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INVESTIGATOR PROFILES |
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SENIOR SCIENTIST ADJUNCT PROFESSOR IACUC CHAIR IACUC MEMBER PAST PRESIDENT CONTACT
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Ralph Buttyan, Ph.D.Research FocusProstate cancer will kill almost 28,000 men in the United States this year. Virtually all of these men will die with the form of the disease referred to as “castrate resistant prostate cancer” (CRPC) because it is able to grow in the androgen-depleted milieu of a hormone-treated prostate cancer patient. My laboratory studies CRPC and we seek to define and understand the molecules and signaling processes that enable these cancer cells to grow in a low androgen environment. Our ultimate goal is to identify new treatments for prostate cancer that target the molecules involved in CRPC growth so that we can significantly reduce mortality from prostate cancer. To this end, we recognize that a “reactivated” androgen signaling pathway, in which the androgen receptor (AR) protein of a prostate cancer cell remains functional, despite low systemic androgen, is the likely culprit for CRPC cell growth. How can we interfere with this abnormally-active signaling pathway? New therapeutics seek to target the low levels of androgen that remain in hormone treated patients. However, hormone depletion therapies are chronic and have unpleasant side effects so more profound hormone suppression is only likely to make these side effects even less tolerable. Others have chosen to target the AR gene and protein with the use of gene therapeutic agents that suppress its expression in CRPC cells. We do not believe that this therapeutic approach is practical at this time and, even if it were, the side effects would likely be similar to profound hormonal suppression therapies. We have chosen to focus our research activities on defining the role of other signaling pathways on androgen signaling in CRPC cells since we hope to interfere with the cross-talk that enables abnormal activity of the androgen signaling pathway by targeting these alternate signaling mechanisms. We feel that certain signaling pathways associated with embryonic development are good targets to fight CRPC in this regard. Embryonic development is a time of rapid cell and tissue growth that mimics the rapid growth of tumors. Embryonic tissue growth requires certain signaling processes that are naturally “turned-down” in adult tissues where rapid growth is not required so that targeting developmental signaling processes for cancer treatment might not have such remarkable side effects. There are three prominent developmental signaling pathways that are needed for embryonic tissue growth and these are referred to as Wnt, Hedgehog and Notch. We believe that these signaling pathways are also involved in, and important for, prostate cancer growth and progression to CRPC and work from the laboratory has already shown that each of these signaling pathways becomes reactivated in prostate tumors, especially in response to hormone therapy. Moreover, they are also involved in maintaining stem cell populations and their activity in CRPC might be conferring a stem cell-like behavior to the cancer cells that makes them more resistant to therapeutics. The potential benefits of exploring these relationships between the developmental signaling pathways and CRPC is enhanced by the availability of drugs that can block their activity in normal and cancer cells. We are working to better understand the mechanism by which these drugs might block the development of CRPC and to test, in preclinical models, their efficacy so that they can be considered for use in human prostate cancer patients. In the end, we believe that these developmental signaling pathways hold the key for understanding how androgen signaling becomes reactivated in CRPC and are the best targets for preventing or treating CRPC. Some Relevant Publications (View)
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