol’s adverse influence.

Dr. Perner and his co-investigators believe MED15 may be a molecular marker that can be used to predict the risk for development of tumor recurrence or metastases that can help clinicians make early diagnosis and treatment decisions. Support for this hypothesis comes from their observations that in 74% of cases, there was a concordance for the presence or absence of MED15 overexpression in samples from a patient’s primary tumor and corresponding lymph node metastasis. In addition, MED15 expression correlated with high proliferative activity in HNSCC tissues and genetic inhibition of MED15 reduced both cell proliferation and migration. They also found that MED15 was highly expressed in the HNSCC malignant cell lines HSC-3 and SCC-25. “Such observations indicate that MED15 overexpression is likely to be a clonal event in the progression of HNSCC,” explained Dr. Perner. (A clonal event is a mutation, deletion, or translocation that occurs within a tumor and recurs in a significant proportion of patients.) “These findings regarding MED15 overexpression are particularly significant, as genetic alterations that provide cells with growth advantages and metastatic potential may be present only in subpopulations of cells in the primary tumor, but increase in tissue from metastases and relapsed HNSCC tumors.” He suggests that a MED15 inhibitor may be a future therapeutic option, especially for patients with advanced disease and tumor recurrence.  Science Daily  Original web page at Science Daily


* New colon cancer culprit found by vet researchers

Christopher Lengner, an assistant professor in the Department of Animal Biology in Penn’s School of Veterinary Medicine, was the senior author on the work. Collaborators from Penn Vet included co-lead authors Shan Wang and Ning Li as well as Maryam Yousefi, Angela Nakauka-Ddamba and Kimberly Parada. Lengner’s research has long focused on how stem cells are able to differentiate into a variety of cell types, an ability known as stem cell potency. His lab’s work dovetails with cancer research in that it is believed that a population of so-called cancer stem cells is responsible for sustaining cancer in the body once it is established, just as normal stem cells are responsible for continually renewing and sustaining our healthy cells. In earlier studies, Lengner and Kharas had found that an RNA binding protein called MSI2 played a role in supporting the potency of hematopoietic stem cells. This same protein was also found to be highly active in blood cancers. Yet unlike other well-established genes that, when mutated, result in increased tumor formation, the MSI2 gene itself is not directly mutated in tumors. Rather, the normal, intact gene becomes highly activated as cancer progresses.

When MSI2 is active, the protein promotes cancer not by changing the expression of genes but by altering the ability of RNA to make proteins. Thus, until now, the contribution of MSI2 went undetected by traditional research techniques that are largely aimed at identifying mutations in DNA sequence and alterations in gene expression patterns. Instead, in the current work, the Penn-led team performed an analysis to look for RNA transcripts that were highly expressed in cancerous tissues but not in normal tissue. They found overexpression of MSI2 was a common characteristic of colon cancer tumors. In addition, when they examined mice bred to lack APC, a key protein that, when lost, is associated with a skyrocketing risk of colon cancer, they found that these animals had high levels of MSI2 expression. Next, they used colorectal cancer cell lines to experimentally block MSI2 activity and found the growth of the tumors was strongly inhibited, another sign that MSI2 promotes cancer growth.

Next the researchers turned to an animal model to see how MSI2 behaved in a whole organism. When they bred mice in which they could induce overexpression of MSI2 in the intestine, they found the mice looked very similar to animals in which APC had been lost; the mice’s cells lost their ability to differentiate and the animals died within three or four days. It’s really unusual to have such a striking phenotype,” Lengner said. These mice had patterns of RNA transcripts nearly identical to mice that lack APC, but MSI2 did not affect APC levels directly, suggesting that MSI2 acts downstream of APC. They also found that MSI2 appears to act in a molecular pathway independent from another critical oncogenic pathway activated upon APC loss, known as the Wnt/β-catenin signaling pathway. “The dogma for the past 15 years has been that colorectal cancer is initiated by the loss of APC that triggers activation of β-catenin, in turn driving uncontrolled stem cell division,” Lengner said. “But there’s been some evidence recently that suggests that, while β-catenin is a critical oncogene downstream of APC loss, it isn’t the only way losing APC leads to tumor formation. Based on our results, we think that activation of MSI2 downstream of APC loss drives this metabolic activation of stem cells and blocks stem cell differentiation.”

