Despite an improved molecular understanding of glioblastoma multiforme (GBM), there are no effective treatments to cure this brain cancer. Our overall goal is to develop oncolytic herpes viral (oHSV) strategies to kill glioblastoma stem cells (GSCs) and improve GBM therapy. This will likely require combinatorial therapy.
In Aim 1 we extend our current studies of combinatorial systemic therapy and local oHSV anti-angiogenesis to GSCs and include a new anti-VEGF agent and two anti-angiogenic oHSV vectors.
In Aim 2, we explore mechanisms involved in targeting GSCs in both the perivascular and hypoxic niches using novel small molecule inhibitors of hypoxia inducible factor (HIF) to increase treatment efficacy.
In Aim 3, we utilize a syngeneic mouse GSC model to test whether the anti-angiogenic oHSV (G47?-mIL12) elicits an anti-tumor immune response in addition to lysing cancer cells and inhibiting tumor growth. We also hypothesize that anti- angiogenic therapy will enhance the immune response and anti-tumor efficacy of G47D-mIL12. The novelty of this proposal involves (1) the new human and mouse GSC models used;(2) the novel anti-angiogenic oncolytic herpes vectors (oHSV) available for study;(3) the synergistic mechanisms of tumor cell death involving both GSC and vasculature;(4) The mechanisms of oHSV killing of GSC in both the vascular niche and hypoxic niche of GBM;(5) the use of small molecule hypoxia inducible factor (HIF) inhibitors in conjunction with oHSV;(6) the ability of a vector to synergistically use multile avenues of tumor cell killing (oncolysis, anti-angiogenesis, inhibiting GSC to endothelial cell differentiation, initiating an anti-tumor immune response). The significance is that (1) therapeuti outcomes for GBM have advanced little in several decades;(2) we are defining mechanisms of synergy capable of killing the GSC population that has evaded most other therapies;(3) we have demonstrated our ability to produce vectors capable of going into clinical trial;(4) the strategies we are pursuing should be readily translatable to the clinic and we expect that these studies will lead to new clinical trials with increased efficacy for this fatal tumor. We started te concept of genetically engineered oncolytic viral (OV) therapy. For brain tumors, oHSV therapy has developed into several early phase clinical trials. For tumors outside the brain, OV therapy is now in Phase III clinical trials and is entering an era of increased interest by pharmaceutical companies for translation into mainstream cancer therapy. Herein, we explore important issues that have prevented GBM from being cured by standard therapies: How to kill the stem cell component;How to kill the hypoxic fraction of tumor;How to enhance killing of distant cells and provide lasting immunity. Our prior studies have led to several clinical trials and we expect the studies in this grant proposal to lead to improved approaches for these important problems and more effective treatment of people with GBM.

Public Health Relevance

Genetically engineered oncolytic herpes viruses in combination with systemic pharmaceuticals are used to explore issues that have prevented glioblastoma from being cured by standard therapies: How to kill the stem cell component;How to kill the hypoxic fraction of tumor;How to kill distant cells and provide lasting immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032677-20
Application #
8290713
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
1994-05-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
20
Fiscal Year
2012
Total Cost
$370,833
Indirect Cost
$152,083
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Esaki, Shinichi; Rabkin, Samuel D; Martuza, Robert L et al. (2016) Transient fasting enhances replication of oncolytic herpes simplex virus in glioblastoma. Am J Cancer Res 6:300-11
Marciscano, Ariel E; Stemmer-Rachamimov, Anat O; Niemierko, Andrzej et al. (2016) Benign meningiomas (WHO Grade I) with atypical histological features: correlation of histopathological features with clinical outcomes. J Neurosurg 124:106-14
Nigim, Fares; Cavanaugh, Jill; Patel, Anoop P et al. (2015) Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment. J Neuropathol Exp Neurol 74:710-22
Peters, Cole; Rabkin, Samuel D (2015) Designing Herpes Viruses as Oncolytics. Mol Ther Oncolytics 2:
Lu, Lei; Saha, Dipongkor; Martuza, Robert L et al. (2015) Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma. J Neurooncol 121:91-100
Ning, Jianfang; Wakimoto, Hiroaki; Rabkin, Samuel D (2014) Immunovirotherapy for glioblastoma. Cell Cycle 13:175-6
Cheema, Tooba A; Fecci, Peter E; Ning, Jianfang et al. (2014) Immunovirotherapy for the treatment of glioblastoma. Oncoimmunology 3:e27218
Ning, Jianfang; Wakimoto, Hiroaki (2014) Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapy. Front Microbiol 5:303
Patel, Anoop P; Tirosh, Itay; Trombetta, John J et al. (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344:1396-401
Suvà, Mario L; Rheinbay, Esther; Gillespie, Shawn M et al. (2014) Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157:580-94

Showing the most recent 10 out of 67 publications