New Genetic Mutations Linked to Subset of Gastrointestinal Stromal Tumors
By LabMedica International staff writers
Posted on 27 Dec 2016
Researchers have identified new gene fusions and mutations associated with a subset of Gastrointestinal Stromal Tumors (GIST) patients who lack the documented tell-tale mutations, making diagnosis and treatment more difficult in these cases.Posted on 27 Dec 2016
“We are continuing to slice the GIST pie into thinner pieces based upon identifying new driver genes,” said study leader Jason Sicklick, MD, associate professor at University of Californai San Diego School of Medicine (La Jolla, CA, USA) and surgical oncologist at Moores Cancer Center at UCSD Health (La Jolla, CA, USA), “This will allow for a more personalized approach to treating GIST patients.” In addition to researchers at UCSD, the study team included collaborators from other USA states and from South Korea.
Image: Radiological response of a Gastrointestinal Stromal Tumor (GIST) possessing an ETV6–NTRK3 fusion following treatment with LOXO-101, a selective TRK inhibitor. A 55-year old male with a T3N0M1 small intestine GIST had progression of disease on five lines of tyrosine kinase inhibitors targeting KIT prior to identification of an ETV6–NTRK3 fusion in the tumor. He was enrolled on a Phase I clinical trial of oral LOXO-101 (Loxo Oncology, Stamford, CT, USA), a selective TRK inhibitor. As compared to baseline PET/CT images (a), the tumors had decreased size and FDG-uptake at week 8 (b). At 4 months, the patient had ongoing partial response (44%) according to RECIST 1.1 criteria (Photo courtesy of the Journal of Translational Medicine).
Prof. Sicklick and colleagues are leading efforts to diagnose and treat GIST, which originates in special cells that signal muscles to contract, moving food and liquid through the digestive system. Many current therapies for GIST are ineffective in patients (About 10–15% of adult and most pediatric cases) whose tumors lack mutations in the classic oncogenic drivers of GIST. Ultimately, over 95% of patients eventually succumb to drug-resistant GIST, highlighting the necessity for alternative therapeutic targets.
Treatment with imatinib (marketed as Gleevec) has proven effective in many GIST cases associated with KIT oncogene mutations, the most common driver of the disease. Building upon that success and approach, the research team used broad genomic sequencing of GIST patients without KIT – or other documented mutations – to identify alterations in at least two new genes: FGFR1 and NTRK3.
“Broad genomic sequencing was critical to expand our search beyond the KIT mutations streetlight,” said Olivier Harismendy, PhD, head of the oncogenomics laboratory at Moores Cancer Center, referring to observational bias of previous studies.
“These findings provide novel insights into the biology of the disease and new potential genetic drivers,” said Prof. Sicklick, “With further studies, we can build an even more complete genetic profile of GIST, which in turn can lead to new individualized treatments and better outcomes for more GIST patients. For example, one patient in this study had an ETV6-NTRK3 mutant GIST and responded to a matched therapy with Loxo-101, a highly selective TRK inhibitor, after progressing on several earlier lines of FDA-approved therapies for GIST.
The study, by Shi E et al, was published December 14, 2016, in the Journal of Translational Medicine.
Related Links:
University of Californai San Diego School of Medicine
Moores Cancer Center at UCSD Health