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Chemotalk NewsletterChemotalk Newsletter, Vol. 48: April 1, 2012 Good April, Everyone ... This is the first time I've added an attachment to the Newsletter. It focuses on a topic of vital importance to many women who have been treated for breast cancer: lymphedema. The article is from Cancernetwork, home of the journal "Oncology". Some of the recent treatments for this condition may be unknown to doctors treating us, so I've put the article into a Word document that can be printed, or passed along. * * * I always like to lead off with good news, so I'm starting with a study that's getting a lot of attention in the metastatic breast cancer community: Researchers Reveal How Cancer Cells Change Once They Spread to Distant Organs CANCER RESEARCH CENTER FINDINGS SUGGEST TARGETING A SINGLE PROTEIN MAY HELP STOP CANCER SPREAD Oncologists have known that in order for CANCER cells to spread, they must transform themselves so they can detach from a tumor and spread to a distant organ. Now, scientists at Weill Cornell Medical College have revealed critical steps in what happens next ‹ how these cells reverse the process, morphing back into classical cancer that can now grow into a new tumor. Their findings, published in Cancer Research, show that a single protein, versican, is key to this process in BREAST CANCER, the tumor they studied. When researchers stopped versican from functioning in mice, breast cancer could not "seed" themselves into the lungs and form secondary tumors. "Our findings both help us understand how breast cancer metastasizes to the lungs and ways to possibly prevent that deadly spread," says the study's senior investigator, Dr. Vivek Mittal, an associate professor of cell and developmental biology in cardiothoracic surgery and director of the Neuberger Berman Lung Cancer Laboratory at Weill Cornell Medical College. "These are exciting insights into a poorly investigated area," Dr. Mittal says. "There are no clinically approved drugs now that can effectively target metastatic lesions, which is why more than 90 percent of human cancer-related deaths come from spread of the disease from a primary tumor." "The results of this study are a critical step in deconstructing the process of metastases ‹ which is critical to curing our patients," says co-author Dr. Linda T. Vahdat, professor of medicine, chief of the Solid Tumor Service and director of the Breast Cancer Research Program at Weill Cornell. "As a direct result of this study, we are working on ways to interrupt the process by which tumors co-opt the infrastructure in our bodies to grow and spread." This important study starts to unravel the mechanistic basis of cancer metastases, not only in breast cancer but possibly in other types of cancer, says Dr. Nasser Altorki, the David B. Skinner Professor of Thoracic Surgery at Weill Cornell Medical College and director of the division of thoracic surgery at NewYork-Presbyterian/Weill Cornell. "The need for a prepared and receptive soil may be required for cancer cell seeding regardless of the primary cancer's site of origin." THE SEED AND THE SOIL Cancer researchers have believed that for a cancer to spread, its "seed" must find the right "soil" in a distant organ in order to thrive. And they have hypothesized that this seed is formed through a process known as epithelial-mesenchymal transition (EMT), in which cancer cells lose their sticky grip to other cells in a primary tumor and become more mobile, able to travel through the blood to a distant organ. But what happens next is conjecture. Scientists have speculated that the cells undergo a reverse process, called mesenchymal-epithelial transition (MET), in which the cancer seeds morph back into epithelial cells that can make contact with tissue and integrate in the new organ. Little is known about MET compared to EMT. In this study, Dr. Mittal, along with his colleagues, studied mouse models of spontaneous breast cancer development. They first discovered that primary breast tumors send a signal that forces bone-marrow-derived hematopoietic cells to move into the lungs of the mice. "This appears to be the soil the cancer seeds need," says Dr. Mittal. The next question was obvious: What is it about the soil that helps the seed? The team found that a subtype of these bone marrow cells expressed versican, which allowed the cancer cells, once they traveled to the lungs, to morph back into epithelial cells. "The primary tumor sets up the lung microenvironment to promote metastasis," he says. "MET resulted not from properties within the cancer cell itself, but due to a unique crosstalk between the microenvironment and tumor cells in the lung." In their next experiment, the researchers blocked versican production by injecting small interfering RNAs (siRNAs) in the bone marrow that silenced the versican gene, which prevented MET and blocked tumor outgrowth in the lung. HUMAN TUMORS EXPRESS VERSICAN Next, they investigated human breast metastases to the lung, utilizing lung samples obtained from breast cancer patients contributed by researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. "We