A hallmark of cancer is glucose catabolism via aerobic glycolysis (the Warburg effect). This phenotype includes marked increases in the expression of glucose and amino acid transporters and a switch in the functions of mitochondria to an anabolic organelle. The combined effect is a marked diversion (~95%) of pyruvate towards lactate, which is exported out of the cancer cell via dedicated 12-transmembrane-pass monocarboxylic acid transporters coined Mct1 and Mct4, which we have shown are overexpressed and inversely regulated in several tumor types. Myc oncoproteins are activated in nearly 70% of human cancers, where they orchestrate wholesale changes in gene transcription that drive tumorigenesis, including a cast of metabolic enzymes. We have shown that most glycolytic enzymes and amino acid transporters are elevated in premalignant Myc-expressing B cells, and that this response is amplified in Myc-driven lymphoma. Accordingly, premalignant and neoplastic Myc-expressing B cells produce excess levels of lactate. Notably, we have shown that Myc coordinates lactate homeostasis in the cell by directly inducing the transcription of Mct1, and that elevated MCT1 is a hallmark of human malignancies with MYC involvement. Importantly, our Multi-PI research team, which combines expertise in cancer genetics and therapeutics (PI Dr. John Cleveland) with a world leader in synthetic organic chemistry and the derivation of novel therapeutics (PI Dr. William Roush), has demonstrated that established and new in-house agents that inhibit Mct1 disable human lymphoma and breast cancer cell metabolism and proliferation, and impair tumorigenesis without side effects. Thus, we hypothesize that blocking Mct1- and/or Mct4-directed lactate transport is an innovative, widely applicable strategy for anti-cancer therapy. Using both mouse and human tumor models, in Aim 1 we test the hypothesis that Mct1 is necessary for both the development and maintenance of Myc-driven lymphoma, and in Aim 2 we test the contribution of both Mct1 and Mct4 to the development and maintenance of breast cancer.
In Aim 3 the drug-likeness of our lead Mct1 inhibitors will be optimized using reiterative efficacy, medicinal chemistry and DMPK screens. We will also develop, validate and refine Mct4 inhibitors and develop pan-Mct1/Mct4 inhibitors. These new agents will be tested for efficacy, safety, and selectivity using our mouse and human lymphoma and breast cancer models.
In Aim 4 we will exploit the increased expression of the glutamine (e.g., Asct2) and large neutral amino acid transporters (e.g., LAT1) manifest in human malignancies. Specifically, we will chemically tether our anti-Mct inhibitors to ligands for these transporters, which we have shown augments their tumor cell delivery and potency. The efficacy, potency, selectivity and safety of these novel conjugates will be tested using lymphoma and breast cancer models. We submit that the assembled research team will generate a cast of new, efficacious and safe anti-cancer agents that will have applications in chemoprevention and as broad-spectrum therapeutics.
A hallmark of cancer is the metabolic switch to aerobic glycolysis, which includes increased expression of glucose and amino acid transporters and the catabolism of glucose via the glycolytic pathway, and which leads to marked increases in the production of lactic acid. Our CA154739A1 multi-PI research team has shown that cancer cells solve this intrinsic 'lactate dilemma'by increasing the expression of monocarboxylic acid transmembrane transporters coined Mct1 and Mct4, and we have discovered that Mct1 is a direct transcription target of Myc oncoproteins, which are activated in ~70% of human tumors and which coordinate the control of cancer cell metabolism. Importantly, we have shown that disrupting Mct1 functions using genetic approaches or new, in-house Mct1-specific inhibitors disables tumor cell metabolism and proliferation and tumorigenesis in vivo, and using genetic and directed synthetic approaches, we will develop, validate, refine and test the selectivity, efficacy and safety of new Mct1 and Mct4-specific inhibitors in preventing and treating cancer.
|Wang, Hui; Yang, Chunying; Doherty, Joanne R et al. (2014) Synthesis and structure-activity relationships of pteridine dione and trione monocarboxylate transporter 1 inhibitors. J Med Chem 57:7317-24|
|Doherty, Joanne R; Cleveland, John L (2013) Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123:3685-92|