State Of The Art Lecture: Molecular Biology Of Prostate Cancer And Its Translation - AUA 2006 - Society Of Urologic Oncology Meeting

Main Category: Urology / Nephrology
Also Included In: Prostate / Prostate Cancer;  Cancer / Oncology
Article Date: 24 May 2006 - 4:00 PDT


UroToday.com - The annual meeting of the Society of Urologic Oncology took place on Saturday, May 20, 2006 during the annual American Urological Association Meeting in Atlanta, Georgia. In the open, afternoon session, Dr. Charles Sawyers, UCLA presented a State of the Art Lecture: Molecular Biology of Prostate Cancer and its Translation.

Dr. Sawyers has examined the differential gene expression in hormone sensitive vs. refractory CAP xenografts. The dominant gene expression change was in the androgen receptor. It is increased 2-5 fold across 5 xenografts examined. Expanding this to human tumors other researchers showed that AR expression was increased at the mRNA level about 9 fold. But is this functional, asked Dr. Sawyers? AR overexpression is sufficient for hormone sensitive/hormone refractory transition in vivo. Using RNAi inhibition against AR leads to decreased function. Increased AR levels in this setting alter the cellular response to classic antagonists, such as anti-androgens. Bicalutamide becomes a weak agonist in this setting. Bicalutamide then induces androgen-regulated genes and may help to explain the anti-androgen withdrawal syndrome. Dr. Sawyers stated that second generation antiandrogens must be effective in cells expressing high levels of AR without acting as an agonist.

Dr. Sawyers discussed approaches of structure-activity relationship studies to identify new anti-androgens. The ideal structure would have regions for high-affinity binding and antagonist activity. RD37, a novel compound has a similar binding affinity to bicalutamide, but a different structural domain for antagonism. Pre-clinical data shows significant activity in hormone sensitive and insensitive LNCaP cells. Furthermore, RD37 did not have the agonist properties seen with bicalutamide in hormone refractory LNCaP cells. Data shows specificity of RD37 for inhibition of AR. RD37 improved antagonism comes primarily from the ability to overcome the increase AR expression perhaps through inducing altered AR conformation, rather than particularly enhanced affinity. Newer derivatives of RD37 result in longer half-life with oral dosing.

Dr. Sawyers talked about a new transgenic mouse model with androgen-regulated expression of the Lux gene for luciferase expression. This model is being used to examine the effects of bicalutamide and their new anti-androgen. RD162, the longer acting derivative had potent, tumor specific effects in pre-clinical models. At 40 days of treatment, tumor growth remains consistently inhibited. This novel agent has been licensed to a pharmaceutical company for development.

By Christopher P. Evans, M.D.

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