# Studies on Lineage Plasticity in Prostate Cancer

> **NIH NIH K08** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $205,990

## Abstract

PROJECT SUMMARY
 Despite the remarkable successes of targeted cancer therapies, certain cancers, including lung, breast, and
prostate cancer and melanoma, invariably become resistant to therapy. One mechanism of secondary
resistance—lineage plasticity—arises when cells transition into aggressive states, and, in the case of prostate
cancer, acquire a neuroendocrine histology. This results in a rapid downhill course for a subset of the so–termed
castrate–resistant prostate cancer (CRPC) patients. This, in essence, not only poses a clinical challenge, but
also confronts us with a wide–open biological question—what are the molecular underpinnings of lineage
plasticity, and importantly, can the process be reversed? We have very recently documented that the activation
of JAK/STAT and FGFR signaling pathways promote lineage plasticity and result in complete insensitivity to
androgen receptor signaling inhibitors (ARSIs) [*Chan, *Zaidi, et al., Science, 2022, PMID: 35981096, *co–
first authors]. Importantly, we found that FDA–approved inhibitors of JAK/STAT (ruxolitinib) and FGFR
(erdafitinib) synergize to reverse lineage plasticity and restore ARSI sensitivity. We therefore hypothesize that
signals downstream of JAK/STAT and FGFR, including novel transcription factors, interact to promote lineage
plasticity, and their timed perturbation can reverse plasticity and ARSI insensitivity. Thus, in Specific Aim 1, to
study how FGFR signals synergize with JAK/STAT to impart plasticity, we will use chemical inhibitors and
CRISPR–Cas9 to delete specific molecules in TP53/RB1–null mouse and human tumor organoids. Specific
Aim 2 will focus on further deconvoluting the molecular complexity of lineage plasticity through unbiased single
cell paired RNA and ATAC (multiome) sequencing in murine organoids. We expect to identify novel transcription
factors and study their DNA accessibility post–TP53/RB1 deletion across the evolution of lineage plasticity, with
and without ruxolitinib and/or erdafitinib. In Specific Aim 3, in proof–of–concept in vivo studies, we will examine
the efficacy of combined treatment with ruxolitinib plus erdafitinib in reversing lineage plasticity and restoring
ARSI sensitivity. For this, the ruxolitinib+erdafitinib combination will be studied in NOD SCID mice grafted either
with TP53/RB1–null murine organoids, orthotopically, or with the human tumoroid MSK–PCA3, subcutaneously.
These studies will not only inform future therapeutic strategies to subvert drug resistance in CRPC patients but
should also provide a unique platform for my Training Aims. Under the tutelage of my primary mentor, Dr.
Charles Sawyers, and my Advisory Committee, I expect to enhance my competencies in advanced computation,
cancer modeling and genetic editing, and bedside translation. Together with the rich scientific environment and
vast array of resources at MSKCC, my research and training should position me to achieve my goal of becoming
an independently funded physician–...

## Key facts

- **NIH application ID:** 10877990
- **Project number:** 5K08CA282978-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** SAMIR ZAIDI
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $205,990
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-03-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877990

## Citation

> US National Institutes of Health, RePORTER application 10877990, Studies on Lineage Plasticity in Prostate Cancer (5K08CA282978-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10877990. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*