Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers

With the foundation pre-laid, research in the new millennium has readily excavated and expanded upon the architectural framework laid out by Otto Warburg's seminal work in a new wave of “westward expansion,” ever widening our understanding of cancer metabolism beyond the telescopic vision seen over a century ago. On this path, the unique circuitry of the cancer metabolic program has been elucidated, illuminating mutations of conserved cellular pathways implicated in tumorigenesis. Paramount among these are mutations in tricarboxylic acid cycle enzymes, succinate dehydrogenase, and fumarate hydratase, leading to deleterious accumulations in metabolic intermediates, “oncometabolites,” the pilots of the disease process. In this work, we seek to reflect on the advancements in the field in recent years, updating knowledge on the exact biochemical mechanisms at the helm of the tumor, providing rationale for clinical trials currently underway, and anticipating directions for the future on this expansive frontier.