The National Cancer Institute's Cancer Disparities Research Partnership Program: a unique funding model 20 years later.

The burden of cancer and access to effective treatment are not experienced equally by all in the United States. For underserved populations that often access the health-care system when their cancers are in advanced disease stages, radiation oncology services are essential. In 2001, the National Cancer Institute's (NCI's) Radiation Research Program created and implemented the Cancer Disparities Research Partnership Program (CDRP). CDRP was a pioneering funding model whose goal was to increase participation of medically underserved populations in NCI clinical trials. CDRP's Cooperative Agreement funding supported for awardees the planning, development, and conduct of radiation oncology clinical research in institutions not traditionally involved in NCI-sponsored research and cared for a disproportionate number of medically underserved, health-disparities populations. The awardee secured and provided support for mentorship from 1 of 2 NCI comprehensive cancer centers named in its application. Six CDRP awards were made over two 5-year funding periods ending in 2013, with the end-of-program accomplishments previously reported. With the current focus on addressing equity, diversity, and inclusion, the 6 principal investigators were surveyed, 5 of whom responded about the impact of CDRP on their institutions, communities, and personal career paths. The survey that was emailed included 10 questions on a 5-point Likert scale. It was not possible to collect patient data this long after completion of the program. This article provides a 20-year retrospective of the experiences and observations from those principal investigators that can inform those now planning, building, and implementing equity, diversity, and inclusion programs.

Overview and Lessons From the Preclinical Chemoradiotherapy Testing Consortium.

PURPOSE: In the current molecular-targeted cancer treatment era, many new agents are being developed so that optimizing therapy with a combination of radiation and drugs is complex. The use of emerging laboratory technologies to further biological understanding of drug-radiation mechanisms of action will enhance the efficiency of the progression from preclinical studies to clinical trials. In 2017, the National Cancer Institute (NCI) solicited proposals through PAR 16-111 to conduct preclinical research combining targeted anticancer agents in the Cancer Therapy Evaluation Program's portfolio with chemoradiation. METHODS AND MATERIALS: The Preclinical Chemo-Radiotherapy Testing Consortium (PCRTC) was formed with 4 U01 programs supported to generate validated high-quality preclinical data on the effects of molecular therapeutics when added to standard-of-care therapies with a concentration on cancers of the pancreas, lung, head and neck, gastrointestinal tract, and brain. RESULTS: The PCRTC provides a rational basis for prioritizing NCI-supported investigational new drugs or agents most likely to have clinical activity with chemoradiotherapy and accelerate the pace at which combined modality treatments with greater efficacy are identified and incorporated into standard treatment practices. CONCLUSIONS: Herein, we introduce and summarize the course of the PCRTC to date and report 3 preliminary observations from the consortium's work to date.

Moving Forward in the Next Decade: Radiation Oncology Sciences for Patient-Centered Cancer Care.

In a time of rapid advances in science and technology, the opportunities for radiation oncology are undergoing transformational change. The linkage between and understanding of the physical dose and induced biological perturbations are opening entirely new areas of application. The ability to define anatomic extent of disease and the elucidation of the biology of metastases has brought a key role for radiation oncology for treating metastatic disease. That radiation can stimulate and suppress subpopulations of the immune response makes radiation a key participant in cancer immunotherapy. Targeted radiopharmaceutical therapy delivers radiation systemically with radionuclides and carrier molecules selected for their physical, chemical, and biochemical properties. Radiation oncology usage of "big data" and machine learning and artificial intelligence adds the opportunity to markedly change the workflow for clinical practice while physically targeting and adapting radiation fields in real time. Future precision targeting requires multidimensional understanding of the imaging, underlying biology, and anatomical relationship among tissues for radiation as spatial and temporal "focused biology." Other means of energy delivery are available as are agents that can be activated by radiation with increasing ability to target treatments. With broad applicability of radiation in cancer treatment, radiation therapy is a necessity for effective cancer care, opening a career path for global health serving the medically underserved in geographically isolated populations as a substantial societal contribution addressing health disparities. Understanding risk and mitigation of radiation injury make it an important discipline for and beyond cancer care including energy policy, space exploration, national security, and global partnerships.

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation's ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields.This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory 'drug' to provide alternatives to the widely adopted 'one-size-fits-all' strategy of frequently used 8 Gy×3 regimens immunomodulation.

