Abstract
Recent progress in understanding the molecular basis of cellular processes, identification of promising therapeutic targets and evolution of the regulatory landscape makes this an exciting and unprecedented time to be in the field of oncology drug development. However, high costs, long development timelines and steep rates of attrition continue to afflict the drug development process. Lack of predictive preclinical models is considered one of the key reasons for the high rate of attrition in oncology. Generating meaningful and predictive results preclinically requires a firm grasp of the relevant biological questions and alignment of the model systems that mirror the patient context. In doing so, the ability to conduct both forward translation, the process of implementing basic research discoveries into practice, as well as reverse translation, the process of elucidating the mechanistic basis of clinical observations, greatly enhances our ability to develop effective anticancer treatments. In this Review, we outline issues in preclinical-to-clinical translatability of molecularly targeted cancer therapies, present concepts and examples of successful reverse translation, and highlight the need to better align tumour biology in patients with preclinical model systems including tracking of strengths and weaknesses of preclinical models throughout programme development.
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Acknowledgements
The authors dedicate this work to the memory of Dr Georgia Hatzivassiliou. They also express gratitude to clinical trial patients and their families for their selfless contributions to research that is crucial for translation research and paves the way for improved patient treatments.
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S.K. is a consultant and member of the advisory boards of Boehringer Ingelheim, Springworks Therapeutics, Bayer, Genome & Company, HarbourBiomed, Seattle Genetics, Mundibiopharma and Gilead. She is also cofounder of PathomIQ, and her spouse is a member of the advisory board of Cadila Pharmaceuticals and cofounder of Arxeon. A.H. is a founder and shareholder of Arxeon. S.V.M. is founder and shareholder of Arxeon and scientific adviser for Cadila Pharmaceutical. M.R.J. is an employee of and owns stocks from ORIC Pharmaceuticals.
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Cancer Therapeutics Response Portal: A CTD 2 Network Resource for Mining Candidate Cancer Dependencies: https://ocg.cancer.gov/e-newsletter-issue/issue-11/cancer-therapeutics-response-portal-ctd%C2%B2-network
DepMap: The Cancer Dependency Map Project at Broad Institute: https://depmap.org/portal/ccle/
Office of Cancer Genomics: https://ocg.cancer.gov/node/300
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Honkala, A., Malhotra, S.V., Kummar, S. et al. Harnessing the predictive power of preclinical models for oncology drug development. Nat Rev Drug Discov 21, 99–114 (2022). https://doi.org/10.1038/s41573-021-00301-6
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DOI: https://doi.org/10.1038/s41573-021-00301-6
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