Can the genetic makeup of their cancers predict how patients with lung cancer will respond to radiation therapy? And can this information be used to advance a genetically guided strategy for patients with these tumors? Cleveland Clinic researcher and radiation oncologist Mohamed Abazeed, M.D., Ph.D., has been awarded a $2 million grant from the National Cancer Institute (NCI) to delve into those and other related questions.
Dr. Abazeed’s overall objective for this award is to identify new genetic markers calibrated on the basis of radiation therapy effectiveness and new drug-radiation therapy strategies that more precisely and effectively target the most resistant lung tumors to radiation.
“Current radiation therapy regimens use a ‘one-size-fits-all’ approach, not taking into account the genetic content of individual tumors,” said Dr. Abazeed. “There is an urgent need to identify genetic markers that can recognize tumors that are more or less likely to respond to radiotherapy and translate these markers for clinical use. This more personalized approach not only can improve treatment responses, but it can also potentially reduce toxicity, resulting in an improved quality of life for survivors who received these treatments.”
Efforts to predict the response to radiotherapy thus far have been limited in large part because the genetic features that regulate tumor survival – and their frequency across and within individual cancer types – had not been studied on a large-scale. In 2016, Dr. Abazeed’s lab published results of the largest profiling effort of cancer cell survival after radiation, comprising a collection of 533 genetically annotated tumor cell lines from 26 cancer types. Results showed significant biological diversity in the survival of cancer cells after exposure to ionizing radiation, and offered evidence that new genetic features regulating cellular response to these treatments can be identified.
Dr. Abazeed’s new NCI-funded investigation aims to advance the clinical translation of a short list of the most important regulators of radiation resistance in lung cancer. The molecular pathways implicated in their studies are found in as high as approximately 30% of patients or as low as 7%. His preliminary work suggests that specific mutations in these pathways confer a strong phenotype of radiation resistance in cells, human-derived mouse xenografts and patients with non-small-cell lung cancer.
Dr. Abazeed’s profiling efforts have also demonstrated that some mutations that cause resistance to radiation can sometimes represent a minor component of the tumor, or are subclonal. Dr. Abazeed contends that these subclones can become dominant during the course of radiation. This treatment-associated subclonal evolution may have significant implications for the ability of radiation to effect complete tumor eradication. On the basis of these studies, Dr. Abazeed seeks to advance a genetically-guided radiosensitization strategy that makes tumor cells more sensitive to radiation therapy.
“If these hypotheses are correct, our results will demonstrate that radiotherapeutic sensitizers can be selected based on both the identity and type of genetic alterations identified in a patient’s cancer, prompting an evolution in the use of radiation from a generic approach to one that is guided by the genetic composition of individual tumors,” added Dr. Abazeed.