To find out how MSI2 might accomplish this, Lengner and colleagues looked at all of the RNA transcripts to which MSI2 — itself an RNA binding protein — bound in the cells that line the intestine. Of particular interest, they found that MSI2 bound to several tumor suppressors, among them Pten, a well-known tumor suppressor whose loss promotes cancer progression in a number of tissues. Further experiments confirmed that MSI2, through inhibition of Pten and other mechanisms, promotes the activation of cellular metabolism through a protein complex called mTORC1. “Normally the mTORC1 complex is tightly regulated by the availability of nutrients and presence of growth factors, helping cells to generate the required building blocks to form new cells when they divide,” Lengner said. “In the context of colorectal cancer, constant activation of mTORC1 through MSI2 enables cancer cells to constantly produce the materials required to form new cells, thus enabling the uncontrolled growth that culminates in the formation of aggressive tumors.”

Lengner noted that drugs that target mTORC1 already exist and could be employed in conjunction with therapies that target the Wnt/β-catenin pathway to better treat colorectal cancers moving forward. But it’s also possible the path to a new, effective cancer treatment won’t be that simple. Lengner and colleagues are also examining the role of the dormant cancer stem cell in maintaining cancers and causing recurrences years after apparent remission. “This is really where we’re heading, to see whether MSI2 has a role in controlling those dormant stem cells and possibly allowing cancers to remain hidden in the body,” Lengner said. “That is a big black box.”  Science Daily  Original web page at Science Daily


Therapeutic cancer vaccine survives biotech bust

The first therapeutic cancer vaccine to be approved in the United States will stay on the market despite the financial collapse of the trailblazing biotechnology company that developed it. The vaccine, Provenge (sipuleucel-T), was purchased on 23 February by Valeant Pharmaceuticals of Laval, Canada, which paid US$415 million for the prostate-cancer treatment and other assets of the bankrupt Dendreon Corporation. The now-defunct Dendreon, of Seattle, Washington, made history in 2010 by showing that complex treatments made fresh for each patient could win regulatory approval, and could be expanded beyond the realm of specialized academic hospitals. Industry took note: today, experimental cancer therapies that spur patients’ immune cells to attack tumours are among the hottest properties in biotechnology. “Dendreon had vision and foresight,” says Usman Azam, head of cell and gene therapies at Novartis, a Swiss pharmaceutical company that has purchased one of Dendreon’s manufacturing plants to fuel its own cell-therapy efforts. “Don’t view Dendreon as a failure: it paved the way.” But although Dendreon created the market for cell therapies, it ultimately could not survive in it.

Provenge is made by harvesting a patient’s dendritic cells and then mixing them with a protein that is particularly abundant in prostate tumours. After being primed by that process to recognize and attack the tumour, the cells are infused back into the patient. The technique was pioneered in the early 1990s by Edgar Engleman, an immunologist at Stanford University in California, who had seen promising results in animal studies of a different cancer, lymphoma. Engleman teamed up with fellow Stanford immunologist Samuel Strober to work out ways to make the process more efficient. When the two pitched their idea for a company to investors, they had little clinical data and were too optimistic about how fast the treatment could reach patients, says Strober. The company was an enormous gamble: harnessing the immune system to fight cancer was still a controversial idea, and no other company had marketed a therapy so personalized and labour-intensive. “But at that time it was a little different from now,” says Strober. “Companies were getting funded on the basis of promise, rather than actually looking at their capacity for early commercial success.”

Engleman and Strober founded Dendreon in 1992; the US Food and Drug Administration approved Provenge in 2010. The approval was celebrated as an important proof of concept by researchers working to develop cancer vaccines and other treatments that stimulate immune responses to the disease. But Dendreon, already strained by the long wait for approval, soon ran into financial difficulty. Confusion over how payment for Provenge would be reimbursed by insurance companies left many doctors in the United States hesitant to use it, says Corey Davis, an analyst at Canaccord Genuity, an investment bank based in Toronto, Canada. When revenues came in far below the company’s initial estimates, Dendreon failed to adjust its operations accordingly, Valeant chief J. Michael Pearson told investors on 23 February. Provenge is, at first glance, an odd purchase for Valeant, a company known for acquiring relatively simple, established products — for example, it controls 10% of the US contact-lens market. But Valeant saw an opportunity to cut costs and improve how the vaccine is marketed to doctors, and thinks it can make back its investment in less than two years, says Davis. The vaccine’s rescue is a relief to Engleman, who had feared that Provenge might disappear along with Dendreon. As the company struggled financially, the scientists who founded it watched helplessly from the sidelines. “This was our baby,” says Engleman. “It was extraordinarily frustrating. There was nothing we could do.” In retrospect, Engleman says, some early scientific choices may have exacerbated Dendreon’s struggle. The company decided not to develop ways to freeze the stimulated immune cells, he notes, which could have simplified the procedure and lowered its cost. And both scientists lament the choice of prostate cancer as the inaugural disease target of the technology. Although the early lymphoma data had been very promising, recalls Engleman, the company decided to switch to a more common cancer with a bigger potential market.