found versican was highly expressed in those lung tumors, which matched what we found in our mice," Dr. Mittal says. "This all made sense to us, because versican has been linked to cancer progression, although no one knew why. "This is the first study demonstrating the significance of MET in the formation of macrometastases in distant organs," Dr. Mittal says. "Given the findings, we now have a potential strategy to stop cancer spread before it starts, or to shut it down if it has already occurred." The study was funded by support from the Neuberger Berman Lung Cancer Laboratory, the Robert I. Goldman Foundation and National Cancer Institute support of the Cornell Center on the Microenvironment and Metastasis. * * * And some not-so-good news: 'PERSONALIZED MEDICINE' HITS A BUMP By Ron Winslow A tumor's genetic makeup can vary significantly even within the same tumor sample, researchers said, a finding that poses new challenges to the personalized-medicine movement in CANCER. One big implication of the new research, published in the New England Journal of Medicine, is that analyzing only a single sample of a patient's tumor‹the current practice‹may miss important genetic mutations that affect the course of the disease. That, in turn, could hinder emerging efforts to match patients with drugs that target the mutations affecting their tumors, a basic strategy of personalized medicine. The findings don't diminish enthusiasm for the idea that genetic knowledge about tumors can transform cancer care, the researchers said. But it could make personalized treatment more complex‹and more costly. "It's a sobering finding," said Andrew Futreal, a co-author of the study who until recently was director of cancer genetics and genomics at Wellcome Trust Sanger Institute in London. In an editorial accompanying the study, Dan L. Longo, an editor at the journal, suggested the varied genetic makeup of tumors described in the study stands in contrast to "overoptimism" among proponents of personalized medicine. The report indicates that matching tumors and treatments based on genetic characteristics won't be as simple as some suggest, he wrote. In the study, led by Marco Gerlinger and Charles Swanton at the London Research Institute, researchers obtained tumor tissue from four patients with KIDNEY CANCER. Using DNA sequencing and other techniques, they obtained genetic profiles from as many as nine places in one sample from the original tumor and three from sites where the tumor had spread, or metastasized. Among the findings: Only about one-third of 128 mutations they detected were present in all of the sites studied. In addition, they identified in a single tumor a genetic signature associated with a good prognosis‹and another linked to a poor one. Moreover, there were significant differences between mutations in the original tumor and the site of metastasis, suggesting the need for additional biopsies as a patient's cancer progresses. With a single biopsy, "you might miss the connection between the mutation and whatever outcome you are looking at," said Dr. Futreal. The researchers cautioned that the study was done in only one type of cancer, and that more research is needed to see how much genetic variation there is in other types of tumors. But the findings describe in more precise detail what many cancer doctors and researchers have long been aware of, said Jennifer Litton, a breast cancer specialist at M.D. Anderson Cancer Center in Houston who wasn't involved in the study. Tumors "are really like a moving target," she said. "As they are growing or when they're exposed to different drugs, they change" from their original form. "That's what we're struggling against when we try to eradicate metastatic disease." She said she recently treated a woman whose breast cancer initially tested negative for a mutation that causes elevated levels of a cancer-promoting protein called HER2, which would have made her a candidate for the drug Herceptin. But a pathologist who examined the tumor after it was surgically removed noticed that some parts of it seemed more aggressive than others. A re-analysis found it to be HER2-positive, and Dr. Litton put her on Herceptin. The report comes amid surging interest at major cancer centers in analyzing tumor tissue with DNA sequencing and other technologies to determine customized treatments. Scott Kopetz, who specializes in GASTROINTESTINAL CANCER at M.D. Anderson, said the research underscores the need to test patients' tumors at the time of treatment since Dr. Kopetz said getting additional biopsies from patients could be costly and inconvenient for patients, but the tumor discovered at diagnosis "may be very different from the tumor that is threatening their lives here and how." Some of the differences may be the result of the initial treatment of the tumor and others "because [the cancer] has spread and gone to different locations in the body." Other experts noted that despite the challenges identified in the study, the most important mutations that actually drive the cancer were consistently present at the various sites tested, indicating it still is worthwhile to target those anomalies. In addition, some of the findings offered potential new treatment targets to attack the cancer. The study was funded by the U.K.'s Medical Research Council and other cancer organizations as well as Novartis SA, which is sponsoring a broader study of one of its drugs that the four patients were enrolled in. * * *
