title: Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.
abstract: There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. Clin Cancer Res; 22(13); 3138-47. ©2016 AACR.
authors.affiliation: Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), NIH, Bethesda, Maryland. ccoleman@mail.nih.gov.
authors.forename: C Norman
authors.initials: CN
authors.lastname: Coleman
authors.affiliation: Cancer Research UK/Medical Research Council, Oxford Institute for Radiation Oncology, University of Oxford, United Kingdom.
authors.forename: Geoff S
authors.initials: GS
authors.lastname: Higgins
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
authors.affiliation: OncoRay National Center for Radiation Research, Technische Universität Dresden/Helmholtz-Zenrtum Dresden-Rossendorf, Dresden, Germany and German Cancer Consortium, Dresden/German Cancer Research Center (DKFZ).
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Henning
authors.initials: H
authors.lastname: Willers
authors.affiliation: Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Pataje G S
authors.initials: PG
authors.lastname: Prasanna
authors.affiliation: Departments of Radiation Oncology, Pathology and Biomedical Engineering, Duke University, Durham, North Carolina.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.affiliation: Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bernhard
authors.affiliation: Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015203:Reproducibility of Results; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents