title: Evaluating new therapies in gastrointestinal stromal tumor using in vivo molecular optical imaging.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the US. The majority (~85%) of GISTs possess gain-of-function mutations in KIT or PDGFRA, causing constitutive activation of the kinase receptor. GIST management has been transformed by the identification of tumor driver mutations leading to unprecedented disease control of advanced GIST with the introduction of imatinib mesylate (IM). Despite IM's efficacy, most patients experience primary and/or secondary resistance within 2 y of treatment. Additional therapies and methods to optimize screening of novel approaches in preclinical studies are warranted. Clinically, treatment efficacy is typically assessed using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines or Choi criteria. Both require a period of time on therapy before changes indicative of response can be observed. In addition, neither informs directly about cell death. We evaluated the use of molecular imaging technology in an animal model using near-infrared (NIR) imaging probes together with three-dimensional fluorescence molecular tomography (FMT) for assessing therapeutic response and ultimately optimizing our understanding of the biologic effects of these agents. We determined the potential of NIR probes (PSVue(TM) 794 and cell-penetrating KcapQ647) for detecting distinct markers of apoptosis and compare this to tumor size measured by MRI in response to IM treatment in GIST-T1 xenografts. Our studies revealed statistically significant increases in apoptosis due to IM treatment using both probes as early as 24 h post IM treatment which was confirmed by IHC. Molecular imaging will allow for faster and more effective screening of novel therapies in preclinical GIST models.
authors.affiliation: Biological Imaging Facility; Fox Chase Cancer Center; Philadelphia, PA USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Hensley
authors.affiliation: Department of Statistics; Fox Chase Cancer Center; Philadelphia, PA USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Devarajan
authors.affiliation: Mallinckrodt Institute of Radiology; Washington University School of Medicine; St. Louis, MO USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Johnson
authors.affiliation: Mallinckrodt Institute of Radiology; Washington University School of Medicine; St. Louis, MO USA; Department of Cancer Systems Imaging; University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.affiliation: Department of Pathology and Laboratory Medicine; University of Kansas Medical Center; Kansas City, KS USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Department of Medical Oncology; Fox Chase Cancer Center; Philadelphia, PA USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.affiliation: Department of Medical Oncology; Fox Chase Cancer Center; Philadelphia, PA USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Rink
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D064593:Heterografts; D000068877:Imatinib Mesylate; D008279:Magnetic Resonance Imaging / Q000379:methods; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods; D015335:Molecular Probes; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D041622:Tomography, Optical / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D015335:Molecular Probes; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate
keywords: GIST; apoptosis; imatinib mesylate; molecular imaging
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