New cancer mutations identified for everolimus responsiveness, resistance

By sequencing the tumor of a patient with thyroid cancer, Dana-Farber and Broad researchers discover new mutations before and after treatment

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BOSTON & CAMBRIDGE, Mass.—Pre- and post-treatment genomic sequencing of the DNA of a woman with thyroid cancer has revealed new mechanisms of cancer response and resistance in the face of treatment, according to recent work by researchers from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard. The study, “Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer,” was published in the Oct. 9 issue of the New England Journal of Medicine.
The patient in question was diagnosed four years ago with anaplastic thyroid cancer, a rapidly growing cancer which is almost always fatal within a matter of months; in this woman's case, the tumors had spread to her lungs despite radiation, surgery and chemotherapy. She joined a trial being led by Jochen Lorch, M.D., a thyroid cancer specialist at the Head and Neck Treatment Center at Dana-Farber and senior author of the report, that was focusing on a more treatable type of thyroid cancer.
The team sequenced the patient's cancer before and after she received treatment and found two previously unknown mutations in the DNA of the cancer. One of the mutations made the patient's cancer highly sensitive to everolimus—an mTOR (mammalian target of rapamycin) inhibitor currently indicated for the treatment of advanced kidney cancer, as well as some types of pancreatic, breast and brain cancer—which led to a significantly long-lasting response: the tumor shrank to a very small size and remained small for 18 months before it began to grow again. The second mutation, found after the patient received treatment, was discovered in the DNA of the tumor after it evolved resistance to everolimus. This mutation was found in the mTOR protein and prevented everolimus from binding to it. It hasn't been seen in humans before.
The first mutation, which made the tumor so susceptible to treatment with everolimus, is in a gene called TSC2, and researchers at Dana-Farber have initiated a clinical trial to evaluate the effectiveness of everolimus in other patients with mutations of this gene. This approach is often known as a “basket” trial, which, rather than focusing on one cancer type, focuses on one target or mutation and opens the trial to a variety of cancer types.
The TSC2 protein normally suppresses mTOR activity. mTOR, a protein kinase that regulates a number of cell functions, including growth and proliferation, is overactive in some cancers. When TSC2 is mutated, mTOR is overactivated, making it a good target for everolimus, which is approved to treat tumors associated with Tuberous Sclerosis Complex (TSC), a rare genetic disorder caused by mutations in the TSC1 and TSC2 genes.
“The study of patients with extraordinary responses can yield critically important insights,” Nikhil Wagle, M.D., an oncologist at Dana-Farber and first author of the report, noted in a press release. “These studies could help us develop methods for matching patients to drugs, highlight effective uses for otherwise ‘failed’ therapies and design new therapeutic strategies to fight cancer.”
Of additional interest is the fact that even after the tumor developed resistance to everolimus, further testing revealed that it was still sensitive to a different type of mTOR inhibitor. A drug in that category will begin clinical trials soon, and the patient that led to this discovery is in line to receive that treatment.
Lorch pointed out that this discovery offers hope for other cancer types as well, noting that “Because we could show that an mTOR inhibitor that is using a different mechanism could overcome resistance in anaplastic thyroid cancer, these findings could provide a rationale for treatment once resistance to everolimus occurs.”
“This is personalized, precision medicine at its best,” Lorch added.
Anaplastic thyroid cancer, according to MedlinePlus of the National Institutes of Health's National Library of Medicine, “accounts for only about 1 percent of all thyroid cancers.” Most patients diagnosed with this subtype “do not survive longer than six months,” due to a lack of treatment options; MedlinePlus adds that “This type of cancer cannot be cured by surgery. Complete removal of the thyroid gland does not prolong most patients' lives.”
Additional authors of the report include researchers at Dana-Farber, Brigham and Women’s Hospital, the Broad Institute, Harvard Medical School, the Whitehead Institute for Biomedical Research and the MIT Department of Biology. This study was supported by the Next Generation Fund at the Broad Institute, Novartis Pharmaceuticals, the Starr Cancer Consortium and the National Cancer Institute.

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