# Development of Tumor and Immuno-Metabolism Based Small Molecule Therapeutics for Refractory Breast Cancer

> **NIH NIH R44** · NIROGYONE THERAPEUTICS, LLC · 2021 · $854,530

## Abstract

Development of Tumor and Immuno-Metabolism Based Small Molecule Therapeutics for Refractory
Breast Cancer
Abstract
Worldwide, approximately 1 million women are diagnosed with breast cancer each year. Triple Negative Breast
Cancer (TNBC) is defined as that which does not express estrogen, progesterone, or Her-2 receptors. TNBC is
the most deadly sub-type of breast cancer, accounting for ~15% of the breast cancer diagnoses and ~25% of
breast cancer-related deaths. Median survival for 30% of the patients with TNBC is one year. TNBC has poor
clinical outcomes due to its high metastatic rate, resistance to chemotherapy, and lack of effective treatment
options. Although immunotherapy for cancers is rapidly expanding with the discovery of new targets and methods
to activate immune function within tumors, it has only shown success in a limited subset of metastatic TNBC
patients. The lactate-rich TNBC tumor microenvironment (TME) has been shown to be highly
immunosuppressive, promoting tumor growth and progression. Cancer cells transport lactate across the cell
membrane to the extracellular matrix via monocarboxylate transporters, MCT1 and MCT4. We have developed
dual MCT1/4 inhibitors (dMCTi) to block lactate excretion to the TME thereby directly killing cancer cells and
simultaneously activating local immunity in the TME. In our preliminary studies, we have shown that dMCTi are
potent compounds against multiple TNBC cell lines. Also, we have shown that in in vivo experiments with both
mouse xenograft models (MDA-MB-231, breast cancer) and syngeneic mouse models of melanoma and TNBC;
SM1 (melanoma, BRAFV600E), and 4T1 (TNBC), dMCTi exert significant anti-tumor efficacy. Anti-tumor efficacy
in MDA-MB-231 immune-deficient xenograft model shows inhibitors’ direct cell killing effect. In the 4T1 and SM1
syngeneic models, we observed a decrease in expression of multiple immunosuppressive molecules such as
B7 family proteins, macrophage polarization to M1, MDSCs, and increase in CD8+ population in treated tumors
compared to the control tumors. Furthermore, profiling of cytokines indicated an increase in pro-inflammatory
IFNγ, TNFα, IL-1β and decrease in tumor promoting TGFβ, IL-10 in treated tumors compared to the control
tumors confirming that the anti-tumor effect of dMCTis is in part due to enhanced immune function. Supported
by these preliminary data, we selected a dMCTi, NGY-B, as a pre-clinical development candidate. In this Direct
Phase-II application, we propose to (1) conduct preclinical pharmacokinetic and safety studies of NGY-B, (2)
Establish an effective dose regimen of NGY-B, investigate the efficacy of NGY-B in several mouse tumor models,
and study the immune suppressive mechanisms in vivo, (3) establish NGY-B scalability for manufacturing, and
request a pre-IND Type B meeting with FDA. Upon completion of these Aims, Nirogyone will have established
NGY-B’s scalability, broader efficacy, and potential dose-limiting toxicities. We will then submit...

## Key facts

- **NIH application ID:** 10266156
- **Project number:** 5R44CA257588-02
- **Recipient organization:** NIROGYONE THERAPEUTICS, LLC
- **Principal Investigator:** Vincent Sandanayaka
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $854,530
- **Award type:** 5
- **Project period:** 2020-09-18 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266156

## Citation

> US National Institutes of Health, RePORTER application 10266156, Development of Tumor and Immuno-Metabolism Based Small Molecule Therapeutics for Refractory Breast Cancer (5R44CA257588-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10266156. Licensed CC0.

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