# Role of GATA2 signaling network in Lethal Prostate Cancer

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $395,976

## Abstract

PROJECT SUMMARY
Despite recent progress in the treatment of advanced prostate cancer this malignancy remains a lethal disease
mainly due to the ability of prostate cancer cells to survive standard therapies and progress to a highly
aggressive state. Therefore, there is a clinical need to identify new molecular targets for advanced prostate
cancer that have progressed to standard therapies. The main goal of this research program is to dissect the
signaling network of GATA2, discover molecular targets by way of developing a mechanistic understanding of
regulation GATA2 exerts and characterize novel therapies in lethal prostate cancer. GATA2 is required for
survival of and to enhance the tumorigenicity of prostate cancer cells by acting as a master regulator gene that
controls a complex signaling network which includes upregulation of well established oncogenes (FOXM1,
IGF2, PAK4) and downregulation of tumor suppressors (GLANT7, ARRDC3). Notably, GATA2 levels are
highest in patients that have progressed to standard anti-androgen and chemotherapy agents. Therefore,
dissecting the GATA2 signaling network may represent a valuable strategy to identify novel therapeutic targets.
To identify clinically relevant GATA2 dependent mechanisms of aggressiveness in prostate cancer cells we
have interrogated the gene expression profiles of GATA2 knockdown chemotherapy resistant prostate cancer
in vitro model systems and public available prostate cancer tissue sample gene expression datasets. Among
the molecules identified is the transmembrane nucleoporin POM121. We hypothesize that GATA2 promotes
prostate cancer aggressiveness by regulating the stoichiometry of the nuclear pore complex and increasing the
nuclear activity of specific oncoproteins and that targeting the nucleocytoplasmic import machinery is an
effective strategy to treat lethal prostate cancer. We will address these hypotheses through three aims. In the
first aim, we will elucidate the mechanistic basis by which GATA2 regulates the nuclear pore composition and
nucleocytoplasmic import through POM121. In the second aim, we will characterize the molecular oncogenic
effectors and mechanisms through which POM121 regulates prostate cancer aggressiveness. In the third aim,
we will investigate the clinical relevance of these findings in circulating tumor cells from metastatic prostate
cancer patients before treatment and after treatment progression along with the in vivo efficacy of targeting the
nucleocytoplasmic import machinery for treating prostate cancer.

## Key facts

- **NIH application ID:** 9973150
- **Project number:** 5R01CA207311-06
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Josep Maria Domingo-Domenech
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,976
- **Award type:** 5
- **Project period:** 2016-08-26 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973150

## Citation

> US National Institutes of Health, RePORTER application 9973150, Role of GATA2 signaling network in Lethal Prostate Cancer (5R01CA207311-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9973150. Licensed CC0.

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