Trials have a huge bearing on the outcome of any patients' future. Here's one that deserves attention: TEVA, ONCOGENEX AMP UP PHASE III FIGHT AGAINST PROSTATE CANCER By Ryan McBride As the field of contenders advancing new drugs for PROSTATE CANCER gets crowded, OncoGenex Pharmaceuticals and partner Teva Pharmaceutical are putting additional muscle behind their late-stage horse in the race, a compound called custirsen. OncoGenex revealed the revamped custirsen strategy, saying the Bothell, WA, company and Teva plan to start a new Phase III trial for the drug in combination with Sanofi's chemotherapy drug Jevtana with the goal of improving survival of prostate cancer patients. The companies are nixing a trial called Saturn that was intended to test custirsen with reduction in cancer-related pain as the main endpoint. Meanwhile, the developers are boosting enrollment from 800 patients to 1,000 patients in a separate Phase III trial called Synergy, which aims to test custirsen in patients with chemo castration-resistant prostate cancer. Prostate cancer--which is the second-most common cancer among U.S. men and is projected to cause 28,170 deaths in the country this year--has garnered lots of interest among biopharma companies. OncoGenex's retooled trial plan comes on the heels of Johnson & Johnson's announcement of early success in a trial with the drug Zytiga in prostate cancer patients who had not yet been treated with CHEMO, a development that could greatly expand the market for the drug. And Medivation and Exelixis are in the hunt with drugs to serve segments of the prostate cancer market. "I think there's going to be a really important need for an agent like custirsen to improve on chemotherapy as the other agents migrate to the pre-chemotherapy setting," OncoGenex CEO Scott Cormack said. As Xconomy reports, OncoGenex expects to shell out more cash this year to bankroll the updated trial plan for custirsen, essentially doubling down on its original bet on the program to see that it has its best shot at FDA approval. * * *
Anti-rejection medications are chemotherapy drugs, so this discovery is positioned to make a huge difference in the lives of transplant patients: STEM CELLS END NEED FOR ANTI-REJECTION MEDS By Mark Hollmer Organ donor stem cells helped five patients with kidney transplants wean themselves off organ rejection drugs within a year of their operation, BBC News reports. Scientists at the University of Louisville in Kentucky and Northwestern Memorial Hospital in Chicago generated the discovery, and the journal Science Translational Medicine highlights the details. It is true, as the BBC points out, that doctors have tested stem cells from organ donors before in transplants, with some promise. But this is the first time they've been used from donors who are not related to the recipients or have similar immunological systems, and it points to potentially using stem cells to modify a patient's immune system so it doesn't attack donated organs. That means this finding has a potentially enormous impact. Patients who undergo transplants survive on anti-rejection medication that suppresses the immune system. They're expensive, and a patient, once recovered, remains vulnerable as a result of the medication to infection, and health problems like high blood pressure and diabetes, the BBC notes. And there is still a risk of organ rejection. But before we get really excited here, many more patients must be tested. We'll be more excited when dozens, and even hundreds of patients end up with the same result. Eight patients took part in the study, undergoing a kidney transplant from a live donor, from whom doctors also harvested blood stem cells. The recipients all were treated with radiotherapy and CHEMOTHERAPY to suppress their immune systems, underwent the transplant and then were treated with the organ donor's stem cells a few days after the surgery. As the BBC reports, patients started with typical anti-rejection drugs, but 5 of the 8 managed to stop using them gradually within 12 months. Stem cells are showing some great versatility in preclinical and early-stage clinical research, as a treatment for liver damage, heart attacks and also a potential fertility drug, among other indications. * * *
