Infectious Selflessness: How an Ant Colony Becomes a Social Immune System.


Ants work together to battle a deadly fungus by diluting the infection across the colony.

In the 2011 blockbuster thriller Contagion, a virus infects and kills 26 million people around the world. But even those who evade the virus are infected with something else:crippling fear. To contain the outbreak, the military imposes a quarantine. People stay indoors, refusing to interact with anyone outside their families. Touching anyone or anything becomes a risk, because the virus lingers everywhere.

Ants do things differently. When a deadly fungus infects an ant colony, the healthy insects do not necessarily ostracize their sick nest mates. Instead, they welcome the contagious with open arms—or, rather, open mouths—often licking their neighbors to remove the fungal spores before the pathogens sprout and grow. Apparently, such grooming dilutes the infection, spreading it thinly across the colony. Instead of leaving their infected peers to deal with the infection on their own and die, healthy ants share the burden, deliberately infecting everyone in the colony with a tiny dose of fungus that each individual’s immune system can clear on its own. Such “social immunization” also primes the immune systems of healthy ants to battle the infection. These are the conclusions of a new study in the April 3 issue of PLoS Biology.

When you encounter a particular pathogen—a virus, a fungus—for the first time, your immune system has to learn how to deal with it. The second time you meet the same pathogen, your immune system is ready—it has developed some resistance. Researchers have found that when some members of an ant colony are exposed to a pathogen for the first time, all members of that colony—even the ones that were not initially infected—build resistance to the pathogen. How this happens was never clear.

To investigate the mystery, Sylvia Cremer of the Institute of Science and Technology in Austria and her colleagues studied Lasius neglectus, a rather common-looking ant that forms supercolonies, and Metarhizium anisopliae, a parasitic fungus that feeds on and kills many insects. Once the fungal spores settle on an insect’s body, they germinate and penetrate the exoskeleton with rootlike structures called hyphae. Eventually the fungus sucks out all the nutrients from the insect and encrusts its emptied husk in what looks like green mold.

To interrupt the pathogen’s life cycle, some ants lick fungal spores off of others. As the ants groom one another, bacteria on their skin—as well as specialized glands in the mouth called infrabuccal pockets—kill most of the spores that they lap up. Later, the ants spit out a compacted ball of dead spores. But Cremer and her colleagues suspected that not all of the spores are killed and that, by tending to infected peers, healthy ants end up with some spores on their bodies.

Cremer and her teammates tested these hunches by first tagging M. anisopliae spores with a protein that glows red under ultraviolet light and subsequently exposing 15 ants to the signature spores. Two days later the researchers dissected the ants under a microscope and detected the blushing spores on 17 of 45 ants that they had not directly exposed to the fungus. Cremer concluded that these ants must have picked up the spores by grooming their infected nest mates. The infection had rippled through the colony. When the researchers dissected the ants and placed their body parts in agar plates, fungi grew on 64 percent of the ants that had not been directly exposed to the spores—an even larger portion of the colony than the scientists had first detected with UV light.

“Even though 60 to 80 percent of nest mates contracted the disease, only about 2 percent of the ants died,” Cremer explains. “Such low-level infections were actually beneficial because they saved the directly exposed ants and built up resistance in the healthy ants.”

When Cremer analyzed the gene activity of ants that picked up spores from infected peers, she found that genes coding for antifungal proteins, as well as more general immune proteins, were more active than usual. Removing fungal spores from a peer seems to prime the immune system to battle any collateral infections. When Cremer prevented healthy ants from touching infected ants, the infection did not spread, the uninfected nestmates did not rev up their immune systems and many of the lone ants died. Cremer also observed that healthy ants are especially attentive to sick nest mates in the first two days after infection, which makes sense because if the spores are not removed within that period, it is usually too late to prevent full-blown infection and death.

Cremer and her colleagues think that the newly observed interactions between healthy and sick ants—as well as the genetic evidence of increased immune responses—explain how an entire ant colony develops resistance to a pathogen, even if only some of the ants are directly exposed to that pathogen. Although each insect has its own immune system, ants seem to have evolved a second immune system—a colony-wide immune response to infection. To thwart contagion, ants embrace it.

