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Temporal heterogeneity and microenvironment dependent to develop marker-driven curative intent treatment strategies
Dr. Christopher Logothetis studies the change in AR signaling over time to treat patients with clinically-significant prostate cancer with curative intent. His group is trying to identify prognostically uniform patient populations to test novel therapies or therapy combinations because currently there are no biology-based markers for performing such stratifications. They believe that delineation of the biology to stratify people with predictive/prognostic accuracy will better inform the design of clinical trials.
He warned that we have more agents than we have knowledge on how to apply them, and highlighted the failure of the “docetaxel+” trials as a cautionary tale for what might happen without better- informed trial design. By highlighting the typical time course for patients with therapy-resistant prostate cancer, he theorizes that there is a time-dependent, therapeutically-relevant increase in tumor heterogeneity that is the cause of chemoresistance. Intratumoral heterogeneity and plasticity of cancer cells may allow for outgrowth of small resistant populations which are present prior to initiation of therapy. For instance, his group and others have shown that abiraterone causes induced outgrowth of androgen receptor (AR)-amplified cells, whereas enzalutamide causes local tissue testosterone levels to increase. Both of these mechanisms may deepen the spiral of castration resistance. He showed early data on the combination of the two drugs which dichotomizes patients into two groups of AR activity in the treated tumors.
He closed by drawing and analogy between castration-resistant prostate cancer and leukemic blast crisis, suggesting that both disease phases might require intratumoral heterogeneity for therapy resistance. Providing data for this hypothesis, he described several disease states including “cancer in transition” which resemble small cell pathologies, except that they still express AR. He showed that such pathologies uniformly harbor loss of p53, Rb, and REST; gain of neural differentiation; or a cell cycle phenotype in the switch to anaplasia. Interestingly, although chemoresistance is common in early disease states, anaplastic groups may become chemosensitive.
AUA/NCI Specialized Programs of Research Excellence (SPORE) Joint Workshop
Presented by Christopher J. Logothetis, MD at the American Urological Association (AUA) Annual Meeting - May 16 - 21, 2014 - Orlando, Florida USA
MD Anderson Cancer Center, Houston, TX USA
Written by Phillip Abbosh, MD, PhD, medical writer for UroToday.com