A Changing Landscape of Advanced Prostate Cancer: Understanding Mechanisms of Resistance to Potent Hormonal Therapies
Technical Report,30 Sep 2013,29 Sep 2018
Weill Medical College of Cornell University New York United States
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Transition to a neuroendocrine prostate cancer NEPC phenotype has emerged as an important mechanism of treatment resistance to androgen receptor AR therapies for patients with metastatic prostate cancer. During the course of this Award, I have performed extensive, first in-field molecular characterization of metastatic tumor biopsies from patients with castration resistant adenocarcinoma and neuroendocrine prostate cancer. Whole exome, transcriptome, and DNA methylation integrative analyses pointed to key drivers of NEPC including loss of RB1 and TP53, gain of MYCN, overexpression of BRN2, and epigenetic changes. Clonality analysis of serial tumor biopsies in individual patients provides new insights into mechanisms of progression, favoring a model most consistent with divergent clonal evolution of NEPC from an adenocarcinoma precursor. Through preclinical studies including the recent development of patient derived preclinical models of NEPC by our lab, we have better characterized mechanisms of trans-differentiation and have identified new drug targets. I have initiated investigator initiated clinical studies based directly on this work. Also as part of this Award, I have evaluated circulating tumor cells CTCs from patients treated with abiraterone and enzalutamide for emergence of NEPC CTC characteristics and found that up to 10 percent harbor NEPC like CTCs characterized by low AR, smaller morphology, loss of CK, and the presence of NEPC CTCs was associated with poor prognostic features. In the current reporting period, I have been using CTCs to detect new biomarkerstherapeutic targets such as DLL3. We have also been using ctDNA for the early detection of NEPC and to chacterize tumor heterogeneity.
- Medicine and Medical Research