# Therapeutic targeting of SIRT3 for aggressive and refractory lymphomas

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $645,866

## Abstract

ABSTRACT
Among aggressive lymphomas, the Diffuse large B-cell lymphomas (DLBCLs) are among the
most highly proliferative, and have massive requirements for production of metabolic precursors.
Along these lines we recently identified NAD+ dependent lysine deacetylase SIRT3, as a master
regulator of mitochondrial stress metabolism, as a critical driver of DLBCL growth and
survival. We showed that SIRT3 loss of function in DLBCL cells kills lymphomas by disrupting
their ability to use glutamine and other amino acids in the TCA cycle, which triggers destructive
autophagy – both in vitro and in vivo. Importantly, we created the mitochondrial targeted SIRT3
selective small molecule YC8-02 that precisely mimics the effect of SIRT3 depletion and potently
killed DLBCL cells in vitro and in vivo. These compounds yielded further enhanced killing effects
in combination with targeted therapies such as venetoclax as well with chemotherapy drugs
commonly used to treat DLBCLs. Finally, our mechanistic data point to pathways in cells that
could eventually lead to resistance to SIRT3 targeted therapy, as well as ways to prevent this
from happening so as to yield maximal therapeutic efficacy. An overarching challenge in
delivering precision medicine for DLBCL patients is their marked genetic heterogeneity and
extreme abundance of somatic mutations. There are currently no targeted agents with activity
and targets relevant to more than a small fraction of patients. However, we identified SIRT3
as a broadly relevant and critical non-oncogene addiction that is required by DLBCLs
independent of their genetic background. Through this proposal we provide the basis for i)
translating SIRT3 inhibitors to the clinic, ii) understanding and mitigating potential resistance
mechanisms, and iii) incorporating SIRT3 inhibitors into rationally designed anti-lymphoma
regimens with broad relevance for the subsets of patients who desperately need improved
therapies. Our proposal uses state of the art model systems physiologically relevant to these
complex tumors, and is poised to deliver highly impactful outcomes from the scientific and clinical
perspective.

## Key facts

- **NIH application ID:** 10799720
- **Project number:** 5R01CA270243-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** ARI M. MELNICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $645,866
- **Award type:** 5
- **Project period:** 2023-03-02 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799720

## Citation

> US National Institutes of Health, RePORTER application 10799720, Therapeutic targeting of SIRT3 for aggressive and refractory lymphomas (5R01CA270243-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10799720. Licensed CC0.

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