# Mechanistically Dissecting Glycolysis Regulation by Lactate and Its Therapeutic Potential in Cancer

> **NIH NIH R00** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $182,226

## Abstract

PROJECT SUMMARY/ABSTRACT
Glucose is an essential fuel for cancer cell proliferation in serving both as a substrate for ATP production and
as an irreplaceable carbon source for biomass accumulation. Cancer cells are especially addicted to glucose
but only to secrete the majority as lactate (known as aerobic glycolysis or Warburg effect), thereby creating an
inhospitable glucose-poor and lactate-rich microenvironment that would otherwise be lethal to most cells.
However, cancer cells can efficiently use the limiting glucose and excess lactate for unlimited growth through
unclear mechanisms. My preliminary data revealed that in low glucose conditions, extracellular lactate
enhances cancer cell proliferation. Mechanistically, I found that lactate preferentially enters the mitochondria
TCA cycle over glucose to increase oxidative phosphorylation (OXPHOS) activity, which in turn suppresses
glycolysis to conserve extracellular glucose, suggesting cancer cells rely on lactate-induced OXPHOS for
optimal growth. The proposed studies are aimed at mechanistically dissecting the metabolic interplay between
lactate-mediated mitochondrial OXPHOS and glycolysis (Aim 1 & 3), and assessing therapeutic potential of
targeting lactate oxidation in cancer (Aim 2). The following specific aims are being pursued: Aim 1. Determine
how lactate-mediated increase in OXPHOS suppress glycolysis; Aim 2. Assess the in vivo therapeutic
potential of targeting lactate oxidation using Phenformin; Aim 3. Mechanistically dissect how cells distinguish
and preferentially use extracellular lactate over glucose for entry into TCA cycle. The knowledge and scientific
expertise gained through these studies will facilitate my transition to independence, with my long-term goal to
study and target metabolic vulnerabilities in cancer as a physician scientist.
In addition to the scientific goals, I have also outlined a detailed career development plan in this application to
obtain skills that are necessary for leading an independent research laboratory. The proposed research and
training plan will be conducted under the mentorship of Dr. Craig Thompson. Memorial Sloan-Kettering
Cancer Center, along with the nearby Rockefeller University and Weill Cornell Medical College will provide the
ideal academic environment to achieve these goals for me to transition to independence.

## Key facts

- **NIH application ID:** 10749952
- **Project number:** 5R00CA256505-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Xin Cai
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $182,226
- **Award type:** 5
- **Project period:** 2023-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749952

## Citation

> US National Institutes of Health, RePORTER application 10749952, Mechanistically Dissecting Glycolysis Regulation by Lactate and Its Therapeutic Potential in Cancer (5R00CA256505-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10749952. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*