A 2018 Pelotonia-funded Idea Grant helped a team of OSUCCC – James researchers gather preliminary data that has led to a larger study that includes a phase I clinical trial designed to benefit patients with anaplastic thyroid cancer (ATC), a tumor with a very poor prognosis.
Principal investigator (PI) for the investigator-initiated clinical trial is Manisha Shah, MD, professor in the Division of Medical Oncology at Ohio State and member of the Translational Therapeutics Program at the OSUCCC – James.
Also providing data that led to the new study was an earlier NCI Thyroid Specialized Program of Research Excellence (SPORE) grant awarded to PI Matthew Ringel, MD, professor and director of the Department of Endocrinology, Diabetes and Metabolism at Ohio State, and co-leader of the Cancer Biology Program at the OSUCCC – James.
Shah says this is a truly collaborative project that stemmed from the thyroid SPORE seed grant and then from the 2018 Pelotonia Idea Grant, for which she was the co-PI along with PI Terence Williams, MD, PhD, associate professor in the Department of Radiation Oncology at Ohio State and member of the Cancer Biology Program at the OSUCCC – James.
“With our Idea Grant,” Shah says, “we met a major goal of Pelotonia, which is to use funding from a starter grant that leads to funding for a much larger project.”
She says ATC is a deadly disease for which therapy includes surgery, radiation and chemotherapy, but patient outcomes are poor, with average survival of less than six to 12 months. Recently, she adds, genetic studies have found that ATC exhibits a high frequency of mutations in an oncogene called BRAF. Those mutations activate this oncogene, which drives tumor growth and causes resistance to current therapy, including radiation.
In their project abstract, Shah and colleagues also state that data from their labs indicated that inhibiting the BRAF oncogene “markedly improves radiation efficacy.” Thus they proposed to conduct a clinical trial to combine radiation with drugs that would inhibit the biologic activity of the BRAF oncogene.
Now underway, that phase I clinical trial is designed 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 external beam radiation therapy (EBRT) in patients who have BRAF-mutant ATC. The investigators note that dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and that radiation therapy uses high-energy beams to kill tumor cells and shrink tumors. They hypothesize that giving dabrafenib, trametinib and EBRT together may kill more tumor cells. The scientists also hope to 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 in Houston and Memorial Sloan Kettering Cancer Center in New York City as participating centers. Patient accrual has begun.
Shah believes this project, involving multiple collaborators and built on sound preliminary data from studies supported by Pelotonia and other sources, could yield findings that result in better therapies and improved prognoses for patients with ATC.