Rebeca Rosengaus of Northeastern University was impressed with the variety of experiments and analyses in the new study, which she says “provides further support that social immunity is a real phenomenon, not only in ants, but also in termites and probably eusocial wasps and bees, too.” In earlier work Rosengaus discovered that termites exposed to a fungus warn one another by “essentially having a seizure”—hopping around like crazy and banging their heads against their nest walls to keep healthy peers away. She also found evidence that ants spread immunity to bacterial infections by transmitting immune proteins in droplets of food passed from one ant’s mouth to another. “It goes against what you might think. Because there are so many individuals living so closely together, if one gets sick, chances are someone else would get sick, but through social immunization the entire colony seems to be doing better.”
Source: Scientific American.

 

 

 

 

Virus Therapy for Extensive-Stage Small Cell Lung Cancer.


Name of the Trial
Phase II Randomized Study of Seneca Valley Virus-001 (NTX-010) after Platinum-Based Chemotherapy in Patients with Extensive-Stage Small Cell Lung Cancer (NCCTG-N0923).

Principal Investigator
Dr. Julian Molina, North Central Cancer Treatment Group

Why This Trial Is Important
Lung cancer is the leading cause of cancer death in the United States. Although about 85 percent of lung cancer cases are non-small cell lung cancer, more than 30,000 people are diagnosed with small cell lung cancer each year in the United States. Small cell lung cancer is the most aggressive type of lung cancer, with 5-year survival rates ranging between 5 percent and 15 percent. The most important prognostic factor is the extent of disease, that is, whether it is limited stage or extensive stage. Unfortunately, about two-thirds of patients have extensive-stage disease at diagnosis.

Combination chemotherapy, in which a platinum drug is paired with one or two other drugs (often etoposide), is the cornerstone of treatment for patients with extensive-stage small cell lung cancer. Although many patients initially respond to treatment, the disease almost always returns. Consequently, the likelihood of long-term survival for these patients is exceptionally low. New treatment approaches are needed to improve long-term survival of patients with small cell lung cancer.

Seneca Valley virus-001 (also called NTX-010) is an oncolytic virus that was originally discovered as a contaminant in cell cultures. In preclinical experiments, the virus was found to readily infect, replicate in, and kill cancer cells with neuroendocrine features (including small cell carcinomas) but was not toxic to normal cells.

These studies led to a phase I dose-escalation trial in patients with small cell carcinomas and carcinoid tumors. The six patients in the study with small cell cancers (five of whom had small cell lung cancer) were all treated at the lowest dose. Nevertheless, the researchers found evidence of viral infection in three of the six patients with small cell cancer, including one who experienced stable disease for 10 months and was still alive more than 3 years after treatment.

In this clinical trial, patients with extensive-stage small cell lung cancer who have received platinum-based chemotherapy will be randomly assigned to receive Seneca Valley virus-001 intravenously or an intravenous placebo. Patients with previously untreated disease are eligible for the trial, but they must undergo four to six cycles of a platinum-based chemotherapy regimen and then be assessed for response. Patients with stable disease or a response will be randomly assigned to treatment or placebo. Patients participating in the study may also undergo two rounds of prophylactic cranial irradiation. The primary objective is to compare progression-free survival between the two groups. The investigators will also compare overall survival and assess adverse events, response rates, and quality of life.

“Our study is aimed at patients who have received first-line chemotherapy for extensive-stage small cell lung cancer; we’re randomizing them on a one-to-one basis to receive either the virus at the highest dose tested in the phase I study or a placebo,” said Dr. Molina. “It’s important that we compare the virus treatment to what you normally do for patients in this situation, which is nothing.”

Source: NCI Bulletin.

FDA Takes Action under the Tobacco Control Act of 2009.


On March 29, the Food and Drug Administration (FDA) released two draft guidance documents intended to provide the public with accurate information about the chemicals in tobacco products and to help prevent misleading marketing by the tobacco industry. The documents are part of the FDA’s implementation of the Family Smoking Prevention and Tobacco Control Act of 2009.

“We are committed to stopping…practices that may cause people to start or continue using tobacco products that could lead to preventable disease and death,” said FDA Commissioner Dr. Margaret Hamburg in a press release.

The first document provides guidance on how tobacco companies will comply with the requirement to report the amount of harmful and potentially harmful constituents (HPHCs) found in their products. There are more than 7,000 chemicals in tobacco and tobacco smoke. The guidance document establishes a list of 93 HPHCs in tobacco and tobacco smoke and identifies 20 representative HPHCs for which testing methods are well established and widely available.  The FDA intends to focus reporting enforcement on these 20 HPHCs during 2012 and to make information about the HPHCs in specific tobacco products available to the public in a consumer-friendly format by April 2013.

