Defining epigenetic underpinnings of neuroendocrine lineage carcinomas
About This Grant
Abstract Phenotypic plasticity is a hallmark of cancer wherein cancer cells can undergo a lineage transformation to evade therapeutic pressure. Cancer lineage plasticity is facilitated by epigenetic changes in chromatin profiles. Up to 15% of prostate cancers develop treatment resistance by transforming from conventional prostate adenocarcinoma (PRAD) to small-cell neuroendocrine prostate cancer (NEPC), a process marked by epigenetic dysregulation. Polycomb repressive complex 2 (Polycomb) is critical for formation and maintenance of facultative heterochromatin for gene silencing and cell-fate specification. Over four years of postdoctoral research in Dr. Himisha Beltran’s lab, I defined the differential activity of Polycomb in PRAD compared to NEPC and identified key genes that are de-repressed driving NEPC lineage reprogramming. My extensive epigenetic profiling of clinical samples and models revealed long facultative heterochromatin regions at key NE-related genes in PRAD, potentially representing insulated Polycomb domains. The transformation of these domains into euchromatin and their role in NEPC lineage plasticity remain unexplored. Understanding Polycomb domains' functional role in NEPC progression could advance our knowledge of cancer lineage plasticity and lead to novel therapeutic strategies. Additionally, the roles of Polycomb domains, chromatin remodelers, and shared epigenetic features in other neuroendocrine cancers remain under studied. The central hypothesis is that Polycomb domains and their modulators drive neuroendocrine lineage carcinoma. I will use genetic perturbation studies in clinically relevant cell line and organoid models, along with integrative epigenetic and transcriptomic analyses, to test this hypothesis through three specific aims: (1) to determine the functional role of Polycomb domains in mediating NEPC lineage plasticity; (2) to define the role of Polycomb regulating factors in NEPC progression; (3) to determine critical epigenetic regulators of neuroendocrine carcinomas. The results will pave the way for development of targeted therapies for neuroendocrine cancers. In addition to my primary mentor, Dr. Beltran, a world leader in NEPC biology and clinical management, my K99 Advisory Committee includes esteemed experts: Dr. Myles Brown, specializing in epigenetics in hormone- dependent cancers; Dr. Matthew Oser, focusing on the epigenetics of small cell lung cancer; Dr. James DeCaprio, a leader in neuroendocrine tumor biology; Dr. Ramesh Shivdasani, an expert in epigenetics and gastrointestinal neuroendocrine carcinoma biology; and Dr. Srinivas Viswanathan, a GU clinican-scientist and accomplished Associate Professor recently transitioning to independence. Collectively, they have mentored over 200 successful trainees worldwide. With their guidance, I will achieve the training objectives set for the K99 phase, emerging as an expert in epigenetic mechanisms mediating neuroendocrine lineage cancers. The K99/R00 award will empower me to pursue the best research and career development opportunities, facilitating a successful transition to independence and enabling me to launch an ambitious research program.
Grant Summary
Defining epigenetic underpinnings of neuroendocrine lineage carcinomas is a NCI - National Cancer Institute grant providing up to $170K for university, nonprofit, healthcare org. Applications are due 2028-06-30 (open). Check eligibility and apply with FindGrants.
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Up to $170K
2028-06-30
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Defining epigenetic underpinnings of neuroendocrine lineage carcinomas: Frequently Asked Questions
Who is eligible for the Defining epigenetic underpinnings of neuroendocrine lineage carcinomas?
Defining epigenetic underpinnings of neuroendocrine lineage carcinomas is offered by NCI - National Cancer Institute and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Defining epigenetic underpinnings of neuroendocrine lineage carcinomas provide?
Defining epigenetic underpinnings of neuroendocrine lineage carcinomas provides up to $170K per award from NCI - National Cancer Institute. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Defining epigenetic underpinnings of neuroendocrine lineage carcinomas deadline?
Applications for Defining epigenetic underpinnings of neuroendocrine lineage carcinomas are due 2028-06-30 (open). Because deadlines can change, verify the date with the funder, NCI - National Cancer Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Defining epigenetic underpinnings of neuroendocrine lineage carcinomas?
To apply for Defining epigenetic underpinnings of neuroendocrine lineage carcinomas, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NCI - National Cancer Institute.