Potential Molecular Targets in the Setting of Chemoradiation for Esophageal Malignancies.

Although the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.

Pathways for Recruiting and Retaining Women and Underrepresented Minority Clinicians and Physician Scientists Into the Radiation Oncology Workforce: A Summary of the 2019 ASTRO/NCI Diversity Symposium Session at the ASTRO Annual Meeting.

Diversifying the radiation oncology workforce is an urgent and unmet need. During the American Society of Radiation Oncology (ASTRO) 2019 Annual Meeting, ASTRO's Committee on Health Equity, Diversity, and Inclusion (CHEDI) and the National Cancer Institute (NCI) collaborated on the ASTRO-NCI Diversity Symposium, entitled "Pathways for Recruiting and Retaining Women and Underrepresented Minority Clinicians and Physician Scientists Into the Radiation Oncology Workforce." Herein, we summarize the presented data and personal anecdotes with the goal of raising awareness of ongoing and future initiatives to improve recruitment and retention of underrepesented groups to radiation oncology. Common themes include the pivotal role of mentorship and standardized institutional practices - such as protected time and pay parity - as critical to achieving a more diverse and inclusive workplace.

Low-Dose Radiation Therapy (LDRT) for COVID-19: Benefits or Risks?

The limited impact of treatments for COVID-19 has stimulated several phase 1 clinical trials of whole-lung low-dose radiation therapy (LDRT; 0.3-1.5 Gy) that are now progressing to phase 2 randomized trials worldwide. This novel but unconventional use of radiation to treat COVID-19 prompted the National Cancer Institute, National Council on Radiation Protection and Measurements and National Institute of Allergy and Infectious Diseases to convene a workshop involving a diverse group of experts in radiation oncology, radiobiology, virology, immunology, radiation protection and public health policy. The workshop was held to discuss the mechanistic underpinnings, rationale, and preclinical and emerging clinical studies, and to develop a general framework for use in clinical studies. Without refuting or endorsing LDRT as a treatment for COVID-19, the purpose of the workshop and this review is to provide guidance to clinicians and researchers who plan to conduct preclinical and clinical studies, given the limited available evidence on its safety and efficacy.

Understanding High-Dose, Ultra-High Dose Rate, and Spatially Fractionated Radiation Therapy.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.

Development of Novel Radiosensitizers through the National Cancer Institute's Small Business Innovation Research Program.

While radiosensitizing chemotherapy has improved survival for several types of cancer, current chemoradiation regimens remain ineffective for many patients and have substantial toxicities. Given the strong need for the development of novel radiosensitizers to further improve patient outcomes, the Radiation Research Program (RRP) and the Small Business Innovation Research (SBIR) in the National Cancer Institute (NCI) issued a Request for Proposals (RFP) through the NCI SBIR Development Center's contracts pathway. We sought to determine the research outcomes for the NCI SBIR Development Center's funded proposals for the development of radiosensitizers. We identified SBIR-funded contracts and grants for the development of radiosensitizers from 2009 to 2018 using the National Institutes of Health (NIH) Reporter database. Research outcomes of the NCI SBIR Development Center-funded proposals were determined using a comprehensive internet search. We searched PubMed, clinicaltrials.gov, company websites and google.com for research articles, abstracts and posters, clinical trials, press releases and other news, related to progress in the development of funded radiosensitizers. To protect the intellectual property of the investigators and small businesses, all information obtained and reported is publicly available. The SBIR Program has funded four contracts and 11 grants for the development of novel radiosensitizers. Two companies have received phase IIb bridge awards. Overall, 50% of companies (6/12) have successfully advanced their investigational drugs into prospective clinical trials in cancer patients, and all but one company are investigating their drug in combination with radiation therapy as described in the NCI SBIR Development Center proposal. To date, only one company has initiated a randomized trial of standard of care with or without their radiosensitizer. In conclusion, the NCI SBIR Development Center has funded the development of novel radiosensitizers leading to clinical trials of novel drugs in combination with radiation therapy. Continued follow-up is needed to determine if any of these novel radiosensitizers produce improved tumor control and/or overall survival.

Radiation Biomarkers: Can Small Businesses Drive Accurate Radiation Precision Medicine?

