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Hensley H , Devarajan K , Johnson JR , Piwnica-Worms D , Godwin AK , von Mehren M , Rink L
Evaluating new therapies in gastrointestinal stromal tumor using in vivo molecular optical imaging
Cancer Biol Ther. 2014 Jul;15(7) :911-8
PMID: 24755645    PMCID: PMC4100992    URL: https://www.ncbi.nlm.nih.gov/pubmed/24755645
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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.
Hensley, Harvey Devarajan, Karthik Johnson, James R Piwnica-Worms, David Godwin, Andrew K von Mehren, Margaret Rink, Lori eng P50 CA094056/CA/NCI NIH HHS/ T32 CA113275/CA/NCI NIH HHS/ F32 EY020051/EY/NEI NIH HHS/ K99 CA158061-01A1/CA/NCI NIH HHS/ F32 EY20051/EY/NEI NIH HHS/ UL1 TR000001/TR/NCATS NIH HHS/ R00 CA158065/CA/NCI NIH HHS/ CA 06-927/CA/NCI NIH HHS/ UL1 TR000001-02S1/TR/NCATS NIH HHS/ R01 CA106588/CA/NCI NIH HHS/ R01 EY019587/EY/NEI NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cancer Biol Ther. 2014 Jul;15(7):911-8. doi: 10.4161/cbt.28880. Epub 2014 Apr 22.