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.
|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|
|Reátegui, 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|
Showing the most recent 10 out of 223 publications