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Can Genetic Mutations Impact Radiation Sensitivity?


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A new study identified both common and rare genetic mutations that may impact radiation resistance and sensitivity, an important step toward providing more individualized and effective radiotherapy for patients with cancer, according to findings published by Gopal et al in Clinical Cancer Research.

Radiotherapy continues to be delivered using generic schedules and doses, unlike newer targeted drug therapies that are guided by the genomics of an individual’s cancer.

“The lack of incorporation of genetic data into [radiotherapy] is a significant, unmet clinical need,” said corresponding author and radiation oncologist Mohamed Abazeed, MD, PhD, Associate Professor of Radiation Oncology at Northwestern University Feinberg School of Medicine and Co-Leader of the Lung Cancer Program at the Robert H. Lurie Comprehensive Cancer Center. “This information ultimately will allow us to better calibrate the dose of radiation for patients in the clinic. We can give higher doses to [patients with] more resistant tumors based on their genetic mutations and a lower dose to [those with] the more sensitive cancers, allowing us to both improve treatment efficacy and reduce toxicity. The findings hasten a new paradigm in the field of [radiotherapy].”

Study Methodology

Studying tumors from individuals with 27 different types of cancer, investigators profiled 92 genes with 400 unique mutations and determined the impact these genes had on radiation response.

The researchers also developed a computational algorithm that nominated mutations in genes that were likely to affect sensitivity to radiation. They tested these mutations by placing them in several human cells and assessed their impact using high-volume arrayed phenotypic profiling.

“Cancer genomics over the last decade has revolutionized how we treat [patients with] cancer from a drug perspective. If you find the right mutation in a patient’s tumor, there are now a host of drugs that can selectively target that mutation and, therefore, that tumor,” said Dr. Abazeed. “But [radiotherapy] hasn’t been able to take advantage of this now readily available genetic information, because the relationship between the cancer genome and our therapy is more complex. There are many genes that regulate the response to radiation in human tumors. It requires large-scale projects like ours to begin to tease out this complexity and identify gene targets that are clinically actionable.”

Approaching the Clinic

Dr. Abazeed and his colleagues have tested different radiotherapy dosages based on mutations in human tumors grown directly in mice.

“Our strategies appear to work in a subset of the targets we identified,” Dr. Abazeed highlighted. The next step will be a clinical trial testing different radiation doses or combinations of radiation with other drugs based on the genetic alterations of individual tumors.

Dr. Abazeed and his team are also investigating how to alter gene activity to provide greater resistance to environmental radiation and reverse these interventions later to prevent unforeseen impacts on human health, including the development of cancer.

“There are potentially ways you can give someone a drug for a short period of time to activate a gene that confers resistance to radiation, and then remove the drug and return gene activity back to baseline,” Dr. Abazeed concluded.

Disclosure: The research in this study was supported by grants from the National Cancer Institute of the National Institutes of Health. For full disclosures of the study authors, visit aacrjournals.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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