Therapeutic Targeting of Cancer Cell Metabolism in Lymphoid Neoplasia

Abstract SCI-27

The MYC oncogene plays a pivotal role in human lymphoid neoplasias, specifically in lymphomas and acute leukemias, which are characterized by altered glucose metabolism, termed the Warburg effect. The Warburg effect or elevated conversion glucose to lactate by cancer cells has been a prevailing model of cancer metabolism. Since the 1980’s, genetic alterations of oncogenes and tumor suppressors have provided insights into tumorigenesis. However, whether metabolism contributes to tumorigenesis was highly debated. In 1997, we reported that the MYC oncogene product, the Myc transcription factor, regulates the lactate dehydrogenase A (LDHA)gene. Myc also activates many glycolytic enzymes, mitochondrial biogenesis, and glutamine metabolism by inducing glutaminase (GLS) and glutamine transporters, thereby providing not only ATP through the TCA cycle but also anapleurotic building blocks. Myc also induces biomass accumulation by stimulating ribosomal biogenesis. It stimulates the cell cycle machinery and DNA replication. Deregulated MYC in cancer results in enforced biomass accumulation, such that cell death occurs when bioenergetic demands exceed nutrient availability. In this regard, we have exploited this conceptual framework and targeted LDHA and GLS with small molecular inhibitors as proof-of- concept that altered cancer metabolism could be targeted for cancer therapy. Specifically, we documented that a drug-like inhibitor of LDHA could decreased tumor xenograft growth, providing evidence that metabolic therapy is feasible. We further found in a human Burkitt lymphoma model that Myc induces a genetic program that drives glutamine metabolism both under aerobic and hypoxic conditions. Inhibition of glutaminase, which converts glutamine to glutamate for its catabolism by the TCA cycle, by a drug-like molecule also diminished lymphoma xenograft growth in vivo. These studies indicate that targeting cancer cell metabolism could constitute a novel strategy to treat lymphoid neoplasias.