And prostate cancer had another advantage: people can live without a prostate, which helped to calm fears (since proved unfounded) about what would happen if the primed immune cells attacked healthy tissue. But the results in prostate cancer were not as dazzling as Engleman had hoped on the basis of his animal results in lymphoma. Dendreon did extend survival in some people with advanced prostate cancer, but by a median of only four months. Recently, the UK National Institute for Health and Care Excellence advised that at more than £47,000 (US$73,000) per course of treatment, Provenge is too expensive to justify its use by the National Health Service. The Dendreon experience has not dampened Engleman’s enthusiasm for entrepreneurship. He and Strober, along with other collaborators, have teamed up on a company that aims to develop a technique to reduce the likelihood that recipients of transplanted organs will develop an immune response to the new tissue. They are again on the hunt for funding, but this time the team is backed by more than a decade of clinical-trial data that backs the method. “We’re thinking that this one will progress a lot faster than the Dendreon thing,” says Strober.

Nature doi:10.1038/nature.2015.16990 Nature Original we page at Nature


How pancreatic cancer cells sidestep chemotherapy

Pancreatic cancer is one of the deadliest forms of the disease. The American Cancer Society’s most recent estimates for 2014 show that over 46,000 people will be diagnosed with pancreatic cancer and more than 39,000 will die from it. Now, research led by Timothy J. Yen, PhD, Professor at Fox Chase Cancer Center, reveals that one reason this deadly form of cancer can be so challenging to treat is because its cells have found a way to sidestep chemotherapy. They hijack the vitamin D receptor, normally associated with bone health, and re-purposed it to repair the damage caused by chemotherapy. The findings, which have been published in the January 3 issue of the journal Cell Cycle, raise hopes that doctors will one day find a way to turn this process against the tumor and help chemotherapy do its job.

Most patients diagnosed with pancreatic cancer receive a drug called gemcitabine, which works by preventing cells from replicating their DNA — thus stopping tumor cells from dividing and causing them to die off. Sadly, many patients die within a few months, often because their cancer finds a way to work around treatment. But how does that happen? “Maybe there is something we don’t understand about how gemcitabine works,” says Dr. Yen. “More likely, cancer cells have found a way to avoid DNA-damaging drugs.” To determine how pancreatic cancers sidestep chemotherapy and the effects of gemcitabine, Dr. Yen and his colleagues removed every one of the ~24,000 genes, one by one, in pancreatic cancer cells, exposed the cells to gemcitabine, and noted which gene “knockout” caused cells to be more sensitive to the drug. One of those “knocked-out” genes was particularly important, namely, the gene for a protein which normally binds to vitamin D.

“When we inactivated this vitamin D receptor in cancer cells and added gemcitabine, almost all of them died,” says Dr. Yen. That’s when the researchers realized they had identified a key mechanism driving chemotherapeutic effectiveness against pancreatic cancer. “If we find a drug that inactivates the vitamin D receptor, it may allow gemcitabine to selectively kill pancreatic cancer cells while leaving healthy cells unharmed,” says Dr. Yen. “Patients would just need to drink lots of milk or take calcium supplements to make sure their bones stay healthy.” Although the precise role of the vitamin D receptor in pancreatic cancer remains uncertain, it’s clear that pancreatic cancer cells need it, says Dr. Yen. “Cancer cells are good at finding ways to survive,” he explains. “We suspect that cancer cells hijacked the vitamin D receptor and reassigned it to perform other cellular functions, such as by repairing DNA damage caused by gemcitabine so the cancer can continue to divide and spread.”

