# Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer

> **NIH NIH P20** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $280,905

## Abstract

Project Summary: "Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer"
Prostate cancer (PC) is the second leading cause of cancer-related deaths in the USA. PC is a slow growing
disease, curable if detected early. However, the treatment resistant lethal form of PC is fast growing and
metastatic. The goal of our proposed research is to identify genetic factors that are essential for the switch
from indolent to lethal metastatic PC. We have generated a unique collection of a) PC patient derived
organoids and b) primary cell lines from the tumor and metastasis of the RapidCaP mouse model for lethal PC
(PTEN and TP53 deficient). Our preliminary data highlights a fundamental shift in cellular phenotype and
growth signaling associated with the transition to metastasis. Most importantly, the loss of TAM kinase receptor
Axl is key to this metastasis associated cellular reprogramming event. These discrete cellular states are
associated with divergent signaling behavior, which enables or restricts the metastatic potential of cancer cells.
Therefore, we now focus on the receptor tyrosine kinase Axl and its control of the switch from primary to
metastatic disease in vivo. In this proposal we will mechanistically validate the role of Axl receptor in PC
cellular lineage reprogramming and maintenance of pro-metastatic phenotype (Aim 1). Next, we will assess the
effect of androgen deprivation therapy (ADT) on a relevant mouse model of Axl-deficient PC and perform
transcriptomic profiling to identify molecular changes occurring under the stress of ADT (Aim 2). To develop
therapeutic strategies we will use a phosphoproteome approach and identify targetable kinase dependencies
in these Axl-deficient metastatic cells (Aim 3). To execute the proposed aims, we will closely collaborate with
experts in receptor signaling and PC disease biology. Our background in mouse genetics, cell biology and
translational oncology is well aligned with the expertise required to carry out the proposed work and unravel
the genetic dependencies of lethal metastatic PC cells.

## Key facts

- **NIH application ID:** 10891541
- **Project number:** 5P20GM121316-07
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Grinu Mathew
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $280,905
- **Award type:** 5
- **Project period:** 2018-03-16 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891541

## Citation

> US National Institutes of Health, RePORTER application 10891541, Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer (5P20GM121316-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10891541. Licensed CC0.

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