Radiation-Drug Combinations to Improve Clinical Outcomes and Reduce Normal Tissue Toxicities: Current Challenges and New Approaches: Report of the Symposium Held at the 63rd Annual Meeting of the Radiation Research Society, 15-18 October 2017; Cancun, Mexico

Abstract

The National Cancer Institute's (NCI) Radiation Research Program (RRP) is endeavoring to increase the relevance of preclinical research to improve outcomes of radiation therapy for cancer patients. These efforts include conducting symposia, workshops and educational sessions at annual meetings of professional societies, including the American Association of Physicists in Medicine, American Society of Radiation Oncology, Radiation Research Society (RRS), Radiosurgery Society, Society of Nuclear Medicine and Molecular Imaging, Society for Immunotherapy of Cancer and the American Association of Immunology. A symposium entitled "Radiation-Drug Combinations to Improve Clinical Outcomes and Reduce Normal Tissue Toxicities" was conducted by the NCI's RRP during the 63rd Annual Meeting of the RRS on October 16, 2017 in Cancun, Mexico. In this symposium, discussions were held to address the challenges in developing radiation-drug combinations, optimal approaches with scientific evidence to replace standard-of-care, approaches to reduce normal tissue toxicities and enhance post-treatment quality-of-life and recent advances in antibody-drug conjugates. The symposium included two broad overview talks followed by two talks illustrating examples of radiation-drug combinations under development. The overview talks identified the essential preclinical infrastructure necessary to accelerate progress in the development of evidence and important challenges in the translation of drug combinations to the clinic from the laboratory. Also addressed, in the example talks (in light of the suggested guidelines and identified challenges), were the development and translation of novel antibody drug conjugates as well as repurposing of drugs to improve efficacy and reduce normal tissue toxicities. Participation among a cross section of clinicians, scientists and scholars-in-training alike who work in this focused area highlighted the importance of continued discussions to identify and address complex challenges in this emerging area in radiation oncology.

FIG. 1.

Proposed timelines for a new drug-radiotherapy combination, with suggested interactions with Regulatory Agency. MTD = maximum tolerated dose; BED = biologically effective dose; IND = investigational new drug; FDA = Food and Drug Administration; EMA = European Medicines Agency; NDA = new drug application; CHMP = Committee for Medicinal Products for Human Use. Modified and re-published with permission, from Sharma RA et al., “Clinical development of new drug-radiotherapy combinations.” Nat Rev Clin Oncol 2016; 13:627–42 (5).

FIG. 2.

Funding of clinical trials, stratified by phase and whether or not the trial involves use of radiation therapy. Based on an analysis from database www.clinicaltrials.gov (52).

FIG. 3.

Antibody drug conjugate targeted radiosensitization. Panel A: Cy5-labeled ADC with four molecules of radiosensitizing drug conjugated. Panel B: Cy5-labeled cetuximab (C-MMAE) or trastuzumab (T-MMAE) ADC bound specifically to EGFR⁺ cells (CAL27) and HER2⁺ cells (OE19), respectively. Panel C: Conjugating radiosensitizing maytansinoid to trastuzumab (T-DM1) restricts maytansinoid toxicity to HER2-expressing tumor cells. Unconjugated maytansinoid (mertansine) is equally cytotoxic to tumor cells irrespective of HER2 status. Panel D: T-DM1 in combination with irradiation results in significantly enhanced survival in preclinical murine tumor models. Survival of mice bearing HER2-expressing OE19 or NCI-N87 tumors. Trastuzumab or T-DM1 were given intravenously followed by localized irradiation to the tumor. Modified and re-published with permission, from Adams et al. “Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.” Nat Commun 2016; 7:13019 (26).

FIG. 4.

Repurposed drugs cause oxidative stress in cancer cells. BSO and AUR disrupt glutathione and thioredoxin-dependent peroxide scavenging pathways. DSF and DPEN in combination with copper as well as vitamin C in combination with iron induce production of superoxide and peroxide. BSO = buthionine sulfoxamine; AUR = auranofin; DSF = disulfiram; DPEN = d-penicillamine; GSH = glutathione; Trx = thioredoxin; TR = thioredoxin reductase; PRx = peroxiredoxin; GPx = glutathione peroxidase; H₂O₂ = hydrogen peroxide; O₂^·− = superoxide.