Prostate cancer arises as an androgen driven disease and therefore therapies targeting the androgen receptor (AR) have been a major focus of prostate cancer treatment. Despite recent advances in the development of highly effective AR-directed therapies, the development of acquired resistance remains a significant challenge. An emerging concept of anti-AR resistance is the induction of epithelial plasticity to a heterogeneous state that has lost its AR-dependent luminal identity and ultimately develops neuroendocrine prostate cancer (NEPC). There are no effective therapies for patients with NEPC and prognosis is extremely poor (average survival = 7 months). NEPC retains many of the genomic alterations that arise in prostate adenocarcinoma castration resistant prostate adenocarcinoma suggesting a clonal origin. Recently, we and others have identified and validated new therapeutic targets and drivers of cell transformation from CRPC to NEPC (e.g. induction of MYCN (encodes N-Myc) or loss of Retinoblastoma-1 (RB1) and TP53. We have shown that N-Myc is over- expressed in the majority (>95%) of NEPC cases and in 20% of CRPC tumors that also display features of NEPC. RB1 loss occurs in majority of NEPC cases (70%) and in 32% of CRPC tumors which overlaps, in part, with N-Myc over-expression. Currently, the synergy between MYCN induction and RB1 loss, mechanisms downstream of induction of MYCN induction/PTEN loss with or without RB1 loss in driving lineage switching and treatment response are not well understood. Our over-arching hypothesis is that specific molecular alterations (e.g. MYCN induction) in prostate cancer cells drive lineage plasticity by establishing a molecular program associated with the neural lineage and epigenomic reprogramming as a mechanism of resistance to anti-AR therapy and transformation towards a neuroendocrine phenotype. To address this hypothesis we have formulated the following three Specific Aims: We will use murine and human in vitro, in vivo and ex vivo models to establish the role of N-Myc and downstream mediators (e.g. NKX2-1, SOX11,) in gene expression and epigenetic reprogramming driving CRPC-Adeno towards NEPC (Aim 1); we will also define essential N-Myc- transcriptional complex proteins that mediate the transition from CRPC-Adeno towards NEPC (Aim 2); finally, we will evaluate the preclinical efficacy of therapy targeting CRPC-Adeno to NEPC transition (Aim 3). We expect that during the transformation process and before epigenetic hardwiring, tumor cells will retain the capacity to revert to a luminal phenotype as a result of molecular or pharmacological intervention. This project leverages unique model systems to study drivers of lineage switching and treatment response. The multidisciplinary project builds upon a long-standing collaboration between the PI and co-Is and extensive preliminary data. At the conclusion of this study, we will have a better understanding of the mechanisms underlying lineage plasticity associated AR-directed treatment resistance. !
Based on data from our lab and other labs, it has recently been suggested that transformation from castrate resistant prostate cancer (CRPC toward neuroendocrine prostate cancer (NEPC), a lethal form of prostate cancer (up to 25% of prostate cancer related death), is associated with epithelial plasticity and induced by either N-Myc induction or RB1 loss. Currently, the synergy between MYCN induction and RB1 loss and downstream events that promote lineage switching and treatment response are clinical unmet needs. Our multidisciplinary project, which builds on extensive and validated preliminary data, will provide insight and clinical rationale for treatment decisions and for patient selection for appropriate therapies, a step towards personalized cancer care.
