# Metabolic Modulation Suppresses Survival Signals in B-Cell Lymphoma

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2026 · —

## Abstract

Significance to VA
 : Metabolic remodeling is integral to cancer biology. The discovery of somatic mutations
in genes encoding metabolic enzymes provided insights into how subverting metabolism promotes
cancer. These studies also uncovered opportunities for metabolic interventions with anti-cancer activity.
Building on this idea, we postulated that the intermediate metabolite alpha-ketoglutarate (αKG) could
suppress tumor growth. We tested this concept in a large panel of lymphomas (cell lines and primary
tumors), in vitro and in vivo, and found that αKG significantly inhibited lymphoma cell growth, induced
apoptosis, and decreased tumor burden/improved survival of mice harboring lymphomas. Testing new,
more effective and less toxic treatment strategies for lymphoma is particularly important for Veterans,
and the VHA, because lymphoma is a cancer type uncontrovertibly associated with military service. The
increased risk for lymphoma development is firmly linked to exposure to agent orange and lymphoma is
a presumptive condition in veterans of recent campaigns who may have been exposed to environmental
toxins in the theater of operations.
Innovation and impact
: We found that αKG suppresses lymphoma
growth by promoting amino acid depletion. This finding unveiled an innovative way to “starve” cancer
cells, a long-sought goal in cancer therapeutics. Further, we also found that treatment with αKG uncovers
multiple additional cancer vulnerabilities, which can be targeted with existing, clinical grade, small-
molecule inhibitors. Thus, this project may have a significant impact in the treatment and cure rate of
lymphomas and related cancers.
Specific aims
: Aim 1. Characterize αKG’s impact on BCAT activity/flux
direction, leucine depletion and MTORC1 inhibition. Hypothesis: αKG imposes the flux of BCAT reactions
towards the conversion of BCAA into BCKA, and the attendant leucine depletion inhibits MTORC1 via
Sestrin2-GATOR-Rag2 interactions. Aim 2. Examine the role of GOT

## Key facts

- **NIH application ID:** 11297406
- **Project number:** 1I01RD001059-01
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** Ricardo C Aguiar
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2026
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2026-04-01T00:00:00 → 2030-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11297406

## Citation

> US National Institutes of Health, RePORTER application 11297406, Metabolic Modulation Suppresses Survival Signals in B-Cell Lymphoma (1I01RD001059-01). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/11297406. Licensed CC0.

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