# Implications of Metabolic Regulation of BCL-2 Dependence for Myeloma Therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $382,432

## Abstract

PROJECT SUMMARY
Multiple myeloma (MM) is a plasma cell malignancy accounting for 13% of all hematological malignancies and
11,000 deaths annually in the US, with the majority succumbing to disease due to the development of
resistance. Evasion of apoptosis is central to tumor development and resistance. A key component to the
development of resistance across most cancers lies in the ineffective engagement of the BCL-2 family of
apoptosis regulators. Induction of the intrinsic pathway of apoptosis is dictated by the release of pro-apoptotic
BH3-only activator proteins (BIM, PUMA, BID) from anti-apoptotic BCL-2 family members (BCL-2, BCL-xL,
MCL-1, BCL-w and A1) that in turn activate BAX and BAK leading to mitochondrial membrane permeabilization
and release of cytochrome C. BH3 activator proteins are released either by reduction in expression of an anti-
apoptotic BCL-2 protein to which they are bound or if a sensitizer (such as NOXA, BAD or a BH3 mimetic)
releases the BH3 activator protein from binding the anti-apoptotic. When a cell has its anti-apoptotics largely
bound by pro-apoptotics (bringing it closer to the apoptotic threshold) it is “primed for death”. Resistant MM,
acute myelogenous and lymphocytic leukemia and various solid tumors are found to be less primed for death
that contributes to resistance. Thus finding alternative strategies to effectively re-engage BCL-2 proteins to
increase the primed state can potentially circumvent resistance. Glucose and glutamine are key nutrients
promoting proliferation and importantly, evasion of apoptosis through discrete regulation of BCL-2 proteins
such as PUMA, BIM, NOXA, BAX, BAD and MCL-1. We have determined that nutrient deprivation leads to
BCL-2 family alterations that effectively lower the apoptotic threshold i.e. increase the “primed state”.
Comparative metabolomics enabled identification of a subset of metabolites with potential roles in regulating
BCL-2 protein expression and interactions. Inhibition of this subset of metabolic pathways sensitized a
genetically diverse panel of MM cell lines and relapse/refractory patient samples to the BH3 mimetic class of
small molecules. Furthermore, examination of gene expression profiles of MM patient's revealed upregulation
of the enzymes involved in generation of these specific metabolites and segregated out patients with lower
overall survival. One of the central questions we will investigate is how elevated expression of these enzymes
correlates with actual metabolic flux to inform us of actionable targets. These observations form the basis of
our rationale that delineating non-redundant rate-limiting metabolic enzymes regulating BCL-2 dependence will
reveal strategies of potent metabolically-driven synthetic lethality with selectivity for tumor cells given the lower
BCL-2 dependence of normal cells. Therefore, our long-term goals are to 1) understand how specific metabolic
enzymes regulate the BCL-2 family of proteins and 2) demonstrate the feasib...

## Key facts

- **NIH application ID:** 9901468
- **Project number:** 5R01CA208328-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** MALATHY (MALA) SHANMUGAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,432
- **Award type:** 5
- **Project period:** 2017-04-11 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901468

## Citation

> US National Institutes of Health, RePORTER application 9901468, Implications of Metabolic Regulation of BCL-2 Dependence for Myeloma Therapy (5R01CA208328-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9901468. Licensed CC0.

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