A multidisciplinary team of researchers at the OSUCCC – James will use a five-year, $2.1 million R01 grant from the National Cancer Institute (NCI)
to study how BRAF
gene mutations promote therapeutic resistance to radiation and other genotoxic therapies in patients with anaplastic thyroid cancer (ATC), a solid tumor with a very poor prognosis.
Studying the mechanisms of this resistance will enable principal investigator (PI) Terence Williams, MD, PhD, co-PI Manisha Shah, MD, and their colleagues to develop tumor-selective approaches to enhancing sensitivity to genotoxic therapies for BRAF-mutant and BRAF wild-type ATC, thus improving physicians’ ability to treat and control this disease.
Williams is an associate professor in the Department of Radiation Oncology at Ohio State and member of the Cancer Biology Program at the OSUCCC – James. Shah is a professor in the Division of Medical Oncology at Ohio State and member of the Translational Therapeutics Program at the OSUCCC – James.
Previous studies funded by an NCI Thyroid Specialized Program of Research Excellence (SPORE) grant (PI: Matt Ringel, MD, co-leader of the Cancer Biology Program at the OSUCCC – James) and by a Pelotonia Idea Grant provided data that helped pave the way for this new NCI grant.
In their project abstract, the researchers state that BRAF-activating mutations are the most common oncogenic mutations in ATC, occurring in 30-40% of tumors. “Our preliminary data supports that BRAF mutations promote therapeutic resistance to radiation and other genotoxic therapies” for ATC, such as external beam radiation therapy (EBRT) and cytotoxic chemotherapy, they write.
Because of this resistance, patients with ATC face high rates of recurrence. The researchers note that local/regional recurrence “is particularly difficult for patients with ATC, resulting in airway and/or esophageal compromise that contributes to mortality and metastatic dissemination. Novel therapies are needed to improve disease control and lengthen survival.” The researchers will explore ways to improve radiation sensitivity and chemotherapy for multiple subtypes of BRAF-mutant and BRAF wild-type ATC.
In their first aim, they will conduct a phase I clinical trial to determine the maximum tolerated doses of the drugs dabrafenib (a BRAF gene inhibitor) and trametinib (a MEK-1/2 gene inhibitor) to be used concurrently with EBRT in patients with BRAF-mutant ATC, and then they will identify biomarkers of response and molecular pathways leading to resistance. Shah is leading this investigator-initiated clinical trial at Ohio State (OSU-17277). The trial is conducted in collaboration with the International Thyroid Oncology Group (ITOG), with MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center as participating centers.
Their second aim is to perform mechanistic studies to better understand how BRAF-mutant ATC leads to accelerated DNA repair, test novel therapeutic strategies that target components of DNA repair, and develop and optimize strategies for targeting DNA repair in combination with EBRT and other genotoxic therapies for BRAF-mutant ATC.