Cancer cells have altered metabolism compared to normal cells that allows them to rapidly proliferate and grow unchecked. One of the hallmarks of cancer is changes in how cancer cells derive energy and building blocks through various metabolic pathways. Cancer cells preferentially use aerobic glycolysis even in the presence of oxygen, a process known as the Warburg effect. This allows cancer cells to generate energy and intermediates needed for biomass production at a rapid rate to support uncontrolled growth and division. Cancer cells also alter metabolism of other pathways such as fatty acid, amino acid and nucleotide synthesis to meet the high demand of building blocks for new cells. Understanding the specific metabolic alterations in different cancer types is key to developing effective targeted therapeutics.
Inhibiting Cancer Metabolism Based Therapeutics
Given the altered Cancer Metabolism Based Therapeutics requirements of cancer cells compared to normal cells, targeting specific metabolic pathways that are upregulated in cancers is a promising therapeutic strategy. Several metabolic enzymes that are overexpressed in cancers are being investigated as drug targets. Monocarboxylate transporter 4 (MCT4) involved in lactate efflux is overexpressed in many cancers and MCT4 inhibitors are being studied. Fatty acid synthase (FASN) which produces fatty acids is overexpressed in breast and prostate cancers and FASN inhibitors show anticancer activity. Glutaminase which breaks down glutamine is elevated in many cancers and glutaminase inhibitors reduce tumor growth in preclinical models. Inhibiting key enzymes in metabolic pathways preferentially utilized by cancer cells offers the potential for increased selectivity and reduced toxicity compared to conventional chemotherapy.
Targeting Metabolic Dependencies
Beyond direct inhibition of metabolic enzymes, targeting the metabolic dependencies or Achilles heels of different cancer types also holds promise. For example, inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ salvage pathway, is synthetically lethal to cancers dependent on NAMPT expression. NAMPT inhibitors are being evaluated in clinical trials. Many cancers also depend on mitochondrial metabolism and inhibitors of mitochondrial complex I such as metformin show anticancer effects in certain contexts by imposing metabolic stress. Another dependency is on serine synthesis pathway (SSP) required for one-carbon metabolism, with SSP inhibition antiproliferative in SSP-dependent cancers. Advances in understanding cancer metabolism based therapeutics throughmulti-omics analyses will aid in matching the right metabolic dependencies to the right cancer types for improved patient outcomes.
Metabolic Immuno-Oncology Approaches
Novel therapeutics are also exploring the interaction between cancer metabolism based therapeutics and immunity. Metabolism shapes the tumor microenvironment and immune cell functions in tumors. For example, lactate produced during aerobic glycolysis in tumors suppresses antitumor T cell activities. Blocking lactate efflux enhances T cell functions and response to immunotherapy. Targeting other aspects like glucose and glutamine metabolism can also modulate immunosuppressive mechanisms in the tumor microenvironment to synergize with checkpoint inhibitors. Dual targeting of cancer metabolism and immune system holds promise to improve current immunotherapies which work in only a subset of patients. Metabolic modulators are being studied alone or in combination with checkpoint blockade to improve response rates across more cancer types.
Cancer Metabolism Based Therapeutics as Biomarker
Beyond direct therapeutic targeting, cancer metabolism alterations also offer opportunities as predictive and prognostic biomarkers to guide clinical management. Gene expression signatures or enzyme/metabolite levels related to specific metabolic pathways can classify cancers and predict patient outcomes and treatment responses. For example, high expression of glycolytic enzymes correlates with worse prognosis in many cancers. Detecting serine/glycine metabolite ratios via magnetic resonance spectroscopy holds potential as a non-invasive biomarker to predict response to SSP pathway inhibitors in early clinical trials. Multi-omics profiling provides comprehensive maps of metabolism alterations in tumors that may help stratify patients to appropriate metabolic therapies. Continued biomarker development is important to fully realize the potential of cancer metabolism-based precision oncology approaches.
Combination Strategies
Given the complexity and redundancy in cancer biology, targeting a single pathway is unlikely to achieve durable responses in the vast majority of patients. Combination strategies provide synergistic effects by simultaneously attacking cancer at multiple vulnerabilities. Combining metabolic therapies with each other, immunotherapies or conventional treatments offers opportunities to improve outcomes. For example, combination of metformin with immunotherapy or chemotherapy shows improved efficacy preclinically compared to monotherapy. Given metabolic interactions between cancer and stromal cells, targeting metabolism of both tumor and supporting stroma also holds promise. Advancements in high-throughput drug combination screening and mechanistic understanding will pave the way for rationally designed combination regimens that optimally leverage cancer metabolic liabilities to tackle treatment resistance.
Understanding alterations in cancer metabolism based therapeutics provides new avenues for developing selective therapeutics with potentially improved safety profiles compared to conventional chemotherapy. While promising results have emerged from early clinical trials, challenges remain in matching the right therapeutic strategy to individual cancer types and patients based on their specific metabolic profiles and dependencies. Further refinement of predictive biomarkers and combining metabolic therapies with each other or other treatment modalities holds promise to improve clinical efficacy. Advancements in multi-omics technologies, high-throughput screens, computational systems modeling will accelerate progress towards realizing the full potential of exploiting cancer metabolism based therapeutics for clinical benefit. With continued foundational research investments, cancer metabolism-based approaches have potential to transform cancer treatment landscape in the coming decades.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
About Author – Money Singh
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, chemicals and materials, defense and aerospace, consumer goods, etc. LinkedIn Profile