Glioma microvesicles are abundantly shed into circulation, can be detected in the majority of clinical patients and are being explored as biomarkers for therapy assessment. A current major challenge and opportunity is the ability to develop methods for rapidly determining the abundance and composition of microvesicles from clinical samples. We have recently developed a novel, highly sensitive, nanotechnology based, point-of-care diagnostic method termed """"""""DMR"""""""" (diagnostic magnetic resonance). The molecular specificity of DMR is achieved through magnetic nanoparticles that act as sensors for specific molecular targets. In preliminary feasibility experiments, we have profiled intact cancer cells in a prospective clinical trial (Science TransI Med 2011, in press) and also shown that we can sensitively detected and profile (via CD63, EGFR, EGFRv3, PDGFR, podoplanin, EphA2, CD41, MHCII) microvesicles in plasma samples. The overall goal of this revised proposal is to further advance the DMR technology and to apply it to more comprehensive profiling of microvesicles in glioma patients undergoing treatment.
In aim 1 we will develop, calibrate and validate DMR for measuring microvesicle concentration and protein markers of interest (EGFRvlll, EGFR/pEGFR, S6 ribosomal protein/pSSrp, CD63, Gag polyprotein pr65, CYR61) in cells and novel mouse models.
In aim 2 we will develop a new microfluidic chip that integrates filters, mixing chambers and micro-NMR components to separate microvesicles from whole blood and directly detect them in one step. Finally, in aim 3 we will study clinical samples in an effort to predict therapeutic efficacy in individual patients undergoing glioma treatment. Patient samples originate from two different sources: 1) an ongoing multi-institutional clinical trial in glioma patients undergoing standard-of-care, and 2) a prospective clinical trial evaluating new glioma therapy approaches. This project is highly interactive with Project 3 (Drs. Breakefield/Skog) and Project 1 (Drs. Chiocca/Kaur). The Biorepository Core (Core B;Dr. Carter) will supply samples from clinical trials and the Mouse Models Core (Dr. Charest) will provide mouse models for preclinical testing. We ultimately envision using this technology in a point-of-care setting to quantitate both exosome number and composition, which could serve as a rapid measure of therapeutic efficacy in clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA069246-16
Application #
8475586
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
16
Fiscal Year
2013
Total Cost
$203,340
Indirect Cost
$47,792
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Rooj, Arun K; Ricklefs, Franz; Mineo, Marco et al. (2017) MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells. Cell Rep 19:2026-2032
Choudhury, Sourav R; Hudry, Eloise; Maguire, Casey A et al. (2017) Viral vectors for therapy of neurologic diseases. Neuropharmacology 120:63-80
Maas, Sybren L N; Breakefield, Xandra O; Weaver, Alissa M (2017) Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Trends Cell Biol 27:172-188
Speranza, Maria-Carmela; Passaro, Carmela; Ricklefs, Franz et al. (2017) Preclinical investigation of gene-mediated cytotoxic immunotherapy and checkpoint blockade in glioblastoma. Neuro Oncol :
Min, Changwook; Park, Jongmin; Mun, Jae Kyoung et al. (2017) Integrated microHall magnetometer to measure the magnetic properties of nanoparticles. Lab Chip 17:4000-4007
Yeo, Alan T; Charest, Alain (2017) Immune Checkpoint Blockade Biology in Mouse Models of Glioblastoma. J Cell Biochem 118:2516-2527
Im, Hyungsoon; Lee, Kyungheon; Weissleder, Ralph et al. (2017) Novel nanosensing technologies for exosome detection and profiling. Lab Chip 17:2892-2898
Godlewski, Jakub; Ferrer-Luna, Ruben; Rooj, Arun K et al. (2017) MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer. Stem Cell Reports 8:1497-1505
Wei, Zhiyun; Batagov, Arsen O; Schinelli, Sergio et al. (2017) Coding and noncoding landscape of extracellular RNA released by human glioma stem cells. Nat Commun 8:1145
Zappulli, Valentina; Friis, Kristina Pagh; Fitzpatrick, Zachary et al. (2016) Extracellular vesicles and intercellular communication within the nervous system. J Clin Invest 126:1198-207

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