A Changing Landscape of Advanced Prostate Cancer: Understanding Mechanisms of Resistance to Potent Hormonal Therapies

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 Beltran et al, Nature Medicine, 2016. Whole exome, transcriptome, and CpG DNA methylation integrative analyses point 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 ofprogression, favoring a model most consistent with divergent clonal evolution of NEPC from an adenocarcinoma precursor. Through preclinical analyses, we have better characterized mechanisms of transdifferentiation Dardenne, Beltran et al, Cancer Cell 2016 Bishop et al, Cancer Discovery 2016 Mu et al, Science, in press. 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 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 Beltran et al, Clinical Cancer Research, 2016. Circulating tumor DNA analysis is ongoing. I have also started to look even earlier in prostate cancer progression evaluating high risk prostate cancers and patients treated with neoadjvuant therapy on the CALGB90203 Phase 3 trial for emergence of NEPC features and harbingers of early resistance. These studies have potential clinical implications for early detection, prognostication, and identification of patients less likely to respond to subsequent AR-targeted therapies.