Recent publications from the laboratories of three separate ITOG members have reported the presence of a new type of mutation in certain thyroid cancers that could lead to use of specific use of certain drugs targeting that genetic abnormality. Mutations in the gene ALK have previously been identified in certain lymphomas and types of lung cancer, and patients whose tumors harbor those mutations have often responded well to therapy with ALK inhibitors such as crizotinib. Generally, these mutations are rearrangements of DNA, bringing parts of two genes together to create an active new gene that can cause the malignancy. Now, ALK rearrangements have been found in a subset of tumors from patients with thyroid carcinoma that could lead to new treatment approaches for those patients, as reported by ITOG investigators at scientific meetings in 2013 and published online in the past several months.
A report focusing on the frequency of ALK mutations came from the laboratory of ITOG member Dr. Yuri Nikiforov (abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/24613930). With his colleagues, Nikiforov performed very detailed DNA sequencing and genetic analysis of more than 300 thyroid cancers. A specific new rearrangement, called STRN-ALK was found in nearly 2% of papillary carcinomas, 9% of poorly differentiated carcinomas, and 4% of anaplastic carcinomas; none were identified in a small group of medullary carcinomas. Further laboratory experiments suggested that inhibitors of ALK, such as crizotinib, could block the growth of thyroid cancer cells containing this mutation.
A report describing a beneficial clinical outcome of ALK-directed therapy came from the laboratory of ITOG member Dr. Micheal Demeure (abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/24633422). Demeure and his collaborators studied the tumor DNA from one individual patient who had a highly aggressive form of papillary carcinoma. After identifying another rearrangement, called EML4-ALK, in this patient’s tumor, they initiated treatment of the patient’s progressive metastatic disease with crizotinib. After six months, the patient’s tumor growth remained halted, and thyroglobulin levels had declined.
These two studies build upon the earlier work of ITOG member Dr. Mingzhao Xing (abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/21596819), who first reported rare ALK mutations involving single DNA sequence changes or point mutations in about 11% of anaplastic thyroid carcinomas.
As described in a recent commentary in the influential journal Cancer Discovery, taken together, “these results implicate ALK fusion genes as drivers of thyroid cancer that may be exploited therapeutically.” ITOG researchers will be discussing how to translate these early observations into larger clinical studies at the annual meeting of the organization’s members to be held later this month in Boston, MA.