Tumor cell metabolism has recently attracted substantial attention as an area for the development of drugs to treat cancer. Rafael Pharmaceuticals is one of the most effective leaders in this area.
It has been known for nearly a century that cancer cells have a unique metabolism that becomes substantially altered in the course of emergence of malignant disease. This altered metabolism is considered to be fundamental to the transformation of normal cells into cancer cells and is believed to be conserved in most, if not all, cancers, including solid tumors, lymphomas, and leukemias.
This hallmark metabolic transformation includes diversion of metabolic resources for anabolic purposes, supporting creation of biosynthetic intermediates, or building blocks, for new cell growth and proliferation. As a result, metabolic requirements and nutrient uptake by cancer cells are altered fundamentally compared to normal cells. For example, one widely understood link between cancer and metabolism is the increased uptake of glucose by tumor cells. This increased uptake has been utilized to provide enhanced imaging, diagnosis, and staging of tumors in humans via Positron Emission Tomography (PET) imaging, illustrating the pervasiveness of altered metabolism in cancer.
Glucose is metabolized to pyruvate which then is either reduced to lactate by lactate dehydrogenase (LDH) or oxidized to acetyl coenzyme A (acetyl-CoA) by pyruvate dehydrogenase (PDH) for introduction into the mitochondrial tricarboxylic acid (TCA) cycle. This acetyl-CoA then can be used for either energy generation (catabolism) or biosynthetic intermediate production (anabolism), both crucial to tumor cell survival. Glutamine is an additional carbon source, also essential for sustaining the TCA cycle in tumor cells. Glutamine transport and metabolism are also upregulated in many tumor types. Glutamine is converted to glutamate, then to α-ketoglutarate (α-KG). α-KG enters the TCA cycle through conversion to succinyl-CoA by α-ketoglutarate dehydrogenase (KGDH).
In service of these crucial functions of PDH and KGDH in the modified metabolism of tumor cells, the regulation of these two enzymes is substantially altered during emergence of metastatic disease. Central to these altered cancer regulatory systems are those responding to levels of catalytic intermediates formed by the lipoate cofactors of both PDH and KGDH. Rafael’s first-in-class drug CPI-613® (devimistat) is designed to be a stable analog of these lipoate catalytic intermediates, thereby targeting these tumor-specific regulatory processes. This CPI-613 targeting misinforms these tumor regulatory systems, shutting off both PDH and KGDH, selectively in tumor cells. CPI-613 tumor selectivity is further enhanced because cancer cells take up the drug preferentially. This tumor-specific drug attack on PDH and KGDH is sufficient to profoundly compromise tumor cell survival under diverse conditions relevant to clinical effect.
More specifically, CPI-613 selectively inactivates PDH in tumor cells by hyper-activating the corresponding tumor-specific configuration of regulatory pyruvate dehydrogenase kinase (PDKs). PDKs phosphorylate and inactivate PDH. As well, CPI-613 simultaneously inactivates KGDH by hyper-activating a redox feedback loop normally controlling the enzyme’s activity and reconfigured in tumors. The simultaneous inhibition of these two TCA cycle enzymes dramatically compromises mitochondrial catabolic and anabolic functions, an outcome contributing to multiple, redundant apoptotic and necrotic cell death pathways selectively in tumor cells [Zachar et al., J Mol Med. 2011 89:1137; Stuart et al., Cancer Metab. 2014 2:4; reviewed in Bingham et al., Expert Rev Clin Pharmacol. 2014 7:837].
This robust, redundant effect of CPI-613 on tumor metabolism sensitizes tumor cells in patients to traditional standards of care. Moreover, the very low toxicity of CPI-613 (resulting from its high tumor selectivity) allows the drug to be readily combined with diverse existing standards of care in the clinic. CPI-613 has shown encouraging signals in such combinations in investigational clinical trials (Alistar, et al. 2017 Lancet Oncol 18:770) and is currently in Phase III registrational trials for two difficult-to-treat cancers, acute myeloid leukemia (AML; NCT03504423) and pancreatic ductal adenocarcinoma (PDAC; NCT03504410).
Alternative cancer treatments also under investigation focus on other elements of cancer cell metabolism, including glutatmine, 1-carbon, methionine/methylation, arginine, and oncometabolites (like 2-hydroxyglutarate)(reviewed in Vazquez, et al., 2016 J Cell Science 129:3367). While oncometabolite targeting has proven effective against cancer epigenetics, the other approaches targeting tumor metabolism, sensu stricto, have thus far proven clinically limited. This likely reflects their targeting of isolated components of a highly redundant system of cancer metabolism. In contrast, the TCA cycle is central and indispensible for the large majority of anabolic and catabolic processes; by redundantly targeting the TCA cycle, CPI-613 apparently produces useful clinical effects.
Please read the Cancer Metabolism Backgrounder to learn more!