NEW MOLECULAR DISCOVERY COULD MEAN FEWER CHEMO SIDE EFFECTS While it can often work wonders against invading CANCER cells, CHEMOTHERAPY can also bring on very undesirable side effects, such as hair loss, nausea and vomiting. But the recent discovery of the structure of a certain molecule could potentially lead to the development of new drugs that could target tumors while avoiding damage to healthy tissue, resulting in possibly fewer side effects. The molecule, known as a transporter, can carry specific anti-cancer and antiviral drugs directly into cells. The drugs can then prevent tumor cells from dividing and multiplying. "If you really know what this transporter looks like, you can potentially design a cancer drug to be recognized by this transporter and carried into the cells, and you can lower the dose of cancer drugs and decrease the side effects as a result," said Seok-Yong Lee, an assistant professor of biochemistry at Duke University School of Medicine and lead author of the research, published in the journal Nature. Experts not involved with Lee's research say development of such drugs is still a very long way off, but focusing on the ability of a drug to get into cancer cells makes scientific sense. "If it could be manipulated to help with drug delivery or avoiding the toxicity of these drugs. It could have clinical relevance years from now," said Dr. Minetta Liu, director of translational breast cancer research at the Georgetown Lombardi Comprehensive Cancer Center in Washington. "We have these very effective drugs, and the question is can we make them even more effective by giving them the homing devices for cancer cells so they can avoid normal cells?" "There are two newer compounds that are doing that now. They can invade cells so we don't have to give as much of it to target tumors," said Dr. Stefan Gluck, a professor of medicine at the University of Miami's Miller School of Medicine. Many other drugs that treat cancer, however, are administered intravenously and are distributed throughout the body. "We need to achieve specific levels in cancer tissues, but at the same time, that level will be reached in normal tissues. Some of the normal tissues are sensitive to chemotherapy and can be harmed," Gluck explained. Damaging normal tissues can lead to a number of the effects often associated with chemotherapy. * * * ADDING PREDNISONE TO RHEUMATOID ARTHRITIS TREATMENT IMPROVES SYMPTOMS Patients¹ RHEUMATOID ARTHRITIS symptoms improved after adding prednisone at the start of a methotrexate-based treatment strategy, according to research published in the Annals of Internal Medicine. The study was conducted by several health facilities on behalf of the Utrecht Rheumatoid Arthritis Cohort Study Group. Researchers conducted a 2-year prospective, randomized, multicenter trial at 7 hospitals in The Netherlands, enrolling 236 patients with early RA (less than a year). Patients were randomly assigned to a methotrexate-based, tight-control strategy, starting with either methotrexate and 10 mg/d of prednisone, or methotrexate and placebo. Erosive joint damage after 2 years was limited and less in the group receiving methotrexate and prednisone than in the group receiving methotrexate and placebo. According to researchers, the methotrexate and prednisone strategy was also more effective in reducing disease activity and physical disability and achieving sustained remission. The need for additional treatment such as cyclosporine or adalimumab in the methotrexate and prednisone group was significantly less than that in the methotrexate and placebo group, according to the researchers. The reduced need for additional treatments, along with better physical functioning and quality of life, could affect cost-effectiveness of treating RA in the future, the researchers wrote. ³On the basis of these data, a cost-effectiveness trial comparing a tight control strategy of methotrexate and prednisone with a strategy directly starting with a biologic agent seems justified,² the researchers stated. * * *
LEUKEMIA GENE MUTATIONS LINKED TO SURVIVAL ODDS Advances in genetic profiling are paving the way for more precise, and effective, treatment of the aggressive bone marrow cancer known as ACUTE MYLOGENUS LEUKEMIA, or AML, according to new research. Two studies, published in the latest edition of the New England Journal of Medicine, show that genetic testing can guide doctors in how best to use current therapies as well as identify new drug targets. "As lots of studies identify new alterations in genes in leukemia and other cancers, we need to begin to understand how these alterations in DNA can predict outcomes and determine differences in treatment," said Dr. Ross Levine of Memorial Sloan-Kettering Cancer Center in New York, the lead author of one of the studies. Such personalized therapy is considered the new frontier for medical practice, and hopes for its success underpin a $5.7 billion hostile bid by drugmaker Roche Holding for gene sequencing company Illumina. The second study, from Washington University in St. Louis, found that 85 percent of bone marrow cells in patients with myelodysplastic syndrome, a blood-related disorder that can precede AML, were linked to mutations in progressive cancer. The Sloan-Kettering study analyzed bone marrow samples from 502 AML patients for mutations in 18 genes associated with the disease. The researchers were able to categorize two-thirds of the patients into groups clearly defined by their survival chances. The study found that high-dose CHEMOTHERAPY improved the rate of survival for patients with three specific genetic mutations, compared with standard-dose chemo. It also showed that genetic profiling makes it possible to more precisely