Biomarker Analysis of GIST Tumors Suggests New Potential for Old Treatments

Researchers for Caris Life Sciences have used the company’s proprietary tumor profiling platform to identifybiomarkers in GISTthat may be used to identify more effective therapeutic regimens for individuals with TKI-resistant GIST.¹Rebecca Feldman, PhD, and colleagues reported data from their study at the 2015 Gastrointestinal Cancer Symposium in San Francisco, California, from January 15-17, 2015.

Typical first-line treatment for GIST is the tyrosine kinase inhibitor (TKI) imatininb mesylate (Gleevec).²The TKI, sunitinib mesylate, (Sutent) is used as second-line treatment for patients who cannot tolerate or have disease refractory to imatinib.³Response to TKI therapy varies. Some patients are resistant to TKI therapy from the outset due to the molecular nature of their primary disease, whereas others respond initially and then acquire resistance.⁴

At least 10 molecular subtypes of gastrointestinal stromal tumors (GISTs) have been previously identified (Table). The most frequent GIST subtype involves aKITmutation, most commonly at exon 11. Other less frequent GIST mutations are found on thePDGFRA,NF1,BRAF,SDHB,KRAS, orNRASgenes.⁴

Feldman’s research team used Caris Molecular Intelligence, a technological platform that combines next-generation gene sequencing, immunohistochemistry, in situ hybridization (fluorescence and chromogenic), and polymerase chain reaction methods, to analyze 147 GIST specimens for patterns of protein and gene expression. The Caris Molecular Intelligence platform then scanned the medical literature for reported associations between the GIST biomarkers detected and various approved or investigational agents.

Chemotherapy is generally not recommended in the treatment of GIST.²However, Feldman and colleagues concluded that the relative frequency of GIST tumors found to express low levels of DNA repair genes suggests cytotoxic therapies for other solid tumors may have a role in treating patients with GIST that progresses despite TKI therapy or patients whose tumor does not have aKITorPDGFRAmutation. Through its comprehensive literature review, Caris Molecular Intelligence identified some cytotoxic agents as potential treatments for GIST based on their reported effectiveness at killing TKI-responsive and TKI-resistant GIST cells.

Table. Molecular Subsets of GIST⁴

Mutations at

• KITexon 9, 11, 13, 14, 17, or 18
• PDGFRAD842V or non-D842V

KIT and PDGFRA wild-type with mutations at

• NF1
• BRAFV600E
• KRASorNRAS
• SDHBorSDHC
• Overexpression of IGF1R

The study underscored the heterogeneous nature of GIST. According to study investigators, Caris Molecular Intelligence showed that at least half the tumors (52% to 68%) expressed 1 or more proteins known to confer multidrug resistance (P-glycoprotein, multidrug resistance protein 1, or both). Patients with these tumors would be unlikely to respond to first-line treatment with a TKI.Almost three-quarters of tumors (72%) expressed low levels of tubulin beta 3 (TUBB3), which the investigators said suggests agents that bind tubulins such as taxanes (eg, paclitaxel and docetaxel) or vinca alkaloids (eg, vincristine, vinblastine, and vinorelbine) may be active in a large proportion of GIST patients. Expression of topoisomerase enzymes 1 and 2A was detected in 34% and 32% of specimens, respectively. Thus, tumors in one-third of patients may respond to treatment with anthracyclines or topoisomerase inhibitors such as topotecan, irinotecan, etoposide, or doxorubicin.

Nine GIST specimens were analyzed for expression of the programmed cell death protein 1 (PD-1) and the PD-1 ligand (PD-L1). Of these samples, 56% expressed positive tumor-infiltrating lymphocytes and 33% expressed PD-L1. Two PD-1 inhibitors have been approved thus far in the United States, both for melanoma: pembrolizumab in September 2014 and nivolumab in December 2014. Many other PD-1 and PD-L1 immunotherapies are in development, and the Caris investigators said these immune checkpoint inhibitors may represent viable options for patients with TKI-resistant GIST.

In a press release,⁵Sandeep K. Reddy, MD, chief medical officer at Caris Life Sciences and a co-investigator of the GIST study, said, “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.” Clinical trials will be needed to determine whether or not the agents that the Caris Molecular Intelligence platform identified are safe and effective in patients with TKI-resistant GIST.

References

1. 1. Multiplatform tumor profiling from Caris Molecular Intelligence identifies therapeutic options for patients with TKI-resistant gastrointestinal stromal tumors. Presented at: 2015 Gastrointestinal Cancer Symposium. San Francisco, California. January 15-17, 2015.
2. National Cancer Institute at the National Institutes of Health. Gastrointestinal stromal tumors treatment (PDQ): treatment option overview. http://www.cancer.gov/cancertopics/pdq/treatment/gist/HealthProfessional/page4. Updated August 26, 2014. Accessed January 18, 2015.
3. National Cancer Institute at the National Institutes of Health. Gastrointestinal stromal tumors treatment (PDQ): metastatic or recurrent gastrointestinal stromal tumors. http://www.cancer.gov/cancertopics/pdq/treatment/gist/HealthProfessional/page7. August 26, 2014. Accessed January 18, 2015.
4. Blay JY, Le Cesne A, Cassier PA, Ray-Coquard IL. Gastrointestinal stromal tumors (GIST): a rare entity, a tumor model for personalized therapy, and yet ten different molecular subtypes.Discov Med. 2012;13:357-367.
5. Research presented at 2015 gastrointestinal cancers symposium highlights clinical utility of Caris Molecular Intelligence [press release]. http://www.carislifesciences.com/news/multiplatform-tumor-profiling-from-caris-molecular-intelligence-identifies-therapeutic-options-for-patients-with-tki-resistant-gastrointestinal-stromal-tumors. Published January 15, 2015. Accessed January 18, 2015.