IRVING, Texas, Jan. 15, 2015 /PRNewswire/ -- Caris Life Sciences® today announced the presentation of data from a study in which Caris Molecular Intelligence™, the company's panomic, comprehensive tumor profiling service, identified potential therapeutic options for patients with gastrointestinal stromal tumors (GIST) that are resistant to standard tyrosine kinase inhibitor (TKI) therapy. Presented at the 2015 Gastrointestinal Cancers Symposium in San Francisco, Calif., the data suggest that various cytotoxic chemotherapeutics and novel targeted agents may be viable treatment options for patients with GIST, due to these agents' apparent ability to circumvent TKI resistance mechanisms.
"Whereas a range of multi-targeted TKIs are available to treat gastrointestinal stromal tumors, resistance mechanisms invariably emerge with these agents," commented Rebecca Feldman, Ph.D., research scientist at Caris Life Sciences. "Through multiplatform molecular profiling of GIST biomarkers, we identified several types of cytotoxic agents that have been shown in separate reports to effectively kill TKI-responsive and TKI-resistant GIST cells, suggesting a range of potential treatment options that extend beyond TKIs."
Using Caris Molecular Intelligence, Dr. Feldman and colleagues employed a multiplatform approach that included a combination of gene sequencing (Sanger and next-generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (in situ hybridization [ISH]) to evaluate biomarkers in 147 GIST cases. They identified a multidrug resistance phenotype (P-glycoprotein [PGP] and/or multidrug resistance protein 1 [MRP1]) in 52-68% of patients. They also observed a high frequency (72%) of low tubulin beta 3 (TUBB3) expression in the studied cases, suggesting that tubulin-binding agents such as taxanes or vinca alkaloids may be of potential use in patients with GIST.
According to the investigators, as many as one-third of patients with GIST may benefit from anthracyclines and topoisomerase inhibitors, based on the expression patterns of topoisomerases 1 (TOPO1, 34%) and 2A (TOPO2A, 32%). Due to the high frequency of low expression of the DNA repair genes MGMT (47%), thymidylate synthase (TS, 70%), and RRMI1 (79%), the investigators concluded that cytotoxic agents used in non-GIST solid tumors should strongly be considered as an alternative therapy for GIST once TKI's fail and/or for GIST that are cKIT and PDGFRA wild type.
Additionally, of the nine patients whose tumor samples were examined for presence of the programmed cell death protein 1 (PD-1) and its ligand, PD-L1, 56% exhibited positive tumor-infiltrating lymphocytes (TILs) and 33% exhibited PD-L1 tumor expression, suggesting the potential viability of targeted agents that inhibit these immune regulatory checkpoints.
"While TKIs have long been a mainstay of treatment for patients with GIST, the emergence of TKI resistance underscores the urgency of identifying alternative therapeutic approaches," noted Sandeep K. Reddy, M.D., chief medical officer at Caris Life Sciences, and a co-investigator in the study. "This study demonstrates the value of Caris Molecular Intelligence in identifying non-TKI targeted therapies as potential treatments for GIST, in that patients may benefit from inhibition of specific molecular targets while avoiding the resistance associated with standard therapy. In particular, the observed protein expression patterns and gene variations suggest the potential viability of various cytotoxics and non-KIT/PDGFRA-targeted agents in this patient population."
About Caris Life Sciences® and Caris Molecular Intelligence™
Caris Life Sciences® is a leading biosciences company focused on fulfilling the promise of precision medicine through quality and innovation. Caris Molecular Intelligence™, the industry's leading tumor profiling service with more than 68,000 patients profiled, provides oncologists with the most potentially clinically actionable treatment options available to personalize cancer care today. Using a variety of advanced profiling technologies to assess relevant biological changes in each patient's tumor, Caris Molecular Intelligence correlates biomarker data generated from a tumor with biomarker-drug associations supported by evidence in the relevant clinical literature. The company is also developing a series of tests based on its proprietary Carisome® TOP™ platform, a revolutionary blood-based testing technology for diagnosis, prognosis, and theranosis of cancer and other complex diseases. Headquartered in Irving, Texas, Caris Life Sciences offers services throughout Europe, the U.S., Australia and other international markets. To learn more, please visit www.CarisLifeSciences.com.
SOURCE Caris Life Sciences