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Researchers discover melanoma drug target that occurs in prostate cancer

Anti-RAF drugs already in clinical trials for melanoma; could be evaluated in lethal RAF-driven prostate cancers

-added 06/08/2010

Ann Arbor - Researchers at the University of Michigan Comprehensive Cancer Center have discovered the RAF oncogene that drives fatal melanomas may also drive the aggressive forms of prostate cancer in the clinic.

The DNA rearrangement in prostate cancer cells, caused by chromosomal fusions of RAF, appears to be diagnostic, and permit the rapid creation of clinical trials that include both melanoma and prostate cancer patients in the same trial to receive anti-RAF drugs. Melanomas and prostate cancers are not usually associated with each other in treatment approaches.

The finding is reported online ahead of print publication in Nature Medicine.

The rearrangements, or gene fusion, occur in a pathway called RAF, which is known to play a role in cancer cell metastasis and death. Four "anti-RAF" drugs have already been developed to inhibit RAF and have entered clinical trials. RAF was not known to be involved in human prostate cancer biology until this finding. The U-M discovery suggests these RAF inhibitors could be an effective treatment for prostate cancer patients with this gene fusion marker.

The gene fusion was found using advanced techniques to sequence genes from prostate cancer tissues and using novel applications of computer science for cancer research. The researchers found the genes that rearranged and fused together involved the RAF1 and BRAF genes. Under the traditional cancer pathologist's microscope, however, a RAF fusion cannot be diagnosed from other DNA fusions or no fusions at all.

These researchers had previously shown that genes can trade places and fuse together, initiating the start of prostate cancer. This original gene fusion involves the ETS gene and occurs in at least half of all prostate cancers, but it has been challenging to find drugs that target these fusions.

The RAF gene fusions, meanwhile, are rare - occurring in only 2% of prostate cancers. But because it's an easy drug target, the implications could be far more exciting and immediate.

"For that 2% of 192,000 prostate cancer patients, we may have something that is targetable - we have drugs against the RAF pathway," says study author Arul Chinnaiyan, M.D. Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Endowed Professor of Pathology at the U-M Medical School. More men are estimated to have RAF prostate cancers than all the children diagnosed with leukemia this year in the United States, making this a very important finding in a common human cancer.

"The Chinnaiyan group with its leadership and team of young scientists have just discovered that some prostate cancer patients have a melanoma-type genetic engine on the inside, propelling a prostate cancer cell chassis on the outside, and the melanoma RAF engine-fusion propels that cell down the road towards metastasis at highest speed," said Dr. Jonathan Simons CEO and President of the Prostate Cancer Foundation. "You do not see connections between cancers in dermatology and urology under the microscope which was invented four centuries ago -- but you do 'see it' with the seminal invention of new chromosome fusion biotechnology from Michigan. The finding is also seminal because it is actionable with new targeted anti RAF medicines-- just as the Her2 diagnosis made herceptin actionable for treatment in breast cancer," added Simons.

The new RAF gene fusions do not occur in cancers with the previously discovered gene fusions, and the new fusions appear to be linked to more aggressive cancers.

In addition, the researchers found rare incidences of these BRAF and RAF1 rearrangements in gastric cancer and melanoma, suggesting the same approach could be taken with multiple cancer types to fully identify every cancer patient's tumor susceptibility to anti-RAF drugs.

"Rather than treating cancer as just an entity classified under the microscope as a 'prostate tumor' or a 'gastric tumor,' it needs to be thought of as a 'RAF mutant tumor.' We need to think about what the driving molecular basis for each tumor is and what oncologists can then do about that for the patients," says Chinnaiyan, who is also a Howard Hughes Medical Institute investigator and an American Cancer Society Research Professor.

The researchers tested two drugs - one already approved by the U.S. Food and Drug Administration as a RAF kinase inhibitor - in cells lines expressing the RAF fusions and found that the cells were exceptionally sensitive to these drugs.

Prostate cancer statistics: 192,280 Americans will be diagnosed with prostate cancer this year and 27,360 will die from the disease, according to the American Cancer Society. Researcher's estimate 3,600 of these diagnoses may be RAF-driven.

Additional authors: From U-M: Nallasivam Palanisamy, Bushra Ateeq, Shanker Kalyana-Sundaram, Kalpana Ramnarayanan, Sunita Shankar, Bo Han, Qi Cao, Xuhong Cao, Khalid Suleman, Chandan Kumar-Sinha, Saravana M. Dhanasekaran, Javed Siddiqui, Douglas R. Fullen, Timothy M. Johnson, Joel K. Greenson, Thomas J. Giordano, Scott A. Tomlins, Sooryanarayana Varambally, and Christopher Maher; from Weill Cornell Medical College: Dorothee Pflueger, Ying-bei Chen, Racquel Esgueva, Samprit Banerjee, Christopher J. LaFargue, Francesca Demichelis, and Mark A. Rubin; from University Hospital Ulm, Germany: Dorothee Pflueger, Peter Moeller, and Rainer Kuefer; from University of Calgary, Canada: Tarek A. Bismar; from Duke-NUS Graduate Medical School, Singapore: Patrick Tan.

Funding: National Institutes of Health, Early Detection Research Network, Prostate Specialized Program of Research Excellence (SPORE), National Center for Integrative Bioinformatics, National Center for Functional Genomics, U.S. Department of Defense, Prostate Cancer Foundation, Doris Duke Charitable Foundation, Burroughs Wellcome Foundation, Melanoma Research Alliance, American Association for Cancer Research, Canary Foundation, American Cancer Society, Genentech Foundation, Expedition Inspiration, Canadian Institute of Health Research.

Disclosure: The University of Michigan has filed for patent protection on this technology.

Reference: Nature Medicine, published online June 6, 2010, DOI: 10.1038/nm.2166.

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Written by: Nicole Fawcett

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