A new Northwestern Medicine study identifies common and rare genetic mutations that affect resistance and sensitivity to radiation, an important step in providing more individualized and effective radiation therapy for cancer patients.
Radiation therapy 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 in radiation treatment is a significant unmet clinical need,” said corresponding author Mohamed Abazeed, MD, associate professor of radiation oncology at Northwestern University Feinberg School of Medicine and oncologist Northwestern Medicine radiation therapist.
“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 a lower dose to more sensitive cancers, allowing us to improve treatment efficacy and reduce toxicity. The findings accelerate a new paradigm in radiotherapy field.
The study was recently published in Cancer Clinical Research.
By studying tumors from 27 different types of cancer, the researchers profiled 92 genes with 400 unique mutations and determined the impact of these genes on response to radiation.
They developed a computational algorithm that nominated mutations in genes that were likely to affect radiation sensitivity. The scientists tested these mutations by placing them in various human cells and assessed their impact using high-volume phenotypic profiling.
Cancer genomics fueled ‘silver bullet’ drugs; radiotherapy is more complex
“Cancer genomics over the last decade has revolutionized how we treat cancer patients from a drug perspective,” said Abazeed, also co-director of the lung cancer program at Robert H. Lurie Comprehensive Cancer Center in New York. Northwestern University. “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.”
“But radiotherapy 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 to unravel this complexity and identify genetic targets that are clinically actionable.”
approaching the clinic
Abazeed and his colleagues have tested different mutation-based doses of radiation therapy on “patient avatars,” human tumors grown directly in mice.
“Our strategies seem to work 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 genetic alterations in individual tumors.
Can we use this information to protect humans from environmental radiation?
The findings also reveal important information about interactions between the human genome and radiation as it relates to environmental radiation exposure.
“We are all exposed to relatively low levels of background radiation through soil, air, some building materials, and our food,” Abazeed said. “Astronauts and future space travelers may be exposed to considerable cosmic radiation. There is also the possibility of incidental radiation exposures through a major nuclear accident or war.
“Understanding the interactions between our genes and radiation exposure is critical to both our evolution and our survival as a species.”
Abazeed and his team are investigating how to alter gene activity to provide increased radiation resistance when a person is exposed to environmental radiation and reverse these interventions later to avoid unforeseen impacts on human health, including concerns about the development of cancer.
“Possibly, there are ways you can give someone a drug for a short period of time to turn on a gene that confers radiation resistance and then remove the drug and return the gene’s activity to baseline,” he said.
Other northwestern 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.