Early Drivers of Lineage Plasticity in Neuroendocrine Prostate Cancer Identify Key Molecular Pathways and Potential Therapeutic Targets

Abstract

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and difficult totreat advanced prostate cancer that often develops when the disease becomes resistant to long-term hormone (androgen) therapy. This transition occurs because cancer cells can significantly alter their identity, reprogramming epigenetic, genetic, and metabolic characteristics, becoming neuroendocrine-like and losing their original dependence on androgen signals. My thesis brings two key drivers in neuroendocrine lineage plasticity and represents a therapeutic vulnerability in prostate cancer. The first highlights the importance of Neuronal Pentraxin 1 (NPTX1), a protein that appears early in prostate tumors and is a potential therapeutic target. NPTX1 reduces REST levels, a crucial gene repressor, which allows HDAC6(Histone Deacetylase 6), an essential protein for neuroendocrine cancer cell survival, to become activated. Blocking HDAC6 activity with targeted drugs inhibits cancer cell growth and survival, highlighting HDAC6 as a promising new treatment target. The second finding focuses on the enzyme DNA methyltransferase 3B (DNMT3B), which controls gene expression in response to androgen deprivation. Increased DNMT3B suppressed REST expression, which promotes neuroendocrine and stem cell-like changes in cancer cells. When DNMT3B is inhibited, either through genetic methods or with drugs like Nanaomycin A, cancer growth slows, and neuroendocrine cancer markers disappear, all without serious side effects. Together, these studies outline a sequence of molecular events and identify new vulnerabilities in how prostate cancer adapts and becomes resistant to treatment. By emphasizing the NPTX1-REST-HDAC6 and DNMT3B-REST pathways as early drivers iv of this process, the research lays the foundation for combination treatments. Those genes were induced in treatment-induced prostate cancer. Therefore, our findings from DNMT3B and NPTX1 suggest that strategies could help prevent or reverse NEPC and improve outcomes for patients with advanced prostate cancer. In my thesis, I introduce a combined approach that builds on the key findings. Using molecular, cellular, and in vivo prostate cancer models, I systematically examine the functional roles of NPTX1 and DNMT3B in driving neuroendocrine lineage plasticity and therapy resistance. By analyzing gene expression patterns, protein markers, and cancer cell behavior under various experimental conditions, my studies reveal that NPTX1 is not only associated with early neuroendocrine features but is also detectable as a potential clinical biomarker. Separately, DNMT3B is shown to promote neuroendocrine and stem-like properties in prostate cancer cells, and its suppression impairs tumor proliferation and lineage switching both in vitro and in animal models. These complementary investigations establish the foundation for understanding how changes in these specific pathways influence the development and progression of aggressive prostate cancer subtypes, while guiding the development of molecularly targeted therapies.