Activation of MYC family oncogenes is prevalent in rapidly dividing, highly glycolytic human tumors, including B-cell lymphoma. These oncoproteins functions as master regulatory transcription factors that coordinate the control of aerobic glycolysis, a hallmark of cancer. Our studies have shown that levels of the fatty acid synthesis enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) are elevated in human and mouse MYC-driven B-cell lymphoma and that these lymphoma cells are exquisitely sensitive to inhibitors that disable ACC1. Further, our studies have shown that MYC drives fatty acid synthesis in lymphoma by directly up-regulating the transcription of the genes encoding ACC1 and FASN (ACACA and FASN, respectively). In the studies of Specific Aim 1 we will use unbiased metabolomic approaches to define intermediates and metabolic pathways that are dependent on ACC1 in MYC-driven lymphoma. Further, using biochemical, molecular and genetic approaches we will address the mechanisms by which ACC1 directs metabolic cross talk.
In Specific Aim 2, we will use genetic approaches and mouse models to test the hypothesis that ACC1 is required for both the development and maintenance of MYC-driven lymphoma. Collectively, the proposed studies will rigorously evaluate the potential of ACC1 as a therapeutic target for lymphoma and whether targeting this enzyme represents an efficacious and selective means for disabling malignancies with MYC involvement. The proposed studies will also define novel interactions between ACC1 and other cancer metabolic pathways, which will enable the development of a platform to test combinatorial strategies with agents targeting ACC1.
Our recent studies have shown that the enzymes that direct de novo fatty acid synthesis, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), are highly elevated in human and mouse B-cell lymphomas driven by the MYC oncogene, and that they are direct MYC transcription targets. We will define the metabolic pathways of lymphomas that are dependent on ACC1 activity, the rate-limiting node in de novo fatty acid synthesis, and will assess the roles of ACC1 in the development and maintenance of MYC-driven lymphoma in vivo. The proposed studies will validate ACC1 as a therapeutic target for treating lymphomas having MYC involvement, and they will provide a platform for identifying, testing and validating new agents targeting this enzyme for cancer therapies.