Most castration resistant prostate tumors remain dependent on androgen receptor (AR) signaling. This knowledge has led to the rational development of highly potent AR-targeted hormonal therapies that have now entered widespread clinical use(e.g., abiraterone, enzalutamide) and several others in clinical development. However, these drugs are not curative, and patients ultimately develop clinical resistance. Our group has focused on identifying patients with metastatic castration resistant prostate cancer (CRPC) that will no longer benefit from potent AR-directed therapies due to loss of AR signaling dependence. Clinically, metastatic biopsies can show pathologic or molecular features consistent with neuroendocrine prostate cancer (NEPC). NEPC is associated with low or absent AR expression and signaling, retention of early genomic mutations from its adenocarcinoma precursor, and acquisition of distinct genomic and epigenomic alterations. The development of novel therapeutic approaches for patients with NEPC represents a clinical unmet need.
Our laboratory is focused on characterizing the molecular landscape of NEPC and has identified new therapeutic targets, including the N-Myc/Aurora A pathway and specific epigenetic modifiers such as (Enhancer of Zeste Homolog 2) EZH2. N-Myc and Aurora-A interact to form a stabilizing complex that can be disrupted by allosteric inhibitors of Aurora-A (e.g. alisertib). These findings led to an investigator initiated multi-center Phase 2 clinical trial of alisertib for NEPC patients (NCT#01799278) led by Dr. Beltran. We have developed patient-derived organoid models from patients with castration resistant adenocarcinoma and NEPC and are using these relevant models to understand mechanism of response to alisertib and other drugs in development and understand the role/timing of molecular alterations that promote AR-indifferent disease. In parallel, through integrative analysis of metastatic biopsies from patients with CRPC/NEPC, we have identified molecular alterations enriched in NEPC including loss of RB1, TP53, CYLD, and others.We have identified downstream lineage and neuronal transcriptional factors, developmental pathways and epigenetic events that contribute to the development of AR indifferent CRPC and the NEPC phenotype. We are using patient derived preclinical models combined with patient data to model the timing of these emerging alterations, assess the reversibility of this lineage plasticity that occurs in the context of AR-therapy, and understand their clinical significance. Serial biopsies to look for NEPC transformation or loss of AR signaling are not often feasible or safe for patient suffering with advanced disease; therefore we are also developing liquid biopsy approaches including circulating tumor cells and circulating tumor DNA (ctDNA) to detect NEPC features non-invasively.
The Beltran Lab has contributed groundbreaking research to develop clinical trials for patients with NEPC.