MAY 10, 2018 9:00 AM PDT

Multi-Omics Approach for Discovering Anti-Folate Drug Resistance Mechanisms in Triple-Negative Breast Cancer: Working Toward the Goal of Personalized Medicine

Sponsored by: Agilent
Speaker
  • Professor of Pharmacology, Director, Advanced Training in Pharmacology, Director, Metabolomics Lab, Weill Cornell Medical College
    BIOGRAPHY

Abstract

Triple-negative breast cancer (TNBC) has poor prognosis with frequent relapses and deaths using current standard of care treatments.  Metabolic reprograming is now recognized as a fundamental driver of cancer and a detailed understanding of the metabolic rewiring that occurs in TNBC will undoubtedly reveal novel target opportunities. Research will be presented that seeks to use a multi-omics discovery strategy to identify metabolic compensatory in TNBC cells to anti-folate agents.  The overarching goal of our studies is to recognize synthetic lethalities that can be targeted for in TNBC. 

Notably, cell proliferation is critically dependent on tetrahydrofolate (THF) as a critical enzyme cofactor for 1-carbon (1-C) transfer reactions - essential for the synthesis of purines, thymidine and methyl transfer reactions, including DNA, RNA, proteins, lipids and small molecules. Given this essential role of folate, inhibitors of mammalian folate transformation reactions (e.g., methotrexate, 5-fluorouracil, pemetrexed) are widely used for cancer chemotherapy, including TNBC.  Knowledge of compensatory mechanisms to anti-folate therapy could reveal synthetic lethalities, identifying effective new targets in TNBC.  

It is well-appreciated that the major source of 1-C units for support of THF-dependent 1-C reactions is formate, predominantly produced in mitochondria from serine by the sequential enzymatic actions of SHMT2, MTHFD2 and MTHFD1L, followed by formate export to cytosol for support of extra-mitochondrial 1-C biosynthetic reactions. Importantly, mitochondrial synthesis and release of formate relies on a discrete pool of THF in the mitochondria that enters via a selective folate transporter, SLC25A32, and becomes trapped by intra-mitochondrial polyglutamylation. The mitochondrial serine/formate release pathway has received much recent interest as a potential target for cancer chemotherapy, although poorly-defined metabolic compensation has emerged as a concern.  Mitochondrial folate transport by SLC25A32 is yet unstudied for its contribution to oncogenesis, despite knowledge that the slc25a32 gene is amplified in human cancers (including >40% of breast cancers) and this amplification is associated with accelerated disease progression and death. 

Preliminary studies applying a multi-omic discovery approach reveal that slc25a32 gene deletion in TNBC results in a marked cell cycle delay, accompanied by profound metabolic rewiring and perturbed cell signaling pathways. Using multi-omics, we identify compensatory changes in TNBC cells that result from slc25a32 gene knockout, as novel targets for the development of personalized chemotherapy in mitochondrial folate-high cases of TNBC. 

For Research Use Only. Not for use in diagnostic procedures.
 


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MAY 10, 2018 9:00 AM PDT

Multi-Omics Approach for Discovering Anti-Folate Drug Resistance Mechanisms in Triple-Negative Breast Cancer: Working Toward the Goal of Personalized Medicine

Sponsored by: Agilent


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