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U-M researchers find family of ‘on switches’ that cause prostate cancer

Gene fusions trigger cancer growth, could impact treatment choices

ANN ARBOR, Mich. — Researchers at the University of Michigan Comprehensive Cancer Center have discovered how genes turn on the switch that leads to prostate cancer.

The team discovered that pieces of two chromosomes can trade places with each other and cause two genes to fuse together. The fused genes then override the “off” switch that keeps cells from growing uncontrollably, causing prostate cancer to develop.

By testing these gene fusions in mice and in cell cultures, the researchers showed that the fusions are what cause prostate cancer to develop. But it’s not just one set of genes that fuse. The researchers found that any one of several in a family of genes can become scrambled and fuse. Results of the study appear in the Aug. 2 issue of Nature.

“Each of these switches, or gene fusions, represent different molecular subtypes. This tells us there’s not just one type of prostate cancer. It’s a more complex disease and potentially needs to be treated differently in each patient,” says lead study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology, a new U-M center whose goal is to translate research into real world practice.

The gene fusion research is the centerpiece project of the new center. In the current study, researchers found one of several abnormal gene fusions in the prostate cancer tissue samples they tested. In 2005, the researchers identified a prostate-specific gene called TMPRSS2, which fuses with either ERG or ETV1, two genes known to be involved in several types of cancer.

The Nature paper reports on five additional genes that fuse with ERG or ETV1 to cause prostate cancer. Gene fusions were involved in 60 percent to 70 percent of the prostate cancer cell lines the researchers looked at. The genes involved are all controlled by a different mechanism. For example, four of the genes are regulated by androgen, a male sex hormone known to fuel prostate cancer. Androgen deprivation is a common therapy for prostate cancer.

Knowing which gene fusion is involved in an individual patient’s tumor could impact treatment options. If an androgen-regulated gene is involved, androgen therapy would be appropriate. But if the gene fusion involves a gene that represses androgen, the anti-androgen therapy could encourage the cancer’s growth. This may also explain why androgen treatment is not effective for some prostate cancers.

“Typing someone’s prostate cancer by gene fusion can affect the treatment given. We would not want to give androgen to someone whose prostate cancer gene fusion is not regulated by androgen,” says Chinnaiyan, who is the S.P. Hicks Collegiate Professor of Pathology at the U-M Medical School.

Rearrangements in chromosomes and fused genes are known to play a role in blood cell cancers like leukemia and lymphoma, and in Ewing’s sarcoma. A fused gene combination that plays a role in chronic myelogenous leukemia led researchers to develop the drug Gleevec, which has dramatically improved survival rates for that disease.

Chinnaiyan believes the prostate gene fusions will eventually lead to similar treatments for prostate cancer.

“More immediately, we hope to develop tests for diagnosis or prognosis. But long-term, we hope this will lead to better therapies to treat prostate cancer. The key challenge is to find a drug that would go after this gene fusion,” Chinnaiyan says.

The gene fusion technology has been licensed to San Diego-based Gen-Probe Inc., which is working on a screening tool to detect gene fusions in urine. The tool could one day supplement or replace the prostate specific antigen, or PSA, test currently used to screen for prostate cancer.

The idea of translating laboratory research findings into a test or treatment that will impact patients is central to the new Michigan Center for Translational Pathology. The center brings together experts in genomics, proteomics and bioinformatics to look at common patterns and potential targets in cancer and other diseases. This is the first center of its kind in the nation in that it is associated with one of 39 National Cancer Institute-designated “comprehensive” cancer centers, a premier medical school and a large health system with both clinicians and patients.

The center’s goal is to study the genes, proteins and other markers on cells to develop new diagnostic tests or screening tools as well as targeted treatments for cancer and other diseases, with the key being to translate these laboratory discoveries into clinical applications.

Chinnaiyan and his team have received numerous awards and honors, including the American Association for Cancer Research Team Science Award for their previously published work on gene fusions, and the Specialized Program of Research Excellence Outstanding Investigator award. The new Center for Translational Pathology supported in part by the Prostate Cancer Foundation, which has offered to match up to $1 million dollars in donations to support work related to developing therapies against prostate cancer gene fusions at the university.