Although pancreatic cancer cells need the vitamin D receptor to survive, other normal cells don’t, which Yen says is good news for patients because future cancer treatments can knock out the receptor without causing too much collateral damage or side effects, as long as patients take calcium supplements to keep their bones healthy. “By knocking out the vitamin D receptor, we could inactivate that DNA repair process that is allowing drug-treated tumor cells to live. As a result, we could eliminate more cancer cells at the outset,” says Dr. Yen. “The Pancreatic Cancer Action Network has launched an initiative to double patients’ survival by 2020; with this new finding, we believe it’s a step in the right direction.” Science Daily Original web page at Science Daily


Human stem cells repair damage caused by radiation therapy for brain cancer in rats

For patients with brain cancer, radiation is a powerful and potentially life-saving treatment, but it can also cause considerable and even permanent injury to the brain. Now, through preclinical experiments conducted in rats, Memorial Sloan Kettering Cancer Center researchers have developed a method to turn human stem cells into cells that are instructed to repair damage in the brain. Rats treated with the human cells regained cognitive and motor functions that were lost after brain irradiation. The findings are reported in the February 5 issue of the journal Cell Stem Cell.

During radiation therapy for brain cancer, progenitor cells that later mature to produce the protective myelin coating around neurons are lost or significantly depleted, and there is no treatment available to restore them. These myelinating cells–called oligodendrocytes–are critical for shielding and repairing the brain’s neurons throughout life. A team led by neurosurgeon Viviane Tabar, MD, and research associate Jinghua Piao, PhD, of the Memorial Sloan Kettering Cancer Center in New York City, wondered whether stem cells could be coaxed to replace these lost oligodendrocyte progenitor cells. They found that this could be achieved by growing stem cells–either human embryonic stem cells or induced pluripotent stem cells derived from skin biopsies–in the presence of certain growth factors and other molecules. Next, the investigators used the lab-grown oligodentrocyte progenitor cells to treat rats that had been exposed to brain irradiation. When the cells were injected into certain regions of the brain, brain repair was evident, and rats regained the cognitive and motor skills that they had lost due to radiation exposure.

The treatment also appeared to be safe: none of the animals developed tumors or inappropriate cell types in the brain. “Being able to repair radiation damage could imply two important things: improving the quality of life of survivors and potentially expanding the therapeutic window of radiation,” said Dr. Tabar. “This will have to be proven further, but if we can repair the brain effectively, we could be bolder with our radiation dosing, within limits.” This could be especially important in children, for whom physicians deliberately deliver lower radiation doses. Science Daily Original web page at Science Daily


* Cancer biopsies do not promote cancer spread, research finds

A study of more than 2,000 patients by researchers at Mayo Clinic’s campus in Jacksonville, Florida, has dispelled the myth that cancer biopsies cause cancer to spread. In the Jan. 9 online issue of Gut, they show that patients who received a biopsy had a better outcome and longer survival than patients who did not have a biopsy. The researchers studied pancreatic cancer, but the findings likely apply to other cancers because diagnostic technique used in this study — fine needle aspiration — is commonly used across tumor types, says the study’s senior investigator and gastroenterologist Michael Wallace, M.D., M.P.H., professor of medicine. Fine needle aspiration is a minimally invasive technique that uses a thin and hollow needle to extract a few cells from a tumor mass. A long-held belief by a number of patients and even some physicians has been that a biopsy can cause some cancer cells to spread. While there have been a few case reports that suggest this can happen — but very rarely — there is no need for patients to be concerned about biopsies, says Dr. Wallace. “This study shows that physicians and patients should feel reassured that a biopsy is very safe,” he says. “We do millions of biopsies of cancer a year in the U.S., but one or two case studies have led to this common myth that biopsies spread cancer.” Biopsies offer “very valuable information that allow us to tailor treatment. In some cases, we can offer chemotherapy and radiation before surgery for a better outcome, and in other cases, we can avoid surgery and other therapy altogether,” Dr. Wallace says. Surgery for pancreatic cancer is “a very big operation,” and “most people should want to make sure they have cancer before they undergo surgery,” he says. One study has shown that 9 percent of patients who underwent surgery because of suspected pancreatic cancer actually had benign disease. Dr. Wallace and his team have conducted two separate studies to examine the risk of biopsy. In a 2013 study published in Endoscopy, the researchers examined outcomes in 256 pancreatic cancer patients treated at Mayo Clinic in Jacksonville, Florida. They found no difference in cancer recurrence between 208 patients who had ultrasound-guided fine needle aspiration (EUS-FNA) and the 48 patients who did not have a biopsy. In the current study, they examined 11 years (1998-2009) of Medicare data on patients with non-metastatic pancreatic cancer who underwent surgery. The researchers examined overall survival and pancreatic cancer-specific survival in 498 patients who had EUS-FNA and 1,536 patients who did not have a biopsy. During a mean follow-up time of 21 months, 285 patients (57 percent) in the EUS-FNA group and 1,167 patients (76 percent) in the non-EUS-FNA group died. Pancreatic cancer was identified as the cause of death for 251 patients (50 percent) in the EUS-FNA group and 980 patients (64 percent) in the non-EUS-FNA group. Median overall survival in the EUS-FNA group was 22 months compared to 15 months in the non-EUS-FNA group. “Biopsies are incredibly valuable. They allow us to practice individualized medicine — treatment that is tailored for each person and designed to offer the best outcome possible,” Dr. Wallace says.  Science Daily  Original web page at Science Daily


