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 feasibility and therapeutic promise of targeting metabolic pathways in MM to circumvent resistance.

Public Health Relevance

This project is relevant to public health as it will enable identification of metabolic checkpoints that can be targeted to sensitize cancers to existing therapy and circumvent resistance. The mechanistic basis for this novel method of metabolically driven synthetic lethality will be elucidated through comprehensive in vitro pre- clinical experimentation. The proposed research is relevant to NIH's mission to foster innovative research to significantly improve health and reduce disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA208328-04
Application #
9901468
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Chen, Weiwei
Project Start
2017-04-11
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322