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Searching for Goldilocks: How Evolution and Ecology Can Help Uncover More Effective Patient-Specific Chemotherapies

Derek S. Park, Kimberly A. Luddy, Mark Robertson-Tessi, Cliona O'Farrelly, Robert A. Gatenby and Alexander R.A. Anderson
Derek S. Park
1Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
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  • For correspondence: derek.park@aya.yale.edu alexander.anderson@moffitt.org
Kimberly A. Luddy
2Trinity Biosciences Institute, Trinity College, Dublin, Ireland.
3Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Mark Robertson-Tessi
1Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Cliona O'Farrelly
2Trinity Biosciences Institute, Trinity College, Dublin, Ireland.
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Robert A. Gatenby
1Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
4Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Alexander R.A. Anderson
1Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
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  • For correspondence: derek.park@aya.yale.edu alexander.anderson@moffitt.org
DOI: 10.1158/0008-5472.CAN-19-3981 Published December 2020
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Abstract

Deaths from cancer are mostly due to metastatic disease that becomes resistant to therapy. A mainstay treatment for many cancers is chemotherapy, for which the dosing strategy is primarily limited by patient toxicity. While this MTD approach builds upon the intuitively appealing principle that maximum therapeutic benefit is achieved by killing the largest possible number of cancer cells, there is increasing evidence that moderation might allow host-specific features to contribute to success. We believe that a “Goldilocks Window” of submaximal chemotherapy will yield improved overall outcomes. This window combines the complex interplay of cancer cell death, immune activity, emergence of chemoresistance, and metastatic dissemination. These multiple activities driven by chemotherapy have tradeoffs that depend on the specific agents used as well as their dosing levels and schedule. Here we present evidence supporting the idea that MTD may not always be the best approach and offer suggestions toward a more personalized treatment regime that integrates insights into patient-specific eco-evolutionary dynamics.

Footnotes

  • Cancer Res 2020;80:5147–54

  • Received December 20, 2019.
  • Revision received August 4, 2020.
  • Accepted September 9, 2020.
  • Published first September 15, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Research: 80 (23)
December 2020
Volume 80, Issue 23
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Searching for Goldilocks: How Evolution and Ecology Can Help Uncover More Effective Patient-Specific Chemotherapies
Derek S. Park, Kimberly A. Luddy, Mark Robertson-Tessi, Cliona O'Farrelly, Robert A. Gatenby and Alexander R.A. Anderson
Cancer Res December 1 2020 (80) (23) 5147-5154; DOI: 10.1158/0008-5472.CAN-19-3981

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Searching for Goldilocks: How Evolution and Ecology Can Help Uncover More Effective Patient-Specific Chemotherapies
Derek S. Park, Kimberly A. Luddy, Mark Robertson-Tessi, Cliona O'Farrelly, Robert A. Gatenby and Alexander R.A. Anderson
Cancer Res December 1 2020 (80) (23) 5147-5154; DOI: 10.1158/0008-5472.CAN-19-3981
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  • Article
    • Abstract
    • Finding the Goldilocks Window
    • Preserving Immune Activity to Maximize Cell Kill
    • Evolutionary Tradeoffs: Resistance and Adaptive Therapy
    • Goldilocks Dosing and Metastatic Risk
    • Conclusions
    • Disclosure of Potential Conflicts of Interest
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