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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-P (O1))
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Massachusetts General Hospital
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Ricklefs, Franz L; Alayo, Quazim; Krenzlin, Harald et al. (2018) Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv 4:eaar2766
Park, Jongmin; Im, Hyungsoon; Hong, Seonki et al. (2018) Analyses of Intravesicular Exosomal Proteins Using a Nano-Plasmonic System. ACS Photonics 5:487-494
Antoury, Layal; Hu, Ningyan; Balaj, Leonora et al. (2018) Analysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies. Nat Commun 9:3906
Zhou, Shuang; Appleman, Vicky A; Rose, Christopher M et al. (2018) Chronic platelet-derived growth factor receptor signaling exerts control over initiation of protein translation in glioma. Life Sci Alliance 1:e201800029
Min, Jouha; Nothing, Maria; Coble, Ben et al. (2018) Integrated Biosensor for Rapid and Point-of-Care Sepsis Diagnosis. ACS Nano 12:3378-3384
Lee, Kyungheon; Fraser, Kyle; Ghaddar, Bassel et al. (2018) Multiplexed Profiling of Single Extracellular Vesicles. ACS Nano 12:494-503
ReƔtegui, Eduardo; van der Vos, Kristan E; Lai, Charles P et al. (2018) Engineered nanointerfaces for microfluidic isolation and molecular profiling of tumor-specific extracellular vesicles. Nat Commun 9:175
Speranza, Maria-Carmela; Passaro, Carmela; Ricklefs, Franz et al. (2018) Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma. Neuro Oncol 20:225-235
Boussiotis, Vassiliki A; Charest, Alain (2018) Immunotherapies for malignant glioma. Oncogene 37:1121-1141
Sahin, Ayguen; Sanchez, Carlos; Bullain, Szofia et al. (2018) Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII-expressing artificial antigen presenting cells for adoptive cell therapy for glioma. PLoS One 13:e0199414

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