Biosynthetic and Energetic Lethality of Targeting Metabolic Plasticity for Cancer Treatment

Abstract

Solid tumors are composed of numerous heterogeneous tissue types with a diverse molecular pathology. Uncontrolled replication and division, along with nutrient and oxygen gradients across the tumor, dictate dynamic intratumoral phenotypes that are reinforced by molecular hallmarks of cancer; largely shaping modern clinical treatment regimens. Importantly, deregulated energetics and reprogrammed tumor metabolism enable constitutive growth in challenging microenvironments. The ability of malignant cells to switch between numerous metabolic phenotypes (metabolic plasticity) allows for the generation of energy, appropriation of biosynthetic building blocks, and control of redox equilibrium. Hence, therapeutic targeting of metabolic plasticity with small molecules holds promise as a novel and enduring therapeutic strategy. In this regard, the current thesis work describes efforts toward developing novel small molecule mitochondrial pyruvate carrier inhibitors to induce bioenergetic and synthetic lethality in cancer cells.