The Tobacco Control Act establishes rigorous scientific criteria that must be met before the FDA can allow a tobacco company to market a product with a claim of “reduced harm.” With this in mind, the second draft guidance document describes the scientific studies and analyses an applicant should submit to the FDA to demonstrate that its product will, or is expected to, significantly reduce harm or exposure to individuals and benefit the health of the population as whole. The “modified risk tobacco product” draft guidance is open for public comment until June 4, 2012.

Source: NCI Bulletin.

U.S. Cancer Deaths Continue Steady Decline.


According to the latest data on nationwide death rates from cancer, overall mortality from cancer declined from 1999 to 2008, maintaining a trend seen since the early 1990s. Mortality fell for most cancer types, including the four most common types of cancer in the United States (lung, colorectal, breast, and prostate), although the rate of decline varied by cancer type and across racial and ethnic groups. The complete Annual Report to the Nation on the Status of Cancr, 1975–2008 appeared March 28 in Cancer.

NCI, the American Cancer Society, the Centers for Disease Control and Prevention (CDC), and the North American Association of Central Cancer Registries (NAACCR) collaborated on the report. Cancer incidence data came from NCI’s Surveillance, Epidemiology, and End Results (SEER) database and from the CDC, with analyses of pooled data by NAACCR. Mortality data came from the CDC’s National Center for Health Statistics.

The declines in cancer death rates (mortality) averaged 1.7 percent per year for men and 1.3 percent per year for women from 1999 through 2008.

Among men, the overall rate of new cancer cases (incidence) fell by an average of 0.6 percent annually from 1999 to 2008. Among women, incidence dropped by an average of 0.5 percent annually from 1999 to 2006 but held steady from 2006 to 2008.

Cancer incidence in children ages 0 to 14 rose from 1999 to 2008 (by 0.5 percent a year), continuing a trend seen in previous Annual Reports to the Nation. However, advances in treatment contributed to a steady decline in mortality rates for children with cancer in the last 5 years (an average of 2.8 percent per year).

“Steady progress, as measured by declines in cancer death rates for many cancers, is good because we have an aging, growing population,” said Dr. Brenda K. Edwards, NCI’s senior advisor for surveillance. “While the number of people diagnosed with cancer or who die of the disease may be increasing, the decline in cancer death rates for more than a decade is the best indicator of progress due to prevention, screening, diagnosis, and treatment,” she added.

Not All Good News

There were some notable exceptions to the overall decreases in incidence and mortality. From 1999 to 2008, death rates rose for pancreatic cancer in men and women, for liver cancer and melanoma in men, and for endometrial cancer in women. The cervical cancer death rate, which had been falling for decades, showed no further decrease over the last 5 years.

And, although incidence rates fell overall for men and women from 1999 to 2008, the decline was not distributed evenly across racial and ethnic groups. Cancer incidence rates did not decrease significantly among American Indian/Alaska Native men and women combined or among black, Asian and Pacific Islander, and American Indian/Alaska Native women.

Although incidence rates in black men did decline, this group still had the highest cancer incidence rate of any racial and ethnic group, 15 percent higher than that of white men and nearly double that of Asian and Pacific Islander men.

Major Modifiable Risk Factors

Each Annual Report to the Nation includes a special feature that focuses on a topic of importance to the cancer research community and the public. This year’s report featured an analysis on the contribution of excess weight (overweight and obesity) and insufficient physical activity to the nation’s cancer burden.

More than 60 percent of the U.S. adult population is estimated to be overweight or obese, and a similar percentage of adults do not get the recommended amount of physical activity. The rates of insufficient physical activity are even worse for children; for example, up to 90 percent of high school girls do not engage in recommended levels of physical activity.

Excess weight “is a major modifiable risk factor for cancer and other diseases—probably second only to tobacco use in terms of its impact on cancer incidence and mortality,” said Dr. Edwards. “The risk may be modest but it’s so pervasive that we felt this was the time to look at [cancer] incidence in this context.” Physical inactivity not only contributes to excess weight but is itself a risk factor for several cancer types.