determine which patients are most likely to have their leukemia return after treatment. AML is typically cured in about 40 percent of adults between the ages of 18 and 60, according to Levine. "We were able to identify a very large subset of patients who need new therapies," he said. "Another set was found to do incredibly well with existing therapies, and that is very informative." The American Cancer Society estimates that AML will be diagnosed in nearly 14,000 Americans this year and that more than 10,000 people will die from the disease. Gene profiling for AML, and most other cancers, is not currently part of standard clinical practice. "There are aspects of this that are ready to be adopted," Levine said, adding that the immediate hurdles are the cost of genetic testing and intellectual property rights pertaining to genes that have been patented. And questions remain about the number of genetic mutations that AML patients should be screened for. "It is exciting to think that the goal of personalized medicine is quickly approaching," Dr. Lucy Godley said in a NEJM editorial. "But it will require careful thought to implement genomic-based clinical evaluation in a way that is meaningful for patients." * * *
The next piece concerns an exciting discovery that is still in stages so early that there is no study. But you can bet there will be a study, and if it works out well, it will translate into treatment for many, if not all cancer patients: MAYO CLINIC CONCOCTS SKIN CANCEER VACCINE USING VIRUS, MELANOMA DNA By Mark Hollmer A relative of the rabies virus blended with human MELANOMA DNA eliminated tumors in 60% of mice over about three months, as part of a potentially groundbreaking preclinical trial fueled by research led by the Mayo Clinic. Consider the implications here: Scientists essentially used CANCER cells to boost the immune system's response in order to kill cancer. The Mayo Clinic team, working with colleagues at the University of Leeds in the U.K., touted their technique as something new, combining a genetically altered version of the vesicular stomatitis virus with a wide spectrum of melanoma cancer cell genes into a vaccine that hits the tumor itself. Quite simply, the vaccine is designed to make the cancer cells more visible to the immune system, training it to attack and defeat them. The idea, they explain, is that the immune system is highly resistant to the vesicular stomatitis virus. It reacts to the modified virus, which then displays a wide variety of cancer-related antigens that should be eliminated. Ordinarily, the researchers note, tumors don't show that many antigens on their own, reflecting a vexing genetic ability to adapt to the immune system and avoid its wrath. "We believe that this new technique will help us to identify a whole set of genes that encode antigens that are important in stimulating the immune system to reject cancer," Mayo researcher and co-author Richard Vile said in a statement. The idea of training the immune system to better recognize and defeat a cancer through an immunotherapeutic vaccine is a profound one that researchers have struggled with for years. We have the Mayo Clinic asserting that this time is different, compared with previous immunotherapy research that hasn't been able to isolate a large number of tumor cell antigens. While 60% of mice in the test showed progress, 40% did not--which may ultimately leave such a treatment helping some patients but not many others, even if it reaches human testing and approval. Meanwhile, the Mayo Clinic is plowing ahead, and envisions further studies that could test lung, brain and other more aggressive cancers. For more details on their melanoma vaccine research, read the journal Nature Biotechnology. * * * Finally, ending on a solid high note: GENENTECH DRUG SHOWS POSITIVE PHASE III RESULTS IN HER2-POSITIVE PATIENTS By Allie Wickman Genentech, a member of the Roche Group, today announced topline results of EMILIA, the first randomized Phase III study of trastuzumab emtansine (T-DM1). The study enrolled people with HER2-positive METASTATIC BREAST CANCER who had previously received treatment with Herceptin® (trastuzumab) and a taxane CHEMOTHERAPY. The study showed people who received trastuzumab emtansine lived significantly longer without their disease getting worse (progression-free survival, or PFS) compared to those who received lapatinib plus Xeloda® (capecitabine). Final results for overall survival (OS), a co-primary efficacy endpoint of EMILIA, are not yet mature. The safety profile of trastuzumab emtansine was consistent with that seen in previous studies. These data will be submitted for presentation at an upcoming medical meeting. Trastuzumab emtansine is an investigational medicine known as an antibody-drug conjugate. It is comprised of the antibody trastuzumab and the chemotherapy DM1 attached together using a stable linker. It is designed to target and inhibit HER2 signaling and deliver the chemotherapy directly inside HER2-positive cancer cells. * * * See you next month... * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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