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Parsels LA, Zhang Q, Karnak D, et al. Translation of DNA Damage Response Inhibitors as Chemoradiation Sensitizers From the Laboratory to the Clinic. Int J Radiat Oncol Biol Phys. 2021;111(5):e38-e53doi: 10.1016/j.ijrobp.2021.07.1708.
Parsels, L. A., Zhang, Q., Karnak, D., Parsels, J. D., Lam, K., Willers, H., Green, M. D., Rehemtulla, A., Lawrence, T. S., & Morgan, M. A. (2021). Translation of DNA Damage Response Inhibitors as Chemoradiation Sensitizers From the Laboratory to the Clinic. International journal of radiation oncology, biology, physics, 111(5), e38-e53. https://doi.org/10.1016/j.ijrobp.2021.07.1708
Parsels, Leslie A, et al. "Translation of DNA Damage Response Inhibitors as Chemoradiation Sensitizers From the Laboratory to the Clinic." International journal of radiation oncology, biology, physics vol. 111,5 (2021): e38-e53. doi: https://doi.org/10.1016/j.ijrobp.2021.07.1708
Parsels LA, Zhang Q, Karnak D, Parsels JD, Lam K, Willers H, Green MD, Rehemtulla A, Lawrence TS, Morgan MA. Translation of DNA Damage Response Inhibitors as Chemoradiation Sensitizers From the Laboratory to the Clinic. Int J Radiat Oncol Biol Phys. 2021 Dec 01;111(5):e38-e53. doi: 10.1016/j.ijrobp.2021.07.1708. Epub 2021 Aug 01. PMID: 34348175; PMCID: PMC8602768.
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Int J Radiat Oncol Biol Phys. 2021 Dec 01;111(5):e38-e53. doi: 10.1016/j.ijrobp.2021.07.1708. Epub 2021 Aug 01.

Translation of DNA Damage Response Inhibitors as Chemoradiation Sensitizers From the Laboratory to the Clinic.

International journal of radiation oncology, biology, physics

Leslie A Parsels, Qiang Zhang, David Karnak, Joshua D Parsels, Kwok Lam, Henning Willers, Michael D Green, Alnawaz Rehemtulla, Theodore S Lawrence, Meredith A Morgan

Affiliations

  1. Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, Michigan.
  2. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  3. Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, Michigan. Electronic address: [email protected].

PMID: 34348175 PMCID: PMC8602768 DOI: 10.1016/j.ijrobp.2021.07.1708

Abstract

Combination therapies with agents targeting the DNA damage response (DDR) offer an opportunity to selectively enhance the therapeutic index of chemoradiation or eliminate use of chemotherapy altogether. The successful translation of DDR inhibitors to clinical use requires investigating both their direct actions as (chemo)radiosensitizers and their potential to stimulate tumor immunogenicity. Beginning with high-throughput screening using both viability and DNA damage-reporter assays, followed by validation in gold-standard radiation colony-forming assays and in vitro assessment of mechanistic effects on the DDR, we describe proven strategies and methods leading to the clinical development of DDR inhibitors both with radiation alone and in combination with chemoradiation. Beyond these in vitro studies, we discuss the impact of key features of human xenograft and syngeneic mouse models on the relevance of in vivo tumor efficacy studies, particularly with regard to the immunogenic effects of combined therapy with radiation and DDR inhibitors. Finally, we describe recent technological advances in radiation delivery (using the small animal radiation research platform) that allow for conformal, clinically relevant radiation therapy in mouse models. This overall approach is critical to the successful clinical development and ultimate Food and Drug Administration approval of DDR inhibitors as (chemo)radiation sensitizers.

Copyright © 2021 Elsevier Inc. All rights reserved.

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