# Targeting breast cancer progression

> **NIH NIH SC3** · UNIVERSITY OF PUERTO RICO MED SCIENCES · 2021 · $112,500

## Abstract

Metastatic disease is the primary cause of cancer mortality, but effective treatments remain elusive. Therefore,
our LONG-TERM GOAL is to address the CRITICAL NEED for more targeted strategies to inhibit metastatic
cancer. Metastatic cancer cells migrate away from the primary tumor and invade the extracellular matrix to
enter the circulatory system and establish secondary tumors at distant sites. Accordingly, this proposal, which
is an extension of an ARRA supplement to SC3 GM084824 to study the role of Rho GTPases in breast cancer
progression via regulation of cancer cell migration, will test novel anti metastatic cancer therapeutics. The Rho
GTPases, Rac and Cdc42, are key molecular switches activated by a myriad of cell surface receptors to
promote cancer cell migration/invasion, proliferation, and survival. However, there is a GAP IN KNOWLEDGE
on the efficacy of Rac and Cdc42 inhibitors as anti metastatic cancer therapeutics. The OBJECTIVE in this
proposal is to characterize small molecule compounds that block the interaction of Rac and/or Cdc42 with their
upstream effectors, guanine nucleotide exchange factors (GEFs) in metastatic cancer. The RATIONALE for
this research comes from our characterization of the Rac inhibitor EHop-016 and the Rac/Cdc42 inhibitor
MBQ-167 in cancer cell and mouse models. EHop-016 and the improved compound MBQ-167 inhibit cancer
cell migration/invasion, viability, and tumor growth, metastasis, and angiogenesis in mouse models with no
apparent toxicity. Using rational drug design principles garnered from our studies with these Rac/Cdc42
inhibitors, the PI's collaborators synthesized a panel of MBQ-167 derivatives (50 compounds). The present
proposal will use 6 of these compounds to test the HYPOTHESIS that MBQ-167 and analogs have
potential as anti metastatic breast cancer therapeutics. SPECIFIC AIM 1 will elucidate the mechanism of
action of MBQ-167 and analogs in non-metastatic and metastatic cancer cell lines, and a normal mammary
epithelial cell line. EHop-016 inhibits the activation of Rac by the oncogenic GEF Vav, but the GEFs that
interact with MBQ-167 remain to be identified. Therefore, this Aim will use novel targeted mass spectrometric
and protein array approaches to identify the GEFs that interact with MBQ-167 and analogs to inhibit Rac and
Cdc42 activities. SPECIFIC AIM 2 will determine the efficacy and toxicity of MBQ-167 in immunocompromised
and immunocompetent mouse models. Successful completion of this study will uniquely advance our
understanding of metastatic cancer by establishing Rac and Cdc42 proteins as viable targets to impede
metastatic breast cancer progression. This study will also result in identification of the variation in GEF
expression and activity in non-metastatic and metastatic cancers and elucidate targeted therapeutic strategies
for our panel of inhibitors. Moreover, these novel chemical probes will be available as tools to validate
Rac/Cdc42 signaling as well as the function of s...

## Key facts

- **NIH application ID:** 10173795
- **Project number:** 5SC3GM084824-12
- **Recipient organization:** UNIVERSITY OF PUERTO RICO MED SCIENCES
- **Principal Investigator:** SURANGANIE DHARMAWARDHANE
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $112,500
- **Award type:** 5
- **Project period:** 2008-09-10 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173795

## Citation

> US National Institutes of Health, RePORTER application 10173795, Targeting breast cancer progression (5SC3GM084824-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10173795. Licensed CC0.

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