Cancer Metabolism Based Therapeutics : Understanding Cancer Cell Metabolism

Cancer Metabolism Based Therapeutics

Cancer cells have unique metabolic properties that distinguish them from normal cells. Cancer cells utilize aerobic glycolysis even in the presence of oxygen, a phenomenon known as the "Warburg effect". This shift to glycolysis provides cancer cells with building blocks for biomass accumulation to support rapid proliferation. Cancer cells also exhibit enhanced glutaminolysis and reductive carboxylation to support biosynthetic pathways. Understanding the metabolic alterations in cancer cells has revealed new opportunities for targeted therapy.

Targeting Glycolysis

One attractive strategy is to target the elevated glycolytic activity in cancer metabolism based therapeutics. 2-deoxyglucose (2-DG) is a glucose analog that enters cells via glucose transporters but cannot be further metabolized. 2-DG competitively inhibits glycolysis and shows promising anticancer activity both alone and in combination with other drugs. Other glycolytic inhibitors in clinical trials include lonidamine targeting hexokinase and 3-bromopyruvate targeting hexokinase and GAPDH. Preliminary results indicate they can induce cancer cell death when glucose is primary energy source. However, targeting a single node of glycolysis may allow compensatory pathways to emerge. Combination therapy blocking multiple points may provide a more durable therapeutic effect.

Modulating Glutaminolysis

Cancer Metabolism Based Therapeutics rely heavily on glutamine metabolism and glutaminolysis to sustain anabolic processes. CB-839 is a first-in-class glutaminase inhibitor showing efficacy against hematologic and solid tumors in early clinical trials. CB-839 blocks glutamine conversion to glutamate, depleting the TCA cycle intermediate alpha-ketoglutarate. This metabolic stress impairs biomass accumulation and tumor growth. Other agents like bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide target glutamate dehydrogenase to limit glutamine-derived anaplerosis. Preliminary results indicate these agents can stunt tumor progression as single agents and in combination with standard chemotherapy. Larger clinical trials are ongoing to validate glutaminolysis inhibition as a viable anticancer strategy.

Enzymes Of Lipid Biosynthesis With Cancer Metabolism Based Therapeutics

Dysregulated lipid metabolism enables cancer cells to synthesize membranes for rapid proliferation. Fatty acid synthase (FASN) overexpression is linked to aggressiveness in many cancers. TVB-2640 is a first-in-class small molecule inhibitor of FASN currently in Phase 1 trials. TVB-2640 limits fatty acid production from glucose/acetyl-CoA, activating AMPK-mediated energy stress responses. Another strategy is blocking reductive carboxylation of glutamine-derived alpha-ketoglutarate to isocitrate by inhibiting IDH1/2. Enasidenib is an FDA-approved IDH2 inhibitor showing clinical activity in acute myeloid leukemia. IDH inhibition not only restricts lipid biosynthesis but also impacts other important anabolic/biosynthetic pathways reliant on alpha-ketoglutarate. These agents demonstrate the therapeutic potential of targeting dysregulated lipid metabolism in cancer.

Interfering with TCA Cycle Function

The TCA cycle interfaces with multiple anabolic pathways supplying precursors and reducing equivalents in cancer cells. Agents targeting specific TCA cycle enzymes are under investigation. AZD3965 is a first-in-class inhibitor of malate dehydrogenase (MDH) catalyzing the interconversion of malate and oxaloacetate. By limiting oxaloacetate availability, MDH inhibition is anticipated to impair lipogenesis, glutaminolysis and nucleotide biosynthesis. MDH inhibition has demonstrated broad anticancer activity across subcutaneous xenograft models as a single agent and in drug combinations. Other candidates targeting isocitrate dehydrogenase 3 (IDH3), succinate dehydrogenase (SDH) or fumarate hydratase (FH) aim to disrupt TCA cycle anaplerosis or disrupt flux through the cycle. Further research is assessing if specific tumors may be "addicted" to individual TCA enzymes.

Combination Therapy Approaches

While monotherapies targeting individual nodes show promise, resistance often emerges. Combining non-overlapping metabolic inhibitors may provide a more durable blockade of cancer cell metabolism. Early trials combining glycolysis inhibitors like 2-DG with glutaminolysis inhibitors such as CB-839 demonstrate increased antitumor activity versus single agents alone. Combining glycolysis inhibitors with lipid synthesis inhibitors like TVB-2640 or TCA cycle inhibitors such as AZD3965 warrants investigation. Preliminary data also support combining metabolic inhibitors with conventional therapy. For instance, 2-DG enhances radiation therapy's tumor control effects. Metabolic therapy combinations disrupt energetic and anabolic redundancy while minimizing compensatory escape pathways. Larger clinical trials are expanding our understanding of optimal metabolic therapy combinations across different cancer subtypes.

Cancer metabolism based therapeutics remains an area of intense research focus. Advances in understanding the unique metabolic requirements of proliferating cancer cells have uncovered vulnerabilities that can be therapeutically targeted. Agents inhibiting glycolysis, glutaminolysis, lipid synthesis and TCA cycle function are progressing through early clinical evaluation, both alone and in combination regimens. Improving metabolic targeting requires overcoming resistance, optimizing drug combinations and identifying biomarkers predictive of response. Further research advances integrating metabolism, genomics and systems biology hold promise to develop more effective personalized metabolic therapy strategies against cancer in the future.
Get more insights on Cancer Metabolism Based Therapeutics
About Author:
Money Singh is a seasoned content writer with over four years of experience in the market research sector. Her expertise spans various industries, including food and beverages, biotechnology, chemical and materials, defense and aerospace, consumer goods, etc. (https://www.linkedin.com/in/money-singh-590844163)