Defining the molecular role of NPTX1 in neuroendocrine prostate cancer

About This Grant

PROJECT SUMMARY/ABSTRACT Neuroendocrine prostate cancer (NEPC) is a lethal variant detected in 20–25% of patients who are initially diagnosed with conventional prostate adenocarcinoma (PrAd). Due to the lack of effective therapeutic targets, standard treatment for NEPC patients typically involves non-specific cytotoxic chemotherapy, with or without radiotherapy. Although these treatments may yield an initial positive response, the disease tends to recur rapidly without effective therapies. Thus, there is an unmet need to identify new molecular targets to better understand the mechanisms driving this aggressive form of cancer. Our research has revealed that Neuronal Pentraxin 1 (NPTX1) is selectively expressed in NEPC but not in PrAd, indicating a distinct role for NPTX1 in NEPC biology. Using in vivo human prostate cancer models, we demonstrated that NPTX1 promotes NEPC cell proliferation and neuroendocrine differentiation, whereas its loss suppresses NEPC development. Our preliminary studies further show that NPTX1 inhibition significantly reduces NEPC growth, downregulates key NEPC-driving transcription factors, and disrupts pathways governing proliferation, differentiation, and metastasis in human NEPC cell lines. Importantly, we identified histone deacetylase 6 (HDAC6) as a direct NPTX1-interacting partner. NPTX1 overexpression induces HDAC6 expression and increases enzymatic activity. Importantly, loss of HDAC6 can phenocopy NPTX1 depletion. Together, these findings support a mechanistic model in which the NPTX1-HDAC6 axis regulates NEPC growth and neuroendocrine differentiation. The primary objectives of this project are to: 1) Define the functional role of NPTX1 and its downstream regulatory genes in NEPC using in vivo preclinical models and a highly efficient human prostate cell transformation assay; 2) Elucidate the molecular mechanisms by which NPTX1 regulates HDAC6 and its HDAC6’s substrates that drive NEPC progression; and 3) Evaluate the therapeutic potential of targeting HDAC6 in NEPC using pharmacologic inhibition and patient-derived xenograft models. Animal models are essential because NEPC growth, differentiation, and therapeutic response depend on complex in vivo tumor biology that cannot be fully modeled in vitro. Human xenograft and patient-derived xenograft models will allow evaluation of the NPTX1-HDAC6 axis and HDAC6-targeted therapies in a physiologically relevant setting. Successful completion of this project will reveal the molecular functions of NPTX1 that promote NEPC aggressiveness, uncover novel mechanisms linking NPTX1, HDAC6, and transcriptional regulators in NEPC growth and neuroendocrine differentiation, and establish HDAC6 inhibition as a promising therapeutic strategy against NEPC. Together, these studies will provide critical mechanistic insight and identify new molecular vulnerabilities underlying NEPC growth, differentiation, and metastasis.