The report was not designed to quantitatively link the trends in excess weight and lack of physical activity to the national trends for cancer, explained Dr. Rachel Ballard-Barbash, associate director of the Applied Research Program in NCI’s Division of Cancer Control and Population Sciences. Many other studies have shown convincing links between excess weight and several cancer types, including endometrial, postmenopausal breast, colorectal, kidney, esophageal, and pancreatic cancer.

The point of the special feature, she noted, “is to highlight specific types of cancer that are related to [excess weight and lack of sufficient physical activity], show how these behaviors relate to these cancers in terms of their relative risks, and briefly describe some of the mechanisms by which they relate.” The special feature also highlights national- and state-level prevention strategies in policy and environmental change that are intended to help people achieve recommended changes in their diets and physical activity levels.

As the nation’s weight has risen, so has the incidence of some, although not all, types of cancer related to excess weight and lack of sufficient physical activity. From 1999 to 2008, incidence rates of kidney cancer and of adenocarcinoma of the esophagus each rose about 3 percent per year for men and women, while incidence of pancreatic cancer rose 1.2 percent per year among men and women.

In addition, incidence rates of endometrial cancer rose significantly among black, Asian and Pacific Islander, and Hispanic women. Incidence of postmenopausal breast cancer stabilized from 2005 to 2008, after a period of decline.

“Although all of these cancers are influenced by multiple factors, the high prevalence of excess weight and insufficient physical activity likely contributed to these observed increases and to the lack of decline in breast cancer,” the authors wrote. “Continued progress in reducing cancer incidence and mortality rates will be difficult without success in promoting healthy weight and physical activity, particularly among youth.”

Excess weight and lack of physical activity also influence cancer survivorship, explained Dr. Ballard-Barbash, as both can negatively affect outcomes after a cancer diagnosis, further increasing the need for these risk factors to be addressed on a personal and societal level.

Source: NCI Bulletin.

 

A Conversation with Dr. Bert Vogelstein about Whole-Genome Sequencing to Predict Cancer Risk.


Johns Hopkins researchers have used mathematical models based on clinical data from identical twins to test the ability of genomic testing to predict risk for 24 common diseases, including cancer. Dr. Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University and an investigator with the Howard Hughes Medical Institute, recently spoke with the NCI Cancer Bulletin about the research, which was published April 2 in Science Translational Medicine.

What was the goal of your study, and what did you learn?

Our goal was to provide a realistic interpretation of what the public can expect to obtain from whole-genome sequencing at some point in the future, in the best circumstances, assuming that the technology will be developed that enables us to fully interpret all of the sequencing information. One question we asked was: In this best possible case, what would whole-genome sequencing achieve for the average individual?

Our results suggest that more than half of people who undergo whole-genome sequencing could, in this best-case scenario, obtain results indicating that they have an increased genetic risk for one or more diseases.

However, most individuals will receive negative test results for most diseases, including most cancers, meaning that they have less than a 10 percent risk of developing those diseases. Therefore, whole-genome sequencing will generally not predict exactly what diseases they will get or what diseases they will die from.

What do your findings mean specifically for estimating cancer risk?

As one example, we estimate that as many as 2 percent of women who have a whole-genome sequencing test could get a positive result for ovarian cancer, which would mean that they have a more than 10 percent risk of developing ovarian cancer, several times higher than the risk of the average woman.

Whole-genome sequencing will not alleviate the need for effective cancer prevention and early detection measures.

On the other hand, 98 percent of women tested would get a negative whole-genome test result. This would not mean that they have no risk for developing ovarian cancer; it would simply mean that they have a level of risk similar to that of the general population and of most women who had not been tested. That’s because most ovarian cancers, and most cancers generally, are caused not by hereditary genetic alterations but by genetic alterations acquired after birth and caused by a combination of environmental influences and random events.

One of the implications of this study is that whole-genome sequencing will not alleviate the need for effective cancer prevention and early detection measures, which we already know can reduce cancer incidence and death. Equally important, we need more research to find better ways to prevent cancer or to detect it early.

What could people who have a positive result on a test, such as the one for ovarian cancer, do with that information?

[Patients] could get the best available surveillance, including ultrasound and gynecological exams to detect cancer as early as possible. And, hopefully, future research will result in more sophisticated and sensitive tests for detecting cancers early.

