# Profilin as a Novel Target for Vascular Normalization in Renal Cancer

> **NIH NIH R00** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $249,000

## Abstract

Project Summary Abstract
Renal cell carcinoma (RCC) is estimated to result in 76,080 new cases and 13,780 deaths in 2021. Clear cell
renal cell carcinoma (ccRCC) is the most common subtype of RCC (>75% of RCC patients) and is
characterized by a high vascularized tumor microenvironment (TME). Anti- angiogenic and vascular
normalization (VN) inducing therapies are initially effective, almost all patients develop resistance to these
therapies. Therefore, there is a need to identify alternative fundamental therapies for ccRCC. Our lab and
others have demonstrated that actin cytoskeleton plays a key role in regulation of vascular endothelial cell
(VEC) in angiogenesis and barrier function. Furthermore, it has been demonstrated that Profilin1 (Pfn1) is an
important regulator of actin-driven processes such as cell migration and proliferation (including in VEC,
affecting angiogenic potential). Pfn1 is also overexpressed in human ccRCC and higher expression of Pfn1
has been linked to poor clinical outcome and advanced disease features. The goal of this study is to further
demonstrate Pfn1’s fundamental role in regulation of progression of ccRCC through modulation of tumor-
promoted vascularization and that Pfn1 serves as a therapeutic target for RCC. Our preliminary data
demonstrates that overexpressed Pfn1 is primarily found in tumor-associated VEC (TAEC). We further
demonstrate that loss of Pfn1 by genetic deletion in vivo or inhibition of Pfn1 by small molecule inhibitor
reduces aberrant vascularization in various pathological settings (including retina and kidney) and attenuates
RCC progression in vivo. Aim 1 of this proposal seeks to test a postulate that endothelial Pfn1 promotes a pro-
tumorigenic TME driving tumor progression in ccRCC and can be diminished by tumor-localized delivery of
novel small molecule antagonist of Pfn1-actin interaction. Aim 2 of this proposal will test a postulate that Pfn1
regulates the intrinsic angiogenic capability of VEC through augmenting mitochondrial function. Aim 3 tests a
postulate that VEC-secreted Pfn1 acts as a paracrine signaling mediator to promote ccRCC aggressiveness.
Aims 1 and 2 will mostly be performed in the K99 mentored stage, during which I will continue my training in
contrast-enabled ultrasound, immuno-, and mitochondrial biology. These trainings will be pivotal in my
transition to independence in the R00 stage where Aim 3 and the rest of Aim 2 will be executed.

## Key facts

- **NIH application ID:** 10949012
- **Project number:** 4R00CA267180-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** David Martin Gau
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949012

## Citation

> US National Institutes of Health, RePORTER application 10949012, Profilin as a Novel Target for Vascular Normalization in Renal Cancer (4R00CA267180-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10949012. Licensed CC0.

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