Coupling head and neck cancer screening, lung cancer scans could improve survival

In an analysis published in the journal Cancer and funded by the National Institutes of Health (NIH), the team provides a rationale for a national clinical trial to assess the effectiveness of adding examination of the head and neck to lung cancer screening programs. People most at risk for lung cancer are also those most at risk for head and neck cancer. “When caught early, the five-year survival rate for head and neck cancer is over 83 percent,” said senior author Brenda Diergaarde, Ph.D., assistant professor of epidemiology at Pitt’s Graduate School of Public Health and member of the UPCI. “However, the majority of cases are diagnosed later when survival rates generally shrink below 50 percent. There is a strong need to develop strategies that will result in identification of the cancer when it can still be successfully treated.” Head and neck cancer is the world’s sixth-most common type of cancer. Worldwide every year, 600,000 people are diagnosed with it and about 350,000 die. Tobacco use and alcohol consumption are the major risk factors for developing the cancer. The early symptoms are typically a lump or sore in the mouth or throat, trouble swallowing or a voice change, which are often brushed off as a cold or something that will heal. Treatment, particularly in later stages, can be disfiguring and can change the way a person talks or eats. Dr. Diergaarde and her team analyzed the records of 3,587 people enrolled in the Pittsburgh Lung Screening Study (PLuSS), which consists of current and ex-smokers aged 50 and older, to see if they had a higher chance of developing head and neck cancer. In the general U.S. population, fewer than 43 per 100,000 people would be expected to develop head and neck cancer annually among those 50 and older. Among the PLuSS participants, the rate was 71.4 cases annually per 100,000 people. Recently, the U.S. Preventive Services Task Force, as well as the American Cancer Society and several other organizations, recommended annual screening for lung cancer with low-dose computed tomography in people 55 to 74 years old with a smoking history averaging at least a pack a day for a total of 30 years. The recommendation came after a national clinical trial showed that such screening reduces lung cancer mortality. “Head and neck cancer is relatively rare, and screening the general population would be impractical,” said co-author David O. Wilson, M.D., M.P.H., associate director of UPMC’s Lung Cancer Center. “However, the patients at risk for lung cancer whom we would refer for the newly recommended annual screening are the same patients that our study shows also likely would benefit from regular head and neck cancer screenings. If such screening reduces mortality in these at-risk patients, that would be a convenient way to increase early detection and save lives.” Dr. Diergaarde’s team is collaborating with otolaryngologists to design a national trial that would determine if regular head and neck cancer screenings for people referred for lung cancer screenings would indeed reduce mortality.  Science Daily  Original web page at Science Daily


