Cancer cells exhibit distinct metabolic requirements compared to healthy cells in order to support their rapid growth and proliferation. One of the key metabolic alterations in cancer is known as the "Warburg effect", named after the scientist Otto Warburg who first described it in 1924. The Warburg effect refers to cancer cells preferentially generating energy through a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than through a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells. This metabolic switch occurs even in the presence of oxygen, a phenomenon known as aerobic glycolysis.Another characteristic metabolic alteration in cancer cells is increased glutaminolysis, the conversion of glutamine to glutamate and further metabolized in the tricarboxylic acid (TCA) cycle. Glutamine serves as a key carbon and nitrogen source for biosynthesis of macromolecules required for rapid cancer cell proliferation. Cancer metabolism based therapeutics also exhibit increased lipogenesis and fatty acid synthesis to provide membrane phospholipids required for new membranes during cell division. Deregulated signaling pathways involved in cell growth and proliferation promote these distinct metabolic modifications required to support higher energetic and biosynthetic demands of cancer cells.Targeting Cancer Cell MetabolismUnderstanding the distinctive metabolic dependencies of cancer cells provides opportunities to develop novel therapeutics targeting Cancer Metabolism Based Therapeutics. Several drug molecules and strategies have been developed to exploit cancer cell-specific vulnerabilities arising from their rewired metabolic pathways.Inhibiting glycolysis in cancer cells is one strategy as they depend more on aerobic glycolysis versus oxidative phosphorylation. Several glycolytic enzyme inhibitors including hexokinase, phosphofructokinase and pyruvate kinase M2 inhibitors have shown preclinical anti-tumor activity. Another approach involves inhibiting glutaminolysis in cancer cells by targeting glutaminase, which converts glutamine to glutamate. Glutaminase inhibitors have demonstrated cell death selectively in glutamine-addicted cancer cells.Fatty acid synthesis is also increased in various cancers to support membrane biosynthesis, thereby providing a druggable target. Drugs targeting fatty acid synthase, a key enzyme of fatty acid synthesis pathway, have shown promise. Inhibition of citrate transport and ATP-citrate lyase, which provide acetyl-CoA for fatty acid synthesis, is another strategy. Recent research indicates that altering cancer cell redox balance by targeting metabolic nodes like malate dehydrogenase represents a novel therapeutic opportunity.Combining Metabolic Inhibitors With Conventional TherapiesCancer metabolism based therapeutics often work best in combination with other anticancer treatments, rather than as monotherapies. Combining metabolic inhibitors with conventional chemotherapies or targeted therapies can offer synergistic effects by blocking complementary survival mechanisms. Additionally, metabolic therapy may help overcome resistance to conventional treatments by blocking metabolic adaptations cancer cells use to evade these therapies.Several studies have demonstrated augmented cytotoxic effects of combining metabolic inhibitors with chemotherapy drugs. For example, co-administration of the glycolysis inhibitor 2-deoxyglucose enhances the anti-tumor activity of doxorubicin. Combining the fatty acid synthase inhibitor orlistat with paclitaxel shows enhanced apoptosis in prostate cancer cells compared to either drug alone. Further, glutaminase inhibition potentiates the effect of mTOR inhibitors in triple-negative breast cancer models.Combining cancer metabolism based therapeutics modulators may also help address challenges like drug resistance and off-target effects seen with single-agent targeted therapies. For instance, concurrent inhibition of glycolysis and glutaminolysis using dichloroacetate and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide respectively overcomes resistance to EGFR inhibitors in non-small cell lung cancer models. Integrating metabolic therapies into treatment regimens thus holds promise to augment the efficacy of standard-of-care regimens and help overcome resistance issues.Moving Metabolic Therapies to the ClinicSeveral cancer metabolism based therapeutics have advanced to clinical trials based on promising preclinical evidence. 2-deoxyglucose entered Phase I/II trials for solid tumors and leukemia but was not pursued further. More selective inhibitors targeting key tumor metabolism enzymes like hexokinase II, lactate dehydrogenase and glutaminase have since been developed and are in early-phase trials.A Phase I study evaluated the glutaminase inhibitor CB-839 in solid tumors and non-Hodgkin's lymphoma. It showed good tolerability andstable disease in some patients. CB-839 is now in Phase II trials in combination with paclitaxel for non-small cell lung cancer. Another glutaminase inhibitor, ONC201, entered Phase II trial for glioblastoma based on its activity in preclinical models.The fatty acid synthase inhibitorTVB-2640 progressed to Phase I trial in solid tumors and lymphoma. It showed favorable safety profile and preliminary signs of clinical activity. Further Phase Ib/II trials are ongoing in combination with chemotherapy. Metabolic imaging techniques using PET scans could facilitate stratifying patients and monitoring responses to metabolic therapies. More robust clinical validation will be vital to realize the potential of targeting cancer metabolism for therapy.
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