# Determining the role of ASCL1 in neuroendocrine prostate cancer

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $35,372

## Abstract

Most patients with prostate adenocarcinoma, an androgen receptor (AR) driven cancer, develop castrate
resistant prostate cancer (CRPC) due to resistance to first-line androgen deprivation therapies. Consequently,
as a second-line therapy, patients are treated with a potent AR antagonist called enzalutamide (Enz). However,
a portion of CRPC patients treated with Enz develop neuroendocrine prostate cancer (NEPC), which is a rapidly
progressing cancer with limited therapies and poor survival outcomes. Current research to understand the CRPC
transition to NEPC suggests a model of lineage plasticity, where the AR-dependent tumors with luminal cell-type
features transition through a multi-potential lineage state. Under selection pressure of the therapy, the cells
progress towards an AR-independent neuroendocrine lineage. Several groups have found human NEPC tumors
have lost RB1 and TP53, and in experimental models, loss of both genes was required for this transition to a
neuroendocrine lineage. Notably, NEPC histology and gene expression resemble another neuroendocrine
cancer, small cell lung carcinoma (SCLC), a cancer also characterized by loss of RB1 and TP53. In SCLC, the
transcription factor ASCL1 is required for tumor cell growth in vitro, and for SCLC formation in a mouse model
of this disease. ASCL1 is present in NEPC tumors and in some cell line models of the disease. The current
proposal is aimed at determining if ASCL1 is required in the transition of prostate adenocarcinoma to NEPC, and
identifying the gene programs regulated by ASCL1 in this process. In addition, mechanisms leading to the
elevated levels of ASCL1 with RB1/TP53 loss will be explored. Gain- and loss-of-function approaches of ASCL1
in NEPC cell lines, NEPC patient-derived xenografts, and mouse prostate organoid models from genetically
engineered mice will be conducted to determine what role if any ASCL1 plays in this cancer. Comparing ASCL1
function and regulation in NEPC with those in SCLC may reveal common mechanisms and vulnerabilities in
these and other neuroendocrine cancers. This fellowship provides training in how to perform scientifically
rigorous and ethical biomedical research and how to communicate scientific findings to the field, particularly as
it relates to biological mechanisms underlying cancer. The expertise from Dr. Jane Johnson’s lab in
developmental transcription factors and neuroendocrine lung cancer, and Dr. Ping Mu’s lab in prostate cancer
therapy resistance will provide the necessary knowledge and techniques required for a successful training
experience and completion of the proposed project.

## Key facts

- **NIH application ID:** 10452507
- **Project number:** 5F31CA265131-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Kathia E. Rodarte
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $35,372
- **Award type:** 5
- **Project period:** 2021-07-09 → 2024-07-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452507

## Citation

> US National Institutes of Health, RePORTER application 10452507, Determining the role of ASCL1 in neuroendocrine prostate cancer (5F31CA265131-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10452507. Licensed CC0.

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