1. McGraw, Mark

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A team led by UPMC Hillman Cancer Center researchers has identified tumor features associated with resistance to radiotherapy; a development that could be a step toward developing more personalized cancer treatments. Recently published in Nature Communications, the study notes that, with a few isolated exceptions, the cure of solid tumors requires effective local therapy, which translates to a need for radiation, either alone or as part of a treatment package including surgery, "in a vast majority of disease sites" (2021;

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The authors point out the large number of targeted and immunotherapies that have been introduced throughout the past decade or so, but note that, in nearly all cases, "the only agents available to improve responses to radiation are the cytotoxic chemotherapies that have been in use since the 1980s or earlier."


Because of this, "an effective and minimally toxic radiosensitizer has the potential to, in short order, positively impact hundreds of thousands of patients."


Head and neck squamous-cell carcinoma is one example of this phenomenon, the curative treatment of which has remained largely unchanged in the past two decades, the researchers added, noting that "while [around] 75 percent of patients with head and neck squamous-cell carcinoma require radiation for the treatment of their disease, the recent failure of cetuximab means there are generally no biologically driven radiosensitizers available to improve response and decrease toxicity of this therapy."


The advent of immunotherapy has not changed the current paradigm either, according to the authors, who note that a recent clinical trial of chemoradiation combined with immunotherapy closed as a result of lack of efficacy.


Still, the authors say that "the search for improved combinations with radiation remains critical," and cite "multiple factors," including the artificial nature of in vitro systems and unforeseen toxicity, as reasons why most antineoplastic agents tested in the preclinical setting fail to be translated to the clinic.


"Targets identified as radiosensitizers in an in vitro model may underperform in vivo due to complex interactions within the tumor itself," the researchers wrote. "Additionally, the same microenvironment interactions could be potential targets for radiosensitization and may not be readily identified using in vitro screening techniques."


In addition, many large-scale approaches that use cell lines with known genomic status have not exposed the cells to radiation, which means they have not pinpointed tumor mutations or alterations that might be linked to specific targets for radiosensitization, according to the study.


Led by Heath Skinner, MD, PhD, a radiation oncologist at UPMC Hillman Cancer Center and Associate Professor of Radiation Oncology at the University of Pittsburgh School of Medicine, the researchers sought to develop more tailored, personalized approaches to improve the outcomes of radiotherapy.


With that goal in mind, the team developed a technique designed to quickly screen head and neck cancer tumors in order to identify genetic targets linked with resistance to radiation. Skinner and his study co-authors generated tumors in mice, then treating the animals with radiation and measuring tumor growth.


In the process, the researchers found that inhibiting proteins known as the CREB-binding protein (CBP) and p300 significantly increased the sensitivity of tumors to radiation, as well as improving mouse survival. This was only true, however, when tumors included certain mutated versions of these proteins, according to the authors, who say this result suggests that these mutations could drive resistance to radiotherapy.


"These mutations exhibit reduced basal-inhibitory function, leading to a hyperacetylated state and potential dependency on homologous recombination and BRCA1 for DNA-damage repair," the researchers say, adding that the importance of CBP and p300 mutation is underscored following analysis of tumor tissues in several cohorts of patients with squamous-cell carcinoma of the head and neck, lung, or cervix treated with radiation therapy, identifying these mutations as associated with resistance to radiotherapy and poor outcome.


In addition to identifying tumor features with resistance to radiotherapy, the study identified a drug that rendered resistant cancer cells sensitive to radiotherapy. The researchers did so by performing in vivo screening of many "druggable" genes, or genes that can be targeted using currently available agents in several different head and neck cancer models, to determine which ones interact with radiation, noted Skinner.


"Through this screen, as well as using additional in vitro and in vivo conformation experiments, we found that, in tumors harboring mutations in the histone acetyltransferases CBP and p300, inhibition of histone acetyltransferase function led to profoundly increased responses to radiation," he added.


Looking ahead, these findings could ultimately help enhance the impact of radiotherapy for patients undergoing cancer treatment, and could affect how cancer care teams, including the oncology team, approach treatment.


"In the same study, we found that mutations in CREBBP and EP300-the genes coding for CBP and p300-were associated with worse patient outcomes following radiation in not only head and neck cancer, but also lung cancer and cervical cancer," said Skinner. "Although not yet ready for clinical use, linking these therapy-resistant tumors to a genetically tailored approach could potentially allow for improved outcomes following radiation therapy as well as reduced toxicity."


Mark McGraw is a contributing writer.