Abstract 3927: Evaluating new therapies in Gastrointestinal Stromal Tumor using in vivo molecular optical imaging.
Authors: Rink Lori A. , Hensley Harvey , Devarajan Karthik , Johnson James R. , Piwinica-Worms David , Godwin Andrew K. , von Mehren Margaret 
Published: August 2014

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors with an estimated annual incidence of ∼6,000 new cases in the United States. The majority (∼75%) of GISTs possess gain-of-function mutations in KIT exons 9, 11, 13 or 17, causing constitutive activation of the kinase receptor, with smaller subsets possessing either gain-of-function mutations in PDGFRA (exons 12, 14 or 18) or BRAF (exon 15). Management of GIST has been transformed by the identification of these tumor driver mutations leading to unprecedented disease control of advanced GIST with the introduction of imatinib mesylate (IM). Despite the efficacy of IM, most patients experience primary and/or secondary resistance within 2 years of treatment. Therefore additional therapies are needed and methods to optimize screening of novel approaches are warranted. Efficacy of treatment is typically assessed using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. Using RECIST, patients with advanced disease have equivalent survival when they have stable disease as when they have complete or partial responses. The Choi criteria define treatment response as a &gt;10% decrease in tumor size or a &gt;15% decrease in tumor density of tumor lesions assessed on CT scans. Response by Choi criteria has been shown to correlate better with FDG-PET than RECIST response, but can only be used with contrast enhanced CT imaging. RECIST and Choi both require a period of time on therapy before changes indicative of response can be observed. None of these criteria however informs us directly about cell death. Here we evaluate the use of molecular imaging technology using near-infrared (NIR) imaging probes in combination with three-dimensional fluorescence molecular tomography (FMT) for assessing therapeutic response and ultimately optimizing our understanding of the biologic effects of these agents. We determine the potential of two NIR probes (PSVueTM794 and KcapQ647) for detecting apoptosis and compare this to tumor size measured by MRI in response to IM treatment in GIST-T1 xenografts. PSVueTM794, used as a marker of apoptosis, binds to phosphatidylserine residues exposed on the surface of apoptotic cells and, in addition, binds to negatively-charged necrotic regions found in various tumors. KcapQ647, a cell penetrating activatable probe was used to detect apoptosis-associated caspase acitivity. Our studies revealed statistically significant increases in apoptotic activity due to IM treatment (compared to control) using both the PSVue TM794 and KcapQ647 probes (p=1.41e-04, 0.002 respectively) as early as 24 hours post IM treatment. These findings were confirmed by IHC. We believe that this methodology will allow for faster and more effective screening of novel therapies in preclinical GIST models.

Citation Format: Lori A. Rink, Harvey Hensley, Karthik Devarajan, James R. Johnson, David Piwinica-Worms, Andrew K. Godwin, Margaret von Mehren. Evaluating new therapies in Gastrointestinal Stromal Tumor using in vivo molecular optical imaging. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3927. doi:10.1158/1538-7445.AM2013-3927