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Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements

Abstract

The rapid development of new therapeutic agents that target specific molecular pathways involved in tumour cell proliferation provides an unprecedented opportunity to achieve a much higher degree of biochemical specificity than previously possible with traditional chemotherapeutic anticancer agents. However, the lack of specificity of these established chemotherapeutic drugs allowed a relatively straightforward approach to their use in combination therapies. Developing a paradigm for combining new, molecularly targeted agents, on the other hand, is substantially more complex. The abundance of molecular data makes it possible, at least in theory, to predict how such agents might interact across crucial growth control networks. Initial strategies to examine molecularly targeted agent combinations have produced a small number of successes in the clinic. However, for most of these combination strategies, both in preclinical models and in patients, it is not clear whether the agents being combined actually hit their targets to induce growth inhibition. Here, we consider the initial approach of the US National Cancer Institute (NCI) to the evaluation of combinations of molecularly targeted anticancer agents in patients and provide a description of several new approaches that the NCI has initiated to improve the effectiveness of combination-targeted therapy for cancer.

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Figure 2: Effects of rapamycin and cyclophosphamide alone and in combination.
Figure 3: Molecular toxicology assessments.

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Acknowledgements

The authors wish to express their appreciation to the members of the National Cancer Institute's Cancer Therapy Evaluation Program who have overseen the clinical trials described in this paper and the members of the National Cancer Institute's Developmental Therapeutics Program who have had an essential role in coordinating the initiatives outlined in the paper. This work was supported by federal funds from the National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or the policies of the US Department of Health and Human Services nor does the mention of trade names, commercial products or organizations imply endorsement by the US government.

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Kummar, S., Chen, H., Wright, J. et al. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat Rev Drug Discov 9, 843–856 (2010). https://doi.org/10.1038/nrd3216

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