There are also environmental factors at play. Obesity is a risk factor for ovarian cancer, for example, and women at increased risk for this disease would certainly want to avoid that.

It’s been suggested that people would be better off spending their money on a gym membership than on genome sequencing. What do your results say about that line of thinking?

Our position is that the more knowledge individuals have, the better informed they will be, and the better the choices they will make. They may look at our data and decide that, for most diseases, whole-genome sequencing is not really going to be much help to them, but they know for a fact that getting more exercise will reduce their risk for several diseases, so they will choose to spend their money on the gym membership.

Another person may say, “My mother died of ovarian cancer, and if I’m at high risk, I want to know about it.” That person might want to buy both the gym membership and the genome-sequencing test. Someone else may say, “Knowing I have a slightly increased risk for some diseases is going to wreak havoc on my psyche, and it’s not worth it.”

I would not make that decision for anyone; like all health care decisions, it is extremely personal. I simply hope that our data will help medical professionals and others involved in health care inform their patients about what this technology can and can’t do.

What was your rationale for doing this study now?

This study evolved from our previous research. One of our goals is to try to understand the basis for familial cancers. In 2009, Alison Klein, Ralph Hruban, Sian Jones, and other members of our group reported on a family with familial pancreatic cancer not caused by a mutation in any of the genes known at that time to be involved in this disease.

Through genome-wide sequencing, we identified a heritable mutation in a gene called PALB2 in this family. This was the first time genome-wide sequencing had been used to identify the basis for a hereditary disease. Since then, a number of studies have identified the value of genome-wide sequencing for identifying the genetic basis of diseases in families.

So we began to wonder: If we could do this in families with a clear predisposition for cancer, could it be done for everybody? As whole-genome sequencing becomes less expensive, this becomes feasible. A few years ago it cost about $50,000 to sequence all of the approximately 20,000 genes in a human cell. Now it can be done for less than $5,000, and a few years from now the cost will be less than $1,000. We began to wonder about the public health implications and the value this might have for consumers.

What are the biggest caveats to note about this study?

The main caveat is that we’re not talking about what’s possible now but about what might be possible at some time in the future. Any perceived value of this approach [to learning about genetic risk] should be tempered by the realization that we’re not there yet.

Much of your cancer data was obtained from Scandinavian twin registries. Would the results have been different if you had looked at people of other ethnicities?

From other studies, and given what we know about cancer, I don’t think the generalities would be different. You can’t change the genes people are born with. You can change their environment, but with cancer, random influences play a large role. In different populations, you would find slightly different results, but we believe that the general conclusions would stand.

What are the implications for public health?

The best possible finding for a study like ours would be that a large part of the screened population [that test positive] might be at high risk for cancer and, conversely, that those who didn’t test positive would have a very low risk. In that scenario, we might have been able to recommend that prevention and surveillance measures be concentrated on individuals at increased risk.

But this study and earlier studies show that individuals at high genetic risk account for only a minority of those who will die of cancer, so the public health implications of whole-genome sequencing are not as strong as we might have wished for.

—Interviewed by Eleanor Mayfield

Source: NCI Bulletin.

Drugs Target Epigenetic Changes to Reprogram Cancer Cells.


Research results presented at the 2012 American Association for Cancer Research (AACR) annual meeting offer new insights into an emerging treatment approach for cancer, known as epigenetic therapy. Rather than killing cancer cells by damaging their DNA or disrupting vital communication pathways, epigenetic therapy attempts to change the behavior of cancer cells by blocking chemical changes to DNA, including a process called methylation that turns genes on or off.

The concept behind epigenetic treatment is to “reprogram” the network of chemical changes that affect the DNA of cancer cells, explained Dr. Jean-Pierre Issa of the Temple University School of Medicine in Philadelphia. This reprogramming can alter the activity of critical genes in cancer cells that drive their growth and survival. The treatments, Dr. Issa said, “can effectively reset DNA methylation.”

Dr. Issa led the first trial in humans to test an investigational epigenetic drug called SGI-110, which is a modified form of a methylation-blocking drug called decitabine (Dacogen). SGI-110 is more stable than decitabine, which may allow for prolonged exposure to the drug. Decitabine is approved by the Food and Drug Administration (FDA) to treat myelodysplastic syndrome (MDS), a precursor to leukemia.

Dr. Issa’s lab and researchers at Astex Pharmaceuticals collaborated to develop SGI-110, with funding from the Stand Up To Cancer initiative.

