We have found that Akt signaling contributes to some of the more notable abnormalities in tumor vascular itroma. Those vascular abnormalities include the propensity for excessive vascular permeability leading to tissue edema and sluggish blood flow, extravasation of fibrin and other matrix proteins that alter the extracellular microenvironment, and the trafficking of inflammatory cells in and out of the tumor-associated vasculature. In addition, we also showed that rapamycin is an effective inhibitor of Akt signaling in the tumor stroma. This grant application has two major goals: (1) to study rapamycin's effects on the tumor stroma and to determine the i.npact of the anti-stromal effects of rapamycin on its anti-tumor efficacy. Both vascular and nonvascular stroma will be studied. (2) to investigate the contribution to angiogenesis by key molecules in the Akt-mTOR pathway that may be critical for the observation effects of rapamycin.
Aim 1 is focused on dentification of the vessel targets of rapamycin.
Aim 2 is designed to explore the effects of rapamycin on the non-vascular tumor stroma Aim 3 investigates rapamycin inhibition of tumor cell trafficking across the endothelium in metastasis. In addition to examing rapamycin's effects, all three aims contain some investigations of individual molecules in the Akt-mTor pathway. A particular focus is proposed to examine Akt isoforms and the TORCH feedback to Akt in the regulation of angiogenesis and endothelial trafficking in order to better understand the key regulatory molecules that are affected by rapamycin to mediate the observed anti-stromal phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA092644-09
Application #
8378437
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$294,886
Indirect Cost
$93,580
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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