Radiation therapy is an essential component of cancer treatment. Currently, tumor control and normal tissue complication probabilities derived from a general patient population guide radiation treatment. Its outcome could be improved if radiation biomarkers could be incorporated into approaches to treatment. A substantial number of cancer patients suffer from side effects of radiation therapy. These side effects can result in treatment interruption. Such unplanned treatment interruptions not only jeopardize anticancer treatment efficacy but also result in poor post-treatment quality-of-life. To develop and translate radiation biomarkers for clinical use, NCI's Radiation Research Program, in collaboration with the Small Business Innovation Research Development Center, funded four small businesses through the request for proposals after peer review during 2015-2019. Here, we summarize publicly available information on intellectual property rights, the status of development, ongoing clinical trials, success in obtaining financing and regulatory approval. An analysis of publicly available information indicates all four companies have completed phase I of SBIR funding and advanced to further development, validation and clinical trials with phase II SBIR funding. These biomarkers are: 1. A panel of genomic biomarkers of radiation response to predict toxicity and radioimmune response (MiraDx Inc., Los Angeles, CA); 2. A multiplex assay for single nucleotide polymorphism (SNP) biomarkers of radiation sensitivity to identify a subset of prostate cancer patients for which radiotherapy is contraindicated (L2 Diagnostics, New Haven, CT); 3. A cell-free DNA assay in blood to measure tissue damage shortly after radiation exposure (DiaCarta Inc., Richmond, CA); and 4. A metabolomic/lipidomic assay to predict late effects that adversely affect quality-of-life among patients treated with radiation for prostate cancer (Shuttle Pharmaceuticals, Rockville, MD). This work also provides a bird's eye view of the process of developing radiation biomarkers for use in radiation oncology clinics, some of the challenges and future directions.

National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC.

Advancing Targeted Radionuclide Therapy Through the National Cancer Institute's Small Business Innovation Research Pathway.

The Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs of the National Cancer Institute (NCI) are congressionally mandated set-aside programs that provide research funding to for-profit small businesses for the development of innovative technologies and treatments that serve the public good. These two programs have an annual budget of $159 million (in 2017) and serve as the NCI's main engine of innovation for developing and commercializing cancer technologies. In collaboration with the NCI's Radiation Research Program, the NCI SBIR Development Center published in 2015-2017 three separate requests for proposals from small businesses for the development of systemic targeted radionuclide therapy (TRT) technologies to treat cancer. TRT combines a cytotoxic radioactive isotope with a molecularly targeted agent to produce an anticancer therapy capable of treating local or systemic disease. This article summarizes the NCI SBIR funding solicitations for the development of TRTs and the research proposals funded through them.

Decreasing the Toxicity of Radiation Therapy: Radioprotectors and Radiomitigators Being Developed by the National Cancer Institute Through Small Business Innovation Research Contracts.

PURPOSE: The use of radioprotectors and radiomitigators could improve the therapeutic index of radiation therapy. With the intention of accelerating translation of radiation-effect modulators (radioprotectors and mitigators), the Radiation Research Program and SBIR (Small Business Innovation Research) Development Center within the National Cancer Institute issued 4 Requests for Proposals (RFPs) from 2010 to 2013. Twelve SBIR contract awards in total were made in response to the 4 RFPs from September 2011 through September 2014. Here, we provide an update on the status of SBIR contract projects for the development of radiation-effect modulators. METHODS AND MATERIALS: To assess the status of research and development efforts under the 4 RFPs on radiation-effect modulators, we searched PubMed for research articles, google.com for published abstracts, clinicaltrials.gov for ongoing or completed clinical trials, and company websites for press releases and other news. All information obtained and reported here is publicly available and thus protects the intellectual property of the investigators and companies. RESULTS: Of the 12 SBIR projects funded, 5 (42%) transitioned successfully from phase 1 to phase 2 SBIR funding, and among the Fast-Track contracts, this rate was 100% (3 of 3). The Internet search identified 3 abstracts and 6 publications related to the aims of the SBIR contracts. One-third of the companies (4 of 12) have successfully launched a total of 8 clinical trials to demonstrate the safety and efficacy of their investigational agents. Two drugs are in clinical trials for their indication as a radioprotector, and 2 drugs are under evaluation for their anticancer properties (an immunomodulator and a small molecule inhibitor). CONCLUSIONS: The National Cancer Institute's SBIR has provided pivotal funding to small businesses for the development of radioprotectors and radiomitigators, which resulted in multiple early-phase clinical trials. Longer follow-up is needed to determine the full impact of these novel therapeutics that enter clinical practice.

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.

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.