Cancer cells alter their metabolic program to maintain cell autonomous proliferation. Some of the most striking changes of tumor cellular bioenergetics include elevation of glycolysis, increased glutaminolytic flux, up- regulation of amino acid and lipid metabolism, enhancement of mitochondrial biogenesis, induction of the pentose phosphate pathway and macromolecule biosynthesis. My interest in metabolic regulation and cancer led me to undertake my PhD study on the role of metabolic stress inducing agents in prostate cancer cell survival. My PhD work helped to understand the role of metabolic perturbations on cancer cell viability and we were among the first groups in the world to uncover the anti-cancer properties of the anti-diabetic drug metformin. My postdoctoral work revealed a new connection between mTORC1 signaling and metabolic pathways. We showed that mTORC1 activation via a physiological or an oncogenic stimulus, led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway, which serves to make building blocks of RNA and DNA required for anabolic cell growth and proliferation. mTORC1 signaling post-translationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates Ser1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), an enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. My goal is to investigate the molecular links between cellular metabolism and oncogenic events. Ultimately, my long-term career goal is to obtain a tenure-track faculty position at an academic institution where I will be able to expand my area of research, train and instruct graduate and undergraduate students and collaborate with my academic peers. The research proposed in the mentored phase of this application will focus on the role of Ser1859 phosphorylation of CAD in tumor metabolism and the role of mTORC1 on de novo purine synthesis. The research outlined in the independent phase will seek to identify novel connections between oncogenic and physiological signals and the de novo and salvage nucleotide synthesis to uncover a potential therapeutic target to specifically kill tumor cells. Th initial discovery that cancer cells exhibit atypical metabolic characteristics can be traced to the pioneering work of Otto Warburg, over the first half of the twentieth century. Deciphering the interplay between oncogenic processes and metabolic pathways that contribute to metabolic reprogramming in a given setting may serve as the critical factor in determining therapeutic targets that enable maximal drug efficacy with minimal deleterious effect on normal cells. Ultimately, my research proposal will ideally facilitate further progress in capitalizing upon the exploitation of atypical metabolic features in cancer as a means of therapeutic intervention.
In cancer, chemotherapeutic agents are commonly used to target all proliferative cells and consequently they induce many adverse side effects in patients. Finding molecular connections between oncogenes and metabolic enzymes that trigger nucleotide synthesis in cancer cells could open new therapeutic avenues to treat cancer.
| Hoxhaj, Gerta; Hughes-Hallett, James; Timson, Rebecca C et al. (2017) The mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels. Cell Rep 21:1331-1346 |
| Ben-Sahra, Issam; Manning, Brendan D (2017) mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol 45:72-82 |