Breast cancer vaccine shows promise in small clinical trial

A breast cancer vaccine developed at Washington University School of Medicine in St. Louis is safe in patients with metastatic breast cancer, results of an early clinical trial indicate. Preliminary evidence also suggests that the vaccine primed the patients’ immune systems to attack tumor cells and helped slow the cancer’s progression. The study appeared Dec. 1 in Clinical Cancer Research. The new vaccine causes the body’s immune system to home in on a protein called mammaglobin-A, found almost exclusively in breast tissue. The protein’s role in healthy tissue is unclear, but breast tumors express it at abnormally high levels, past research has shown. “Being able to target mammaglobin is exciting because it is expressed broadly in up to 80 percent of breast cancers, but not at meaningful levels in other tissues,” said breast cancer surgeon and senior author William E. Gillanders, MD, professor of surgery. “In theory, this means we could treat a large number of breast cancer patients with potentially fewer side effects. “It’s also exciting to see this work progress from identifying the importance of mammaglobin-A, to designing a therapeutic agent, manufacturing it and giving it to patients, all by investigators at Washington University,” he added. The vaccine primes a type of white blood cell, part of the body’s adaptive immune system, to seek out and destroy cells with the mammaglobin-A protein. In the smaller proportion of breast cancer patients whose tumors do not produce mammaglobin-A, this vaccine would not be effective. In the new study, 14 patients with metastatic breast cancer that expressed mammaglobin-A were vaccinated. The Phase 1 trial was designed mainly to assess the vaccine’s safety. According to the authors, patients experienced few side effects, reporting eight events classified as mild or moderate, including rash, tenderness at the vaccination site and mild flu-like symptoms. No severe or life-threatening side effects occurred. Although the trial was designed to test vaccine safety, preliminary evidence indicated the vaccine slowed the cancer’s progression, even in patients who tend to have less potent immune systems because of their advanced disease and exposure to chemotherapy. “Despite the weakened immune systems in these patients, we did observe a biologic response to the vaccine while analyzing immune cells in their blood samples,” said Gillanders, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. “That’s very encouraging. We also saw preliminary evidence of improved outcome, with modestly longer progression-free survival.” Of the 14 patients who received the vaccine, about half showed no progression of their cancer one year after receiving the vaccine. In a similar control group of 12 patients who were not vaccinated, about one-fifth showed no cancer progression at the one-year follow-up. Despite the small sample size, this difference is statistically significant. Based on results of this study, Gillanders and his colleagues are planning a larger clinical trial to test the vaccine in newly diagnosed breast cancer patients, who, in theory, should have more robust immune systems than patients who already have undergone extensive cancer therapy. “If we give the vaccine to patients at the beginning of treatment, the immune systems should not be compromised like in patients with metastatic disease,” Gillanders said. “We also will be able to do more informative immune monitoring than we did in this preliminary trial. Now that we have good evidence that the vaccine is safe, we think testing it in newly diagnosed patients will give us a better idea of the effectiveness of the therapy.”  Science Daily  Original web page at Science Daily


Novel regulatory mechanism for cell division found

A study, led by Zhimin Lu, M.D., Ph.D., professor of neuro-oncology at The University of Texas MD Anderson Cancer Center, showcased the non-metabolic abilities of PKM2 (pyruvate kinase M2) in promoting tumor cell proliferation when cells produce more of the enzyme. The study results were published in Nature Communications. Dr. Lu’s group previously demonstrated that PKM2 controls gene expression by binding to transcriptional factors and phosphorylating histone, proteins that have the unique ability to turn genes on and off. Phosphorylation is a process by which a phosphate group is added to a protein. “PKM2 is expressed at high levels during tumor progression and is important for cell growth. However there’s been little information about whether it directly controls cell division.” said Lu. “Our findings underscored its function in tumor formation during the final stages of cell division known as cytokinesis.” Understanding how cytokinesis goes awry is important since abnormal cell division impacts tumor cell growth and spread. Lu’s team looked at the role of PKM2 in brain tumor development in mice. After analyzing the protein-coding gene, MLC2 (myosin light chain 2), Lu’s group revealed how phosphorylation of MLC2 by PKM2 in brain tumors occurs. Phosphorylation of MLC2 controls a process which allows separation of a dividing parental cell into two ‘daughter’ cells. “The results revealed that PKM2-regulated MLC2 phosphorylation and the related cytokinesis are instrumental in brain tumor development and are found to precisely control cell division,” said Lu. “More importantly, our research shows that PKM2-regulated cytokinesis occurs in malignant tumors with bad outcome, such as glioblastoma, pancreatic cancer, and melanoma.” Tumor cells, in which certain protein-coding genes (EGFR, K-Ras and B-Raf) are activated, develop new patterns of “molecular signatures” for regulating cell proliferation. These changes enable the tumor cells to coordinate their metabolism and cycle progression through PKM2. Science Daily Original web page at Science Daily