Sixty-six patients with MDS or acute myelogenous leukemia (AML) were enrolled in the trial, which tested a series of doses in two treatment schedules of SGI-110. Two patients with AML whose disease had returned after previous treatments had complete responses, and one had a partial response, Dr. Issa reported at the meeting. The patients who had complete responses had the greatest decrease in methylation and the highest levels of the drug in their circulatory system.

Treatment was generally well tolerated, with only moderate side effects. The lack of side effects makes sense, Dr. Issa explained, because “cancer cells are much more reliant on DNA methylation for survival than normal cells.”

One of the dosing regimens inhibited DNA methylation more effectively than the other, he noted, so future trials will use that dosing regimen.

Giving Cancer Cells a New Memory

Dr. Stephen Baylin of the Johns Hopkins University Kimmel Cancer Center presented findings at the AACR annual meeting from a laboratory study of decitabine and another methylation blocker, azacitidine (Vidaza). (The findings were also published March 20 in Cancer Cell.) Azacitidine is also FDA approved for the treatment of MDS.

Dr. Baylin’s team found that low doses of the drugs had antitumor effects in cell lines and in mouse models of different cancer types—including leukemia and breast and colon cancer. Post-treatment analyses of treated cells showed decreased DNA methylation and the reactivation of genes that can affect tumor growth and cell death.

The concept behind epigenetic treatment is to “reprogram” the network of chemical changes that affect the DNA of cancer cells.

The study—which Dr. Cynthia Zahnow co-led and NCI, Stand Up To Cancer, and other groups helped fund—was not necessarily designed to assess the anticancer affects of the drugs, explained Dr. Baylin, but to better understand the epigenetic effects of low-dose treatment.

The cells were treated with the drugs for only 3 days, he noted. Next, the cells were “rested for 1 to 2 weeks, and then we put them into the mice to see what the cells ‘remembered’” in terms of gene activity that influenced their behavior. Tumor growth was substantially inhibited in mice that received the treated cells compared with mice that received untreated cells, implying that the demethylating drugs had produced a “memory” antitumor response.

The drugs, Dr. Baylin continued, also appear to alter gene activity in stem cell-like cancer cells—cells that are capable of self-renewal and that studies have suggested are inherently resistant to most current therapies.

Azacitidine and decitabine were tested extensively in the 1970s and 1980s but were too toxic for patients at the high doses needed to rapidly kill cancer cells. The FDA approved much lower doses of the drugs to treat MDS, however. Low doses of the drugs have also shown efficacyin some patients with AML. Although neither drug is FDA approved for AML, some doctors are using them off-label to treat the disease, Dr. Issa said.

Dr. Baylin believes that these new findings suggest that low-dose azacitidine and decitabine may be of benefit in multiple cancers. He also presented updated results from an early-phase trial (initially reported last year) of low-dose azacitidine combined with entinostat, another epigenetic drug, for patients with advanced lung cancer. Several patients have had strong tumor responses, he reported, some of which continued even after treatment was stopped.

A number of patients in the trial, many of whom had already received multiple prior therapies, “are going on to subsequent therapies,” Dr. Baylin said, “and we have started to see some very robust responses.”

For example, four patients with advanced lung cancer who participated in the azacitidine/etinostat trial at Johns Hopkins went on to receive one of two investigational immunotherapy drugs called anti-PD1 and anti-PD1-L1. Both drugs target molecules involved in blocking immune responses to tumors. Dr. Suzanne Topalian of the Johns Hopkins University Kimmel Cancer Center reported at an AACR plenary session that 3 of the 4 patients have had objective tumor responses.

A Maturing Field of Research

Although epigenetically directed therapy shows promise, there are still many unknowns, stressed Dr. Kornelia Polyak of the Dana-Farber Cancer Institute. Even though the clinical trial and the study found evidence of DNA demethylation, “it could be much more complex than that,” Dr. Polyak said.

The drugs may be having other effects, she continued. Epigenetic therapies may affect the structure of chromatin, the complex of DNA and proteins that forms chromosomes, which could cause side effects over a long period. In patients with advanced cancer, who have few treatment options, this may not be a significant concern, she noted. “But as we push these agents forward into earlier disease, it’s something we’ll need to look at very carefully,” Dr. Polyak said.

