Prostate cancer is known for being heterogeneous with respect to cellular morphologies and histopathological characteristics. The vast majority of prostate cancers have a glandular, adenocarcinoma phenotype; however, a subset reveals a phenotype with neuroendocrine differentiation termed neuroendocrine prostate cancer (NEPC) that typically is diagnosed in the later stages of advanced disease. NEPC has little to no response to androgen deprivation therapy and is associated with the development of metastatic castration-resistant prostate cancer (mCRPC) that has extremely poor prognosis. Unfortunately, little is known about genetic drivers and activated pathways in NEPC, limiting precision medicine strategies. We previously provided a comprehensive study on the oncogenic role of L1 cell adhesion molecule (L1CAM) in CRPC-like prostate cancer growth and metastasis. We recently found that L1CAM is an oxidative stress-response gene contributing in therapeutic resistance of CRPC-like prostate cancer cells, an aggressive phenotype similar to NEPC. Our findings along with the supporting data that L1CAM over-expression is associated with NEPC by reviewing the gene expression profiles in preclinical animal models and clinical cohorts, strongly suggesting that L1CAM may serve as a driver of NEPC for developing mCRPC. In the study, we intend to further unravel the relationship and molecular basis of L1CAM in the aggressive features of NEPC. Specific Aim 1 will characterize the function role of L1CAM in neuroendocrine prostate cancer progression including cancer stem cell properties of de novo NEPC and neuroendocrine transdifferentiation of treatment-related NEPC; and evaluate the clinical relevant of L1CAM as a diagnostic and/or predictive marker for NEPC. Specific Aim 2 will explore the nuclear function of L1CAM in driving NEPC by identifying L1CAM nuclear binding components, with the primary focus on the interaction between a neuron-specific RNA-binding protein ELAVL4 and the released cytoplasmic domain of L1CAM (cyL1CAM).Specific Aim 3 will conduct a proof-of-principle study to investigate the feasibility of nuclear L1CAM as a drugable target for NEPC-associated mCRPC by designing a cell-permeable antibody against cyL1CAM through fusion of a prostate cancer-specific peptide.Since transformation to NEPC is likely to become of increasing clinical relevance in the era of widespread use of potent AR-targeted therapies, findings from this study will impact significantly more prostate cancer patients than previously appreciated and provide rationale for the development of therapeutic strategies for treating this aggressive subtype of prostate cancer.
|Effective start/end date||8/1/18 → 9/30/19|
- castration-resistant prostate cancer
- neuroendocrine differentiation
- L1 cell adhesion molecule
- targeted therapy