# Targeting Vulnerabilities Exposed by Cancer Treatment-Induced Lineage Plasticity

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2022 · $402,600

## Abstract

SUMMARY/ABSTRACT
The AR may be the earliest known example of a lineage oncogene: a master regulator of cell survival and growth
to which neoplastic cells derived from prostate epithelium are addicted. Recognizing this unique feature,
concerted efforts have focused on developing therapeutics capable of suppressing AR signaling. Androgen
deprivation therapy (ADT) and AR pathway signaling inhibitors (ARSI) produce dramatic responses in the vast
majority of patients with metastatic PC (mPC). Unfortunately, these responses are not accompanied by cures,
with near universal development of treatment resistance. Studies from our group and others have determined
that an increasing fraction of mPCs resisting AR pathway inhibition lose AR activity and gain a spectrum of new
phenotypes, each of which exhibit an aggressive clinical course with limited treatment options. The processes
by which tumor cells switch lineages under treatment pressure is not well understood. Determining the
mechanisms that permit or drive this lineage plasticity may identify new treatment strategies.
This proposal is designed to address a major clinical problem whereby AR pathway inhibition promotes tumor
cell plasticity. We will test the hypothesis that targeting permissive epigenetic factors or lineage determinants
together with AR pathway inhibition will prevent lineage-redirection, prolong response rates overall, and cure a
subset of advanced prostate cancers.
AIM 1. Identify the key determinants and permissive factors that promote a lineage switch from conventional AR-
driven prostate cancer to new phenotypes following AR-directed treatment.
AIM 2. Determine if modulating factors that drive or permit lineage specification can prevent, delay, or reverse
resistance to AR pathway inhibition.
AIM 3. Determine if co-targeting characteristics of re-directed lineages that emerge in the context of lineage
switching will prolong responses to AR pathway inhibition.
In order for effective therapeutics to be developed that can adequately address this new class of malignancy,
the pathways permitting or driving lineage conversion must first be clearly defined; this project aims to elucidate
those underlying mechanisms.

## Key facts

- **NIH application ID:** 10343529
- **Project number:** 1R01CA266452-01
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** PETER S NELSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,600
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343529

## Citation

> US National Institutes of Health, RePORTER application 10343529, Targeting Vulnerabilities Exposed by Cancer Treatment-Induced Lineage Plasticity (1R01CA266452-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10343529. Licensed CC0.

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