“Mapping of the human genome was only the beginning. Equipped with the comprehensive analysis of the human genome, we can now systematically examine the blueprint of disease at the molecular level. This essential knowledge may lead to better diagnostic tests and promising new treatments for cancer, cardiovascular disease, diabetes and other illnesses,” Chinnaiyan says.

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For information about the Michigan Center for Translational Pathology, go to http://www.med.umich.edu/mctp.

About 218,890 men will be diagnosed with prostate cancer this year, and 27,050 will die from the disease, according to the American Cancer Society. The gene fusion work is not currently available for treatment or diagnosis, and no clinical trials are currently recruiting. For information about prostate cancer and currently available treatments, go to http://www.mcancer.org or call the U-M Cancer AnswerLine at 800-865-1125.

In addition to Chinnaiyan, U-M study authors were Scott Tomlins; Saravana Dhanasekaran, Ph.D.; Bharathi Laxman; Qi Cao; Beth Helgeson; Xuhong Cao; David Morris, M.D.; Anjana Menon; Xiaojun Jing; Bo Han; James Montie, M.D.; Kenneth Pienta, M.D.; Diane Roulston; Rajal Shah, M.D.; Sooryanarayana Varambally, Ph.D.; and Rohit Mehra, M.D. Mark Rubin, M.D., from Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School is also a study author.

Funding for the study came from the U.S. Department of Defense, the National Institutes of Health, the Early Detection Research Network, the Prostate Cancer Foundation and Gen-Probe Inc.

The University of Michigan has filed for a patent on the detection of gene fusions in prostate cancer, on which Tomlins, Mehra, Rubin and Chinnaiyan are co-inventors. The diagnostic field of use has been licensed to Gen-Probe Inc. Chinnaiyan also has a sponsored research agreement with Gen-Probe; however, GenProbe has had no role in the design or experimentation of this study, nor has it participated in the writing of the manuscript.

Reference: Nature, Vol. 448, No. 7153, Aug. 2, 2007

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System

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August 1, 2007 Posted by | acute lymphoblastic leukemia, Alberta, Baltimore, Barcelona, Bethesda, Calgary, Canada, Cancer, Cancer Biology, Cancer Biology and Therapy, Chemotherapy, Childhood Lukemia, France, Genes, Genetic, Genetic Link, Genetics, Genome, Genomic, Germany, Global, Global Health Vision, Global News, Health Canada, Human Genome, Irvine, Italy, Japan, journal Nature Genetics, Leukemia, Lung Cancer, Medical Journals, Nature Genetics, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, non-Hodgkin's lymphoma, Nova Scotia, Oncology, Osaka, Ottawa, Prince Edward Island, Public Health, Quebec, Research, RSS, RSS Feed, Slovakia, Spain, Toronto, UK, University of Michigan, US, Virginia, Washington DC, Washington DC City Feed, World News | 3 Comments

Flip of genetic switch causes cancers in mice to self-destruct, Stanford researchers find

STANFORD, Calif. – Killing cancerous tumors isn’t easy, as anyone who has suffered through chemotherapy can attest. But a new study in mice shows that switching off a single malfunctioning gene can halt the limitless division of tumor cells and turn them back to the path of their own planned obsolescence.

The surprising possibility that a cell’s own natural mechanism for ensuring its mortality could be used to vanquish tumors opens the door to a new approach to developing drugs to treat cancer patients, according to Dean Felsher, MD, PhD, associate professor of medicine (oncology) and of pathology at the Stanford University School of Medicine. Felsher is the senior author of the study to be published July 30 in the advance online version of the Proceedings of the National Academy of Sciences.

“Our research implies that by shutting off a critical cancer gene, tumor cells can realize that they are broken and restore this physiologic fail-safe program,” said Felsher.

Cancer can be notoriously resistant to medical treatment. Not only do cancer cells proliferate uncontrollably, they somehow circumvent the mechanism that causes normal cells to die when they get old or malfunction. That makes cancer cells effectively immortal unless doctors manage to squelch them.

The gene Felsher’s team studied produces a protein called Myc (pronounced “mick”), which promotes cell division. A mutation of the gene causes cells to overproduce the protein, prompting perpetual cell division and tumor growth. By turning off the mutated gene, the researchers found that not only did uncontrolled cell division cease, but the cells also reactivated a normal physiological mechanism, called senescence, which makes it possible for a cell to eventually die.

