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Targeting cancer metabolism in the era of precision oncology
Zachary E Stine1, Zachary T Schug2, Joseph M Salvino2
1Barer Institute 520 Broad Street, Newark, NJ, USA.
Abstract:
One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood leukaemia, and 20 years since metabolism was linked to oncogenes. However, progress in targeting cancer metabolism therapeutically in the past decade has been limited. Only a few metabolism-based drugs for cancer have been successfully developed, some of which are in - or en route to - clinical trials. Strategies for targeting the intrinsic metabolism of cancer cells often did not account for the metabolism of non-cancer stromal and immune cells, which have pivotal roles in tumour progression and maintenance. By considering immune cell metabolism and the clinical manifestations of inborn errors of metabolism, it may be possible to isolate undesirable off-tumour, on-target effects of metabolic drugs during their development. Hence, the conceptual framework for drug design must consider the metabolic vulnerabilities of non-cancer cells in the tumour immune microenvironment, as well as those of cancer cells. In this Review, we cover the recent developments, notable milestones and setbacks in targeting cancer metabolism, and discuss the way forward for the field.
Insights
Targeting cancer metabolism has seen limited success due to overlooking immune and stromal cells. Future strategies must consider the tumor immune microenvironment
Area of Science:
- Oncology
- Cancer Metabolism
- Drug Development
Background:
- Warburg effect (1920s) and anti-folate therapies (1950s) established cancer metabolism's importance.
- Limited therapeutic progress in targeting cancer metabolism over the past decade.
- Current strategies often neglect the metabolism of non-cancer cells in the tumor microenvironment.
Purpose of the Study:
- Review recent developments in targeting cancer metabolism.
- Identify milestones and setbacks in metabolism-based cancer drug development.
- Propose a forward-looking framework for future drug design.
Main Methods:
- Literature review of cancer metabolism research.
- Analysis of clinical trial data for metabolism-based cancer drugs.
- Integration of insights from immune cell metabolism and inborn errors of metabolism.
Main Results:
- Few metabolism-based cancer drugs have reached clinical trials.
- Failure to account for non-cancer cell metabolism leads to off-target effects.
- Immune and stromal cell metabolism critically influence tumor progression.
Conclusions:
- Future cancer drug design must incorporate the metabolic vulnerabilities of both cancer and non-cancer cells.
- Considering immune cell metabolism can help mitigate undesirable off-target effects.
- A holistic approach is needed to advance metabolism-based cancer therapies.
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