But from a clinical standpoint, she continued, demethylating agents are attractive “because even short-term treatment can have long-term effects. We’ve already seen that in MDS.”

“The field is maturing nicely,” Dr. Issa said. But more work is needed. “The [demethylating] drugs we have don’t cure patients, and we’re seeing resistance to these drugs develop.”

Dr. Baylin and Dr. Issa’s groups are studying DNA demethylating drugs in other cancer types and in combination with other therapies. “One of the biggest things we’re seeing is that these drugs are priming patients for better responses to subsequent therapies,” Dr. Baylin said.

Source: NCI Bulletin.

 

Some Melanoma Cells May Use the Body’s Immune Response to Escape Destruction.


Researchers have found evidence that some melanomas may use a protein induced by T cells—a type of immune cell that can attack cancer cells—to evade the immune system. The retrospective study involving tumor samples from 150 patients suggests that this protein, called B7-H1, suppresses T cells, ultimately preventing the immune system from destroying the cancer cells.

Treatments that block the B7-H1 pathway may, therefore, benefit patients with melanomas that express this protein, wrote Dr. Janis Taube of the Johns Hopkins Medical Institutions and her colleagues in a study published March 28 in Science Translational Medicine.

Almost 40 percent of the tumor samples expressed B7-H1, and expression of B7-H1 was strongly associated with the presence of tumor-infiltrating lymphocytes. Previous studies had shown that the immune-system protein interferon-gamma (IFN-gamma) induces B7-H1 expression in melanoma, and the Hopkins researchers found IFN-gamma in the B7-H1-positive tumors where the tumor cells came into contact with tumor-infiltrating lymphocytes.

The researchers then examined outcomes in patients with metastatic melanoma and found that overall survival was longer in patients with B7-H1-positive tumors than in those with B7-H1-negative tumors. This may be because B7-H1 expression indicates the presence of an active antitumor response that initially fends off cancer before it is turned off by the melanoma cells.

Monoclonal antibodies that target B7-H1, which may help restore the immune system’s recognition of melanoma cells, are being tested in clinical trials.

Source: NCI Bulletin.

 

 

Transplant Recipients at Higher Risk of Aggressive Form of Lymphoma.


Recipients of solid organ transplants are about 14 times more likely than the general population to develop diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin lymphoma (NHL). This finding and additional data from a comprehensive study of risk factors for this NHL subtype in transplant recipients were presented at the 2012 American Association for Cancer Research annual meeting.

Transplant recipients are known to be at increased risk for cancer, due in part to the immunosuppressive therapies they receive to prevent organ rejection. “NHL is one of the most common cancers diagnosed among transplant recipients, and there are many distinct histological types that are likely to have different causes,” explained the study’s senior investigator Dr. Lindsay Morton of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “Previous studies have looked at NHL, but have lacked the large number of patients or the detailed information needed to determine risk factors for NHL subtypes across all solid organ transplants.”

Dr. Todd Gibson of DCEG led the analysis using data from the Transplant Cancer Match Study, which links the Scientific Registry of Transplant Recipients with 14 population-based cancer registries. He and his colleagues identified 948 cases of DLBCL from among more than 175,000 transplant recipients. The risk of DLBCL was greater for younger transplant recipients, those who received a lung or pancreas transplant, and those who tested negative for the Epstein-Barr virus at the time of their transplant.

“Organ transplants are necessary and often life-saving treatments,” said Dr. Gibson. “But our work shows that these patients are at greatly increased risk for this particular subtype of lymphoma. We hope that our work can play a role in identifying the subgroup of people within the transplant population that is at greatest risk and can help inform efforts for surveillance and possibly prevention.”

Additional analyses are examining other risk factors for DLBCL in transplant recipients, including immunosuppressive medication use.

Source: NCI Bulletin.

 

Olaparib Delays Progression of Ovarian Cancer after Initial Treatment.


Long-term therapy with the targeted drug olaparib significantly improved progression-free survival among women with the most common type of ovarian cancer in a randomized, placebo-controlled phase II clinical trial. The interim findings were published online March 27 in the New England Journal of Medicine.

The trial included 265 women with relapsed, high-grade serous ovarian cancer who had responded to previous treatment with platinum-based chemotherapy. Patients were randomly assigned to receive either olaparib, a drug that blocks a DNA-repair protein called PARP, or a placebo.