“What was unexpected was just the fact that cancer cells had retained the ability to undergo senescence at all,” said Felsher. Cancer researchers had long thought the senescence process had to be irreversibly disrupted for a tumor to develop.

The researchers worked with a series of mice engineered to have Myc-triggered cancers of either the liver, blood or bones, along with a specially constructed version of the Myc gene that they could switch off by feeding the mice antibiotics. When the mice dined on doses of the drugs, invariably, the tumors ceased growing and then diminished, with some disappearing over the course of just a few days.

Although Felsher’s lab had previously shown that mouse tumors diminished and disappeared when Myc was switched off, they hadn’t been sure how the process actually worked. Historically, most research involving genetic methods of battling cancer cells has focused on reactivating genes called tumor-suppressor genes, which are generally overcome by a proliferating cancer. No one had explored the idea that senescence might play a key role in diminishing tumors.

Felsher described senescence as acting like a fail-safe mechanism to stop cancer. When a cell detects a deleterious mutation, it launches the senescence process, resulting in the permanent loss of the cell’s ability to proliferate, thus halting any cancer.

“In order to become tumor cells, those cells have to overcome senescence,” said Chi-Hwa Wu, PhD, postdoctoral researcher in Felsher’s lab and first author of the study. Wu had the inspiration to explore whether the sudden diminishment they had observed in the tumors might be due to the reactivation of some latent remnant of the trigger for senescence.

Through a series of experiments looking at enzymes associated with the senescence process, as well as some molecular markers, Wu confirmed her suspicion. And not only was senescence occurring in cells that had been thought to be incapable of it, the process was reactivated in all the different tumors they studied.

Consider it a cell version of the Jekyll-and-Hyde transformation. “It’s sort of like Mr. Hyde realizing that there’s something wrong with him and then being able to put himself back into his normal state as Dr. Jekyll,” Felsher said.

In addition to the deepened understanding of how the process of senescence works, Felsher and Wu see a lot of potential for new approaches to treating cancer, beyond the traditional tactic of trying to kill cancer cells directly. “This work implies that maybe part of the strategy should involve figuring out how to get the cancer cells to just be allowed to do what they originally wanted to do anyway, which is to not be proliferating endlessly and growing uncontrolled,” said Felsher.

The next step for the team is to see how well the approach works in human cancer cells. “And we’re also trying to figure out what the mechanism is,” Felsher said. “What are the molecular mechanisms of this, so that we can figure out how to better treat cancer””

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Other authors on the research paper are Jan van Riggelen, PhD, postdoctoral researcher; Alper Yetil, graduate student in cancer biology; Alice Fan, MD, instructor in medicine (oncology), and medical student Pavan Bachireddy.

The study was funded by the National Cancer Institute, the National Institutes of Health, the Leukemia and Lymphoma Society, the Burroughs Wellcome Fund, the Damon Runyon Lilly Clinical Investigator Award, the Lymphoma Research Foundation and the Howard Hughes Medical Institute.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions – Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at http://mednews.stanford.edu.

Contact: Lou Bergeron
louisb3@stanford.edu
650-723-3900
Stanford University Medical Center

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July 31, 2007 Posted by | acute lymphoblastic leukemia, Alberta, Baltimore, Barcelona, Bethesda, Biological Sciences, Calgary, Canada, Cancer, Cancer Biology, Cancer Biology and Therapy, Childhood Lukemia, France, Genes, Genetic, Genetic Link, Genetics, Genome, Genomic, Germany, Global, Global Health Vision, Global News, Health Canada, Howard Hughes Medical Institute, Human Genome, Italy, Japan, Leukemia, Medical Journals, Molecular Biology, National Cancer Institute, National Institutes of Health, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, non-Hodgkin's lymphoma, Nova Scotia, Nunavut, Osaka, Ottawa, Prince Edward Island, Public Health, Quebec, Research, RSS, RSS Feed, Toronto, UK, US, Virginia, Washington DC, Washington DC City Feed, Wellcome Trust, World News | Leave a comment

U-M study finds lymphoma drug effective over long term

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System

86 percent of patients treated with Bexxar survived after 8 years of follow-up

ANN ARBOR, Mich. — Eight years after being treated with a new drug for non-Hodgkin’s lymphoma, 86 percent of patients were still alive and half had not had a relapse of their disease, according to researchers from the University of Michigan Comprehensive Cancer Center.

