In JoVE (1)
Other Publications (8)
- Discovery Medicine
- Anti-cancer Agents in Medicinal Chemistry
- Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics
- Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
- Cancer Research
- Neoplasia (New York, N.Y.)
- Methods in Molecular Biology (Clifton, N.J.)
Articles by Gregory J. Baker in JoVE
Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells Gregory J. Baker1,2, Maria G. Castro1,2, Pedro R. Lowenstein1,2 1Department of Neurosurgery, University of Michigan, 2Department of Cell and Developmental Biology, University of Michigan Presented here is a straightforward method for the isolation and flow cytometric analysis of glioma-infiltrating peripheral blood mononuclear cells that yields time-dependent quantitative data on the number and activation status of immune cells entering the early brain tumor microenvironment.
Other articles by Gregory J. Baker on PubMed
Gene Therapy and Virotherapy: Novel Therapeutic Approaches for Brain Tumors Discovery Medicine. Oct, 2010 | Pubmed ID: 21034670 Glioblastoma multiforme (GBM) is a deadly primary brain tumor in adults, with a median survival of ~12-18 months post-diagnosis. Despite recent advances in conventional therapeutic approaches, only modest improvements in median survival have been achieved; GBM usually recurs within 12 months post-resection, with poor prognosis. Thus, novel therapeutic strategies to target and kill GBM cells are desperately needed. Our group and others are pursuing virotherapy and gene therapy strategies for the treatment of GBM. In this review, we will discuss various virotherapy and gene therapy approaches for GBM currently under pre-clinical and clinical evaluation including direct or conditional cytotoxic, and/or immunostimulatory approaches. We also discuss cutting-edge technologies for drug/gene delivery and targeting brain tumors, including the use of stem cells as delivery platforms, the use of targeted immunotoxins, and the therapeutic potential of using GBM microvesicles to deliver therapeutic siRNAs or virotherapies. Finally, various animal models available to test novel GBM therapies are discussed.
Targeted Toxins for Glioblastoma Multiforme: Pre-clinical Studies and Clinical Implementation Anti-cancer Agents in Medicinal Chemistry. Oct, 2011 | Pubmed ID: 21707497 Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. GBM is very aggressive due to its poor cellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBM's invasive nature as well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination of human GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surrounding non-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator (uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such as Diptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins for GBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients, efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in the tumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for local delivery.
Lentiviral-induced High-grade Gliomas in Rats: the Effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics. Jul, 2014 | Pubmed ID: 24752661 In human gliomas, the RTK/RAS/PI(3)K signaling pathway is nearly always altered. We present a model of experimental gliomagenesis that elucidates the contributions of genes involved in this pathway (PDGF-B ligand, HRAS-G12V, and AKT). We also examine the effect on gliomagenesis by the potential modifier gene, IDH1-R132H. Injections of lentiviral-encoded oncogenes induce de novo gliomas of varying penetrance, tumor progression, and histological grade depending on the specific oncogenes used. Our model mimics hallmark histological structures of high-grade glioma, such as pseudopalisades, glomeruloid microvascular proliferation, and diffuse tumor invasion. We use our model of gliomagenesis to test the efficacy of an experimental brain tumor gene therapy. Our model allowed us to test the contributions of oncogenes in the RTK/RAS/PI(3)K pathway, and their potential modification by over-expression of mutated IDH1, in glioma development and progression in rats. Our model constitutes a clinically relevant system to study gliomagenesis, the effects of modifier genes, and the efficacy of experimental therapeutics.
Blocking Immunosuppressive Checkpoints for Glioma Therapy: the More the Merrier! Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Oct, 2014 | Pubmed ID: 24879798 Immunosuppressive checkpoints mediated by IDO, CTLA4, and PD1/PDL1 play a critical role in glioma progression and the efficacy of immunotherapies. Combined blockade of these immunosuppressive checkpoints in a glioma model elicited long-term survival. This combined blockade adds to the armamentarium of anti-glioma therapies, which could be implemented in clinical trials. Clin Cancer Res; 20(20); 5147-9. ©2014 AACR.
Natural Killer Cells Eradicate Galectin-1-deficient Glioma in the Absence of Adaptive Immunity Cancer Research. Sep, 2014 | Pubmed ID: 25038230 Natural killer (NK) cells safeguard against early tumor formation by destroying transformed target cells in a process referred to as NK immune surveillance. However, the immune escape mechanisms used by malignant brain tumors to subvert this innate type of immune surveillance remain unclear. Here we show that malignant glioma cells suppress NK immune surveillance by overexpressing the β-galactoside-binding lectin galectin-1. Conversely, galectin-1-deficient glioma cells could be eradicated by host NK cells before the initiation of an antitumor T-cell response. In vitro experiments demonstrated that galectin-1-deficient GL26-Cit glioma cells are ∼3-fold more sensitive to NK-mediated tumor lysis than galectin-1-expressing cells. Our findings suggest that galectin-1 suppression in human glioma could improve patient survival by restoring NK immune surveillance that can eradicate glioma cells. Cancer Res; 74(18); 5079-90. ©2014 AACR.
Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-independent Vascularization, and Resistance to Antiangiogenic Therapy Neoplasia (New York, N.Y.). Jul, 2014 | Pubmed ID: 25117977 As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.
Cracking the Glioma-NK Inhibitory Code: Toward Successful Innate Immunotherapy Oncoimmunology. Nov, 2014 | Pubmed ID: 25941594 Natural killer (NK) cells eradicate galectin-deficient malignant gliomas without the necessity for T cell cooperation. This phenomenon was discovered as a consequence of reducing glioma-derived galectin-1. We propose that stimulation of endogenous antitumor NK cell activity may be achieved by reducing potent tumor-derived NK cell inhibitors, such as galectin-1, and that such agents be tested in the clinic to treatbrain tumors.
Gene Therapy for the Treatment of Neurological Disorders: Central Nervous System Neoplasms Methods in Molecular Biology (Clifton, N.J.). 2016 | Pubmed ID: 26611605 Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a median survival of 16.2-21.2 months post diagnosis (Stupp et al., N Engl J Med 352(10): 987-996, 2005). Because of its location, complete surgical resection is impossible; additionally because GBM is also resistant to chemotherapeutic and radiotherapy approaches, development of novel therapies is urgently needed. In this chapter we describe the development of preclinical animal models and a conditionally cytotoxic and immune-stimulatory gene therapy strategy that successfully causes tumor regression in several rodent GBM models.