The goals of this proposal are to improve treatment for gliomas by enhancement of oncolytic therapy and to develop serum microvesicles as biomarkers for genetic and phenotypic properties of individual GBM tumors and their response to therapy. Project 1 (Chiocca/Kaur) will evaluate whether viral RNA in microvesicles produced by HSV-infected glioma cells increases susceptibility of tumors to oncolysis, and assess viral and cellular mRNAs in tumor-derived serum microvesicles as biomarkers of oncolytic therapy. Project 2 (Weissleder/Hahko) will apply nanotechnology-based diagnostic magnetic resonance (DMR) to characterize micro vesicle number and antigenic profiles in serum based on proteins critical to oncogenesis using serum from mice and patients bearing glioblastoma (GBM) and undergoing different treatment paradigms. Project 3 (Breakefield) will characterize and enrich tumor-derived microvesicles serum using antibody-capture microfluidic chambers and quantities levels and mutations in GBM-related RNAs using serum samples as in Project 2. These projects will be supported by: Core A (Hochberg) to provide oversight for programmatic organization and neuropathology;Core B (Carter) to maintain a biorepository of human GBM tumor and longitudinal serum samples from patients undergoing standard-of-care therapy or clinical Phase l/ll trials, to supply de-identified samples to Project 2 and 3, and to carry out biostatistical correlations with clinical parameters;and Core C (Charest) to provide genetically engineered GBM mice with mutations representing driver mutations in two subtypes of human GBMs to Project 1, and de-identified tumor/serum samples and biostatistical correlations with tumor volume and survival time to Projects 2 and 3. This program will develop and evaluate new accessible serum biomarkers to facilitate evaluation of therapeutic paradigms in mouse models and human patients both in terms of real time response to therapy and mechanisms of resistance to therapy.

Public Health Relevance

Malignant gliomas represent the single most costly and morbid neoplasm per capita. There is a desperate need for accessible biomarkers in these and other forms of cancer to identify genetic/phenotypic characteristics of individual tumors in order to optimize therapies and to monitor responses to therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA069246-16
Application #
8475583
Study Section
Special Emphasis Panel (ZCA1-GRB-P (O1))
Program Officer
Timmer, William C
Project Start
1997-06-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
16
Fiscal Year
2013
Total Cost
$1,253,475
Indirect Cost
$294,593
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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