Women who received olaparib experienced a median progression-free survival of 8.4 months, compared with 4.8 months for those who received the placebo. Patients in the olaparib group had a lower risk of disease progression after researchers took into account factors including BRCA gene mutation status, age, ancestry, and previous time to progression. Side effects were more common among women who received olaparib, but most of these were mild to moderate; few patients stopped therapy because of side effects.

The improvement in progression-free survival did not lead to improved overall survival. In an interim analysis, overall survival was virtually identical between the olaparib and placebo groups, at 29.7 months and 29.9 months, respectively.

Ovarian cancer usually responds to platinum-based combination chemotherapy, and if the disease returns, it may respond again to another platinum-based chemotherapy regimen. However, responses to subsequent courses of chemotherapy tend to be short-lived, explained the authors, who were led by Dr. Jonathan Ledermann of the University College London Cancer Institute.

This trial is one of several recent studies investigating whether maintenance therapy can help improve control of ovarian cancer. Researchers have found that maintenance therapy with either extended chemotherapy or the targeted agent bevacizumab may help delay cancer recurrence. Olaparib was recently found to induce tumor responses in women with recurrent, high-grade serous ovarian cancer or ovarian cancer associated with a BRCA1 or BRCA2 mutation.

The results from the current study show that “maintenance treatment with olaparib [is] associated with a significant improvement in progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer,” the authors wrote. Furthermore, the authors noted that 21 percent of patients were still receiving the drug at the time of writing, which “indicates that the disease is controlled for a prolonged period in some patients,” they concluded.

“This is an important gain for ovarian cancer patients,” commented Dr. Elise Kohn of NCI’s Center for Cancer Research. “The doubling in time to progression with olaparib is an exciting observation and should be the stimulus for further olaparib-based studies.”

Source: NCI Bulletin.

Anal HPV Infections and Precancerous Lesions Are Common in Men Who Have Sex with MenAnal HPV Infections and Precancerous Lesions Are Common in Men Who Have Sex with Men.


A large percentage of men who have sex with men (MSM) have anal human papillomavirus (HPV) infections and anal precancerous lesions, according to a meta-analysis of data from more than 50 studies. The rate is even higher among those infected with the human immunodeficiency virus (HIV). The findings were published online March 23 in Lancet Oncology.

MSM are known to be at elevated risk for developing HPV-associated anal cancer, but because of a lack of data it has been unclear whether anal cancer screening would be beneficial in this subgroup. Dorothy A. Machalek of the University of New South Wales in Sydney, Australia, and her colleagues examined 53 studies published before November 2011 to determine the frequency of HPV infections, anal lesions, and anal cancers in HIV-negative and HIV-positive MSM.

The researchers estimated that nearly three-quarters of HIV-positive MSM are infected with high-risk HPV types, which can cause cancer. In contrast, 37 percent of HIV-negative MSM were infected with the same high-risk types.

Moderate and severe anal lesions were detected in 29.1 percent of HIV-positive and 21.5 percent of HIV-negative MSM. The overall incidence of anal cancer in these two groups was 46 per 100,000 HIV-positive MSM and 5 per 100,000 HIV-negative MSM.

Using these data, the researchers estimated that, each year, high-grade lesions progress to anal cancer in 1 of 600 HIV-positive MSM and in 1 of 4,000 HIV-negative MSM. These progression rates are much lower than those seen for high-grade cervical lesions, which progress to cervical cancer in 1 of 80 women with those lesions every year, suggesting that anal cancer screening in MSM may need to be approached differently than cervical cancer screening.

However, in an accompanying editorial, Dr. Nicolas Wentzensen of NCI’s Division of Cancer Epidemiology and Genetics pointed out that progression rates for cervical cancer and anal cancer may not be directly comparable. The researchers “were not able to differentiate between moderate and severe dysplasia,” said Dr. Wentzensen. “The progression models in the cervix are based only on severe dysplasia. If we also included moderate dysplasia in the cervix, we might find similarly lower progression rates.”

The researchers and editorialist agree that more research is needed before anal cancer screening is recommended as part of standard clinical care for MSM. “There needs to be a lot of standardization and better appreciation for how [screening] methods perform and how the treatment triggered by those findings affects men,” said Dr. Wentzensen. “That is very important data to obtain before implementing widespread screening.”

Source: NCI Bulletin.