ASTRO Presentation Highlights Genomic Research on Resistance to Radiation

Large-scale Cleveland Clinic effort catalogues and targets genetic alterations that confer resistance

Physicians who treat patients with cancer face a key challenge in determining which of those patients will benefit from radiation therapy or chemotherapy.

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To aid these decisions, researchers increasingly turn to genomic medicine to identify mutations that can render a tumor immune to conventional treatment — and to develop targeted therapies that can overcome that resistance. Cleveland Clinic is engaged in an ambitious, large-scale effort to catalogue and target genetic alterations that confer resistance to radiation therapy.

A research team led by Mohamed Abazeed, MD, PhD, associate staff in the Department of Radiation Oncology and assistant professor of medicine, reported their findings September 15 and 16 in oral presentations at the annual meeting of the American Society for Radiation Oncology (ASTRO).

“Fundamentally, our group hunts for mutations and other alterations that represent the Achilles’ heel of cancers when used in combination with radiation,” says Dr. Abazeed. “We use high-throughput technology, computation, and a comprehensive target validation scheme, in an attempt to bring new molecular diagnostics into the clinic.”

Dr. Abazeed’s team created a novel platform to test tumor samples for radiation response in vitro in a high-throughput assay. Results from the assay are informed by genomic data derived from tumor samples. This allows the researchers to compare the response to radiation between samples with mutations in individual genes and wild-type samples that lack mutations.

“It’s a way of identifying what we call cell autonomous (or intrinsic) predictors of radiation response: the genomic biomarkers that make some tumors sensitive or resistant to radiation,” Dr. Abazeed explains.

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A Focus on Lung Cancer
With lung cancer as an initial focus, Dr. Abazeed’s group has identified two strong determinants of resistance to radiation: the NRF2 pathway, which is present in about 25 to 30 percent of patients with non-small cell lung cancer, and BRAF mutations, which are found in 7 percent of patients with adenocarcinoma of the lung.

“We had previously identified NRF2 mutations as a novel predictor of resistance among squamous cancers,” Dr. Abazeed notes, “but the BRAF mutations were not expected determinants.”

The ASTRO presentations on lung cancer provided a detailed description of the extensive biological target validation of the NRF2 pathway as a regulator of radiation resistance. They also included the identification of several P13K/mTOR inhibitors as potent genotype-selective radiation sensitizers. Now that the NRF2 genetic pathway has been identified as a culprit in radiation resistance, researchers at the Dana-Farber Cancer Institute have launched a Phase IIB study to test a compound that counteracts the effect of this pathway.

In addition, Dr. Abazeed’s team is collaborating with commercial partners to develop molecular panels that can help identify lung cancer patients likely to be resistant to therapy. The panels also can inform the use of drugs that target selected pathways to overcome that resistance.

The Role of Androgen Receptors
A separate ASTRO presentation provided data on another aspect of the team’s work: identification of androgen receptor signaling as a novel determinant of radiation resistance in a subset of breast cancers. The presentation also outlined their approach for the clinical incorporation of this finding.

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“The androgen receptor is expressed broadly in breast cancers and appears to be the main driver of proliferation in a subset of breast cancers (triple negative tumors),” Dr. Abazeed says.

“We demonstrated that androgen signaling is a major determinant of therapeutic resistance in these tumors. The combination of enzalutamide — which is a potent anti-androgen drug and is currently being tested in patients with metastatic triple negative breast cancers — confers substantial sensitivity to radiation. This paradigm of lineage-specific regulators of therapeutic resistance is translating into multiple lineages and disease sites. We think it’s a powerful model.”

He also notes that, to date, the team has profiled the radiation response of more than 600 cell lines representing more than 20 solid tumor lineages.