High grade gliomas are uniformly lethal, and resistant to surgery, chemotherapy and radiotherapy. The precise cellular and molecular mechanisms by which glioma cells disperse through the brain and grow to form macroscopic symptomatic tumor masses remains poorly understood. Herein we propose to test novel cellular, molecular and mechanistic hypotheses concerning glioma growth, and how to translate this knowledge into new anti-glioma therapeutics. Preliminary work from my laboratory, using confocal, electron and multiphoton microscopy has shown that glioma cells and human glioma stem cells disperse through the brain in vivo by traveling preferentially along the perivascular compartment, a potential migration network surrounding the brain microvasculature. As glioma cells move throughout the perivascular network they dislodge glial endfeet from blood vessels and compromise adjacent brain tissue;this is later replaced by tumor cells. We have also generated preliminary data that a glycan binding protein, galectin-1, is essential for this growth mechanism. Down regulation of galectin-1 abolishes glioma growth in the brain in vivo, without affecting growth in vitro. These new data have several clinical consequences: (i) lymph drains from the brain through the perivascular compartment;its obstruction by gliomas would contribute to glioma-induced edema;(ii) human glioma tumors grow to large size before causing symptoms;glioma cell replacement of atrophied brain tissue could explain protracted and indolent tumor growth, and the delayed changes in total brain volume;(iii) inhibition of galectin-1 could represent a novel treatment of human gliomas. This proposal will (I) test the hypothesis that rodent and human glioma cells, and glioma stem cells grow preferentially along the perivascular space;(II) test the hypothesis that galectin-1 mediates glioma perivascular invasion and growth, and that inhibition of galectin-1 can be used as a novel therapeutic strategy;and (III) test the hypothesis that inhibition of galectin-1 will enhance specific anti-glioma immune responses. By progressing from glioma pathophysiology to molecular mechanisms of glioma migration to experimental therapeutics, we aim for our work to lead to novel early phase clinical translational trials for the treatment of human gliomas. Of note, our first clinical trial for gene therapy of human gliomas is approaching the start of patient recruitment (it was approved by FDA on 4/7/11 [IND 14574] and very recently by the University of Michigan IBC and IRB). Therefore, our laboratory is in a strong and realistic position to guide our research towards the translational implementation of novel clinical trials for this currently deadly human cancer.
High grade glioma tumors eventually kill affected patients in under 5 years post-diagnosis. Mechanisms by which glioma tumors grow throughout the brain are still poorly understood;recently we have discovered the anatomical pathways used by very early stage brain tumors to spread throughout the brain. By interfering with the molecular mechanisms used by brain tumors to spread throughout the brain we aim to stop these tumors from killing experimental animals. We aim develop this approach further into novel therapeutic strategies for the treatment of patients with GBM, and the implementation of these new therapies in early phase clinical trials.
|Castro, Maria G; Candolfi, Marianela; Wilson, Thomas J et al. (2014) Adenoviral vector-mediated gene therapy for gliomas: coming of age. Expert Opin Biol Ther 14:1241-57|
|Mineharu, Yohei; Kamran, Neha; Lowenstein, Pedro R et al. (2014) Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions. Mol Cancer Ther 13:3024-36|
|Baker, Gregory J; Yadav, Viveka Nand; Motsch, Sebastien et al. (2014) Mechanisms of glioma formation: iterative perivascular glioma growth and invasion leads to tumor progression, VEGF-independent vascularization, and resistance to antiangiogenic therapy. Neoplasia 16:543-61|
|Lowenstein, P R; Yadav, Viveka Nand; Chockley, Peter et al. (2014) There must be a way out of here: identifying a safe and efficient combination of promoter, transgene, and vector backbone for gene therapy of neurological disease. Mol Ther 22:246-7|
|Lynes, John; Wibowo, Mia; Koschmann, Carl et al. (2014) Lentiviral-induced high-grade gliomas in rats: the effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H. Neurotherapeutics 11:623-35|
|VanderVeen, Nathan; Paran, Christopher; Appelhans, Ashley et al. (2014) Marmosets as a preclinical model for testing "off-label" use of doxycycline to turn on Flt3L expression from high-capacity adenovirus vectors. Mol Ther Methods Clin Dev 1:|
|Assi, Hikmat H; Paran, Chris; VanderVeen, Nathan et al. (2014) Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy. J Pharmacol Exp Ther 349:458-69|
|Baker, Gregory J; Chockley, Peter; Yadav, Viveka Nand et al. (2014) Natural killer cells eradicate galectin-1-deficient glioma in the absence of adaptive immunity. Cancer Res 74:5079-90|
|Assi, Hikmat; Espinosa, Jaclyn; Suprise, Sarah et al. (2014) Assessing the role of STAT3 in DC differentiation and autologous DC immunotherapy in mouse models of GBM. PLoS One 9:e96318|
|Candolfi, Marianela; Yagiz, Kader; Wibowo, Mia et al. (2014) Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models. Clin Cancer Res 20:1555-65|
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