Gene mutations in tumors affect radiation sensitivity

Gene mutations in tumors affect radiation sensitivity

A new Northwestern Medicine study identifies common and rare gene mutations that affect resistance and sensitivity to radiation, an important step toward providing more individualized and effective radiation therapy for cancer patients.

Radiotherapy continues to be delivered using generic schedules and doses, as opposed to newer targeted drug therapy that is guided by the genomics of an individual’s cancer.

“The lack of incorporation of genetic data into radiation therapy is a significant unmet clinical need,” said corresponding author Dr. Mohamed Abazeed, associate professor of radiation oncology at Northwestern University Feinberg School of Medicine and radiation oncologist at Northwestern Medicine.

“This information will ultimately allow us to better calibrate the radiation dose for patients in the clinic,” Abazeed said. “We can deliver higher doses to more resistant tumors based on their genetic mutations and lower doses to more sensitive tumors, allowing us to both improve treatment efficacy and reduce toxicity. The findings will accelerate a new paradigm in radiation therapy.”

A study was recently published in Clinical Cancer Research.

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

They developed a computational algorithm that nominated mutations in genes likely to affect radiation sensitivity. The researchers tested these mutations by placing them in several human cells and assessed their impact using large-scale, ordered phenotypic profiling.

Cancer genomics spurred ‘silver bullet’ drugs; radiotherapy is more complicated

“Cancer genomics over the past decade has revolutionized how we treat cancer patients from a drug perspective,” said Abazeed, also co-director of the lung cancer program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “If you find the right mutation in a patient’s tumor, there are now a number of drugs that can selectively target that mutation and therefore the tumor.”

“However, radiation therapy has not 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 this complexity to uncover and identify gene targets that are clinically applicable.”

Approaching the clinic

Abazeed and colleagues tested different doses of mutation-based radiation therapy in “patient avatars,” human tumors grown directly on mice.

“Our strategies seem to be working on a subset of the targets we identified,” Abazeed said. The next step will be a clinical trial testing different doses of radiation or combinations of radiation with other drugs based on the genetic changes of individual tumors.

Can we use this information to protect people from environmental radiation?

The findings also reveal important insights into the interactions between the human genome and radiation when it comes to environmental radiation.

“We are all exposed to relatively low levels of background radiation through the ground, the air, some building materials and our food,” Abazeed said. “Astronauts and future space travelers may be exposed to significant cosmic radiation. There is also the possibility of accidental exposure in a major nuclear accident or war.

“Understanding the interactions between our genes and radiation exposure is critical to both our evolution and survival as a species.”

Abazeed and his team are investigating how to alter gene activity to provide greater resistance to radiation when a person is exposed to environmental radiation, and to reverse these interventions later to avoid unforeseen effects on human health, including concerns about the development of cancer.

“There are potentially ways that 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 the gene’s activity back to baseline,” he said.

Other Northwest authors include Priyanka Gopal, Titas Bera, Trung Hoang and Alexandru Buhimschi.

The research was supported by grants R37CA222294 and P30CA060553 from the National Cancer Institute of the National Institutes of Health.

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