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Multimodal Microvascular Imaging Reveals that Selective Inhibition of Class I PI3K Is Sufficient to Induce an Antivascular Response.
MedLine Citation:
PMID:  23814482     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
The phosphatidylinositol 3-kinase (PI3K) pathway is a central mediator of vascular endothelial growth factor (VEGF)-driven angiogenesis. The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin (mTOR) provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo. This study used an array of micro-vascular imaging techniques to monitor the antivascular effects of selective class I PI3K, mTOR, or dual PI3K/mTOR inhibitors in colorectal and prostate cancer xenograft models. Micro-computed tomography (micro-CT) angiography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), vessel size index (VSI) MRI, and DCE ultrasound (DCE-U/S) were employed to quantitatively evaluate the vascular (structural and physiological) response to these inhibitors. GDC-0980, a dual PI3K/mTOR inhibitor, was found to reduce micro-CT angiography vascular density, while VSI MRI demonstrated a significant reduction in vessel density and an increase in mean vessel size, consistent with a loss of small functional vessels and a substantial antivascular response. DCE-MRI showed that GDC-0980 produces a strong functional response by decreasing the vascular permeability/perfusion-related parameter, K (trans). Interestingly, comparable antivascular effects were observed for both GDC-980 and GNE-490 (a selective class I PI3K inhibitor). In addition, mTOR-selective inhibitors did not affect vascular density, suggesting that PI3K inhibition is sufficient to generate structural changes, characteristic of a robust antivascular response. This study supports the use of noninvasive microvascular imaging techniques (DCE-MRI, VSI MRI, DCE-U/S) as pharmacodynamic assays to quantitatively measure the activity of PI3K and dual PI3K/mTOR inhibitors in vivo.
Authors:
Deepak Sampath; Jason Oeh; Shelby K Wyatt; Tim C Cao; Hartmut Koeppen; Jeffrey Eastham-Anderson; Liliane Robillard; Calvin C K Ho; Jed Ross; Guanglei Zhuang; Hani Bou Reslan; Philip Vitorino; Kai H Barck; Sharon E Ungersma; Jean Michel Vernes; Maresa Caunt; Nick Van Bruggen; Weilan Ye; Ulka Vijapurkar; Yu-Ju Gloria Meng; Napoleone Ferrara; Lori S Friedman; Richard A D Carano
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  15     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  694-711     Citation Subset:  IM    
Affiliation:
Department of Translational Oncology, Genentech, Inc, South San Francisco, CA.
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