The patients had follicular lymphoma, a type of cancer that is not considered to be curable using traditional treatments. Even if patients initially respond to treatment, the disease almost always comes back and becomes more difficult to treat.

The study followed 76 patients with follicular non-Hodgkin’s lymphoma, a cancer of the lymph system, who received the radioimmunotherapy drug Bexxar as their first treatment for the disease. Ninety-five percent of the patients saw their tumors shrink from the treatment and three-quarters of patients went into complete remission. Patients were followed for a median of eight years, and nearly two-thirds have remained in complete remission eight years after treatment.

“For years we have known radioimmunotherapy such as Bexxar is one of the most effective treatments for patients with relapsed follicular lymphoma. These data show Bexxar is particularly effective when used as a frontline treatment,” says Mark Kaminski, M.D., professor of internal medicine at the U-M Medical School. Kaminski will present these results June 4 at the American Society of Clinical Oncology annual meeting in Chicago.

“These results compare quite favorably with those achieved with state-of-the-art chemotherapy regimens that take months to deliver. But Bexxar is given as a single treatment, completed within one week, which makes it an extremely convenient regimen for patients,” Kaminski says.

Non-Hodgkin’s lymphoma, the nation’s sixth leading cause of cancer death, is a cancer of the lymph system, which is part of the immune system. Follicular lymphoma is the second most common type of non-Hodgkin’s lymphoma. Lymphoma spreads easily through the lymph system and the bloodstream and consequently tends to be widespread when it is diagnosed. Traditional treatment often involves intensive chemotherapy, or a combination of chemotherapy and the monoclonal antibody rituximab. These treatments are usually given every three weeks over a span of up to six months and can cause many unpleasant side effects, including nausea, hair loss and infections.

Bexxar, whose chemical name is tositumomab and iodine I 131 tositumomab, combines an antibody that seeks out cancer cells, and a radioactive form of the element iodine. When injected, it travels like a guided missile through the bloodstream to bind to a protein found on the surface of the cancerous cells. The radiation zaps these malignant cells with minimal exposure to normal tissues.

With the Bexxar therapeutic regimen, a patient receives an injected test dose of radioactive Bexxar, followed one to two weeks later with a custom-tailored therapeutic dose. After that, the therapy is considered complete. The most common side effect is a temporary lowering of blood counts several weeks after the treatment. There is no hair loss and nausea is rare.

Kaminski and his colleague Richard Wahl (formerly at U-M and now at Johns Hopkins University) developed the Bexxar regimen, which received approval from the U.S. Food and Drug Administration in June 2003 to treat follicular non-Hodgkin’s lymphoma after other treatments have failed. The current results involve Bexxar as a first-line treatment for this disease.

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In addition to Kaminski and Wahl, U-M study authors were Judith Estes, R.N., a nurse practitioner; Missy Tuck, clinical research coordinator; and Charles Ross, M.D., associate professor of pathology.

Funding for the study was from the National Institutes of Health and GlaxoSmithKline. The University of Michigan holds patents for the Bexxar therapeutic regimen, which is marketed by GlaxoSmithKline under a licensing agreement. U-M receives royalties on sales of Bexxar, a portion of which goes to Kaminski and his co-inventors.

For information about non-Hodgkin’s lymphoma, visit http://www.mcancer.org or call the Cancer AnswerLine at 800-865-1125. For information about Bexxar from its manufacturer, call 877-4-BEXXAR or visit http://www.bexxar.com.

Reference: American Society of Clinical Oncology 43rd annual meeting, June 1-5, 2007, Chicago, Ill. Abstract No. 8033.

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June 4, 2007 Posted by | Calgary, Cancer, Global, Global Health Vision, Global News, Johns Hopkins University, News, News Australia, News Canada, News UK, News US, non-Hodgkin's lymphoma, Research, University of Michigan, Virginia, Washington DC, World News | Leave a comment