MAY 10, 2018 09:00 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
C.E. CREDITS: P.A.C.E. CE | Florida CE
Speakers
  • Professor of Pharmacology, Director, Advanced Training in Pharmacology, Director, Metabolomics Lab, Weill Cornell Medical College
    Biography
      Steven S. Gross, Ph.D., is Professor of Pharmacology, Director of the Mass Spectrometry Core Facility. Dr. Gross' expertise is in pharmacology, and cell and structural biology, particularly in relation to the role of nitric oxide (NO) as a signaling molecule. In the late 1980's, Dr. Gross and colleagues made the initial identification of L-arginine as the precursor of NO in blood vessels. They were also first to establish that NOS inhibition elevates blood pressure in animals, demonstrating that NO plays a physiological role in controlling blood pressure and vascular tone. Since then, research efforts have predominantly focused on elucidating the enzymes and mechanisms that regulate NO synthesis in cells. Results of these basic studies have provided fundamental insights into the therapeutic control of NO synthesis, resulting in core technologies for the creation of ArgiNOx Inc., a biotech start-up that is developing novel NO-based drugs. Dr. Gross has authored or coauthored more than 90 research publications and 40 book chapters, review articles and books in the area of NO biology. He is an active member of NIH Study Sections and is a founder and Board Director of the Nitric Oxide Society, a group that organizes the major annual international meetings on the subject of NO and publishes a peer-reviewed scientific journal with novel reports on NO biology and chemistry. Dr. Gross received his Ph.D. in Biomedical Science from the Mount Sinai School of Medicine in New York City.

    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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