Radioprotectors and Radiomitigators for Improving Radiation Therapy: The Small Business Innovation Research (SBIR) Gateway for Accelerating Clinical Translation

Abstract

Although radiation therapy is an important cancer treatment modality, patients may experience adverse effects. The use of a radiation-effect modulator may help improve the outcome and health-related quality of life (HRQOL) of patients undergoing radiation therapy either by enhancing tumor cell killing or by protecting normal tissues. Historically, the successful translation of radiation-effect modulators to the clinic has been hindered due to the lack of focused collaboration between academia, pharmaceutical companies and the clinic, along with limited availability of support for such ventures. The U.S. Government has been developing medical countermeasures against accidental and intentional radiation exposures to mitigate the risk and/or severity of acute radiation syndrome (ARS) and the delayed effects of acute radiation exposures (DEARE), and there is now a drug development pipeline established. Some of these medical countermeasures could potentially be repurposed for improving the outcome of radiation therapy and HRQOL of cancer patients. With the objective of developing radiation-effect modulators to improve radiotherapy, the Small Business Innovation Research (SBIR) Development Center at the National Cancer Institute (NCI), supported by the Radiation Research Program (RRP), provided funding to companies from 2011 to 2014 through the SBIR contracts mechanism. Although radiation-effect modulators collectively refer to radioprotectors, radiomitigators and radiosensitizers, the focus of this article is on radioprotection and mitigation of radiation injury. This specific SBIR contract opportunity strengthened existing partnerships and facilitated new collaborations between academia and industry. In this commentary, we assess the impact of this funding opportunity, outline the review process, highlight the organ/site-specific disease needs in the clinic for the development of radiation-effect modulators, provide a general understanding of a framework for gathering preclinical and clinical evidence to obtain regulatory approval and provide a basis for broader venture capital needs and support from pharmaceutical companies to fully capitalize on the advances made thus far in this field.

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

“…A pathway for the development of radiation modifiers published recently (8, 67) suggests modifications to address the new biology; however time-honored assessments often referred to pejoratively as “classical” remain critical to both drug and radiation clinical trials (66). While animal normal tissue models may provide only limited information, normal tissue injury remains an integral part of preclinical development (67, 68) The need for studies will depend on the size of the treatment field as highly focused radiation fields in some regimens are designed to be at tissue-damaging doses to limited volumes and thereby minimizing clinically significant late effects.…”

“…It is effective and often curative, but would be more so if radiosensitizers, radioprotectors, and predictive biomarkers of patient and tumor radiation sensitivity were employed (2, 3). Radiation modifiers have been reviewed recently (4-8), as has the potential for radiation therapy to enhance the effectiveness of immunotherapeutics (9-11) to improve local tumor control as well as to induce abscopal effects that result in concomitant responses in distant metastases (12, 13). …”

Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity

“…The goals of this project are to; (1) Discover new SNP associations and validate previously identified SNPs linked with the development of adverse outcomes resulting from radiotherapy, (2) Build clinically useful multi-SNP models that incorporate dosimetric and clinical factors to predict susceptibility for the development of toxicities following radiotherapy and, (3) Develop a low-cost, high performance assay and companion risk assessment tool to predict risk for development of complications resulting from treatment with radiation. Related to this aim, research is being conducted that is supported by the NIH Small Business Innovation program 75 to help rapidly translate the findings from this project into an assay ready for implementation in the clinic and routine medical care.…”

Education and Training Needs in the Radiation Sciences: Problems and Potential Solutions

“…Physical methods for minimizing adverse effects include more precise imaging and target identification/localization, 3D conformal irradiation, intensity modulation of photon beams and particle beam radiotherapy, all of which require the expertise of medical physicists. Translating basic knowledge into the clinic for decreasing the adverse effects of radiation therapy without compromising tumor control is a high priority for research (14), and will require physicists, biologists and physicians working together. Further, subsequent to the terrorist attack on the World Trade Center in 2001, a sizable investment was made by the U.S. government to develop medical countermeasures for mitigating radiation injuries in soldiers, first responders and civilians exposed to ionizing radiation (13).…”

“…These problems are not new; not only have they been discussed in the past, but detailed recommendations have been made in an attempt to standardize dosimetry reporting, particularly in biology publications (14,16,17). However, to date, these recommendations have not been adopted in the U.S.…”