Signature Centers

Signature Center Initiative for the Cure of Glioblastoma

External and Internal Pilot Funding

PI

Agency

Title

Aaron Cohen-Gadol, MD, MSc
Karen Pollok, PhD
(Directors)

IUPUI Signature Center Initiative

The SCI for the Cure of Glioblastoma

Karen Pollok, PhD (PI)

NIH/NCI: R01 CA138798

Dual Targeting of DNA Repair and p53 pathways for treatment of brain cancer

Aaron Cohen-Gadol, MD, MSc (PI)

Indiana University Melvin and Bren Simon Cancer Center’s Translational Research Acceleration

Evaluation of proangiogenic circulating hematopoietic stem and progenitor cells (pCHSPCs) as a biomarker of treatment response or tumor recurrence in patients with glioblastoma multiforme (GBM)

Kari Clase, PhD (PI)

The SCI for the Cure of Glioblastoma 

 Lipidomic, Metabolomic and Proteomic Analyses of Human Glioblastoma Multiforme

Jenna Rickus, PhD
Melissa Fishel, PhD
(Co-PIs)

The SCI for the Cure of Glioblastoma 

Multi-cellular, Multi-niche 3D Culture Model of Glioblastoma

Maria Theresa Rizzo, MD (PI)

The SCI for the Cure of Glioblastoma

Targeting the Microsomal Prostaglandin E Synthase-1 for the Prevention of Recurrent Glioblastoma Multiforme

Ahmad Safa, PhD (PI)

The SCI for the Cure of Glioblastoma

Selective targeting of histone deacetylase 6 (HDAC6) for glioblastoma multiforme (GBM) treatment


PI:  Karen Pollok, PhD

Title: Dual Targeting of DNA Repair and p53 pathways for treatment of brain cancer

Abstract

Development of efficacious strategies for treatment of brain cancers remains a significant challenge in both pediatric and adult patients. Some improvements, such as treatment with radiation and temozolomide (TMZ), have led to increased survival. However, the prognosis for brain tumor patients remains poor, and is largely due to the ability of these malignancies to acquire chemoresistance by modulation of p53-regulated signaling pathways that control cell survival. In this proposal, we investigate the efficacy of a novel combination therapy that targets the Mdm2/p53 network and DNA repair. Inhibition of Mdm2 interactions with key signaling molecules-p53, p73a, and HIF1a- by the small molecule inhibitor, nutlin3a, can modulate their downstream effector function. Depending on the cell type studied, exposure to the Mdm2 antagonist can lead to cell cycle arrest, senescence, apoptosis, decreased migration, and attenuation of VEGF production. To what extent TMZ and radiation in combination with nutlin3a can modulate these critical intracellular targets has not been studied. Our data indicate that nutlin3a can significantly potentiate TMZ- and radiation-mediated cytotoxicity in glioblastoma cells in vitro. In addition, nutlin3a also enhanced TMZ-mediated glioblastoma cell kill in an ectopic xenograft model.  Our overall objective is to develop efficacious treatment strategies that kill brain tumor cells but not normal cells. For drug efficacy studies, ectopic and orthotopic glioblastomas will be established in NOD/SCID/IL2Rnull mice. A panel of glioblastoma cell lines that differ in EGFR gene amplification, p53 status (wild-type or mutant), Mdm2 status, MGMT expression, and sensitivities to TMZ and irradiation will be utilized. Real-time bioluminescence imaging will be utilized to serially monitor glioblastoma progression over time. Our central hypothesis is that nutlin3a potentiates the TMZ- and/or radiation-induced DNA damage response by perturbing Mdm2-mediated regulation of key signaling molecules, and leads to increased glioblastoma cell death in vivo. To test this hypothesis, the following specific aims are proposed: 1)Develop therapeutic regimens and validate intracellular target modulation mediated by inhibition of Mdm2-protein interactions during exposure to DNA-damaging agents 2) Assess in vivo the outcome of modulating Mdm2-dependent signaling to increase therapeutic efficacy of TMZ- and/or radiation-mediated DNA damage. 3) Employ intracranial GBM xenograft models in combination with serial real-time bioluminescence imaging to monitor therapeutic impact of modulating Mdm2-dependent signaling in combination with TMZ- and/or radiation-mediated DNA damage. The treatment strategies investigated here will use clinically relevant in vivo models and novel multi-targeting approaches and have the potential to improve treatment efficacy and quality of life for patients with GBM.


PI:  Aaron Cohen-Gadol, MD, MSc

Title: Evaluation of proangiogenic circulating hematopoietic stem and progenitor cells (pCHSPCs) as a biomarker of treatment response or tumor recurrence in patients with glioblastoma multiforme (GBM)

Abstract

Timely diagnosis of recurrence of highly aggressive tumors such as GBM is a critical factor for evaluation of treatment efficacy and improving patients’ survival. To date, there is no readily available test that can estimate the patients’ tumor burden and response to therapy.  The use of peripheral blood biomarkers could significantly improve the early detection of tumor recurrence and treatment response.   In this project, we build on existing expertise and preliminary data from our institution to assess the implications of the above-mentioned novel biomarker.  The longitudinal analysis of the ratio of proangiogenic to nonangiogenic CHSPCs by multi-parametric flow cytometry has been shown to correlate with treatment response in breast cancer and pediatric patients with solid tumors at the IUSM. The tracking of this cell ratio has not been studied before among adult GBM patients.  The data obtained from this pilot study will provide us with a foundation to investigate the true predictive value of this potentially useful cellular biomarker for monitoring the impact of GBM therapy and timely assessment of tumor recurrence.


PI: Kari Clase, PhD

Title: Lipidomic, Metabolomic and Proteomic Analyses of Human Glioblastoma Multiforme

Abstract

Glioblastoma (GBM) is the most common and malignant form of primary brain tumor1 with an average survival rate of 12-15 months from diagnosis. GBM is highly invasive and the impact of treatment options on survival rate has improved very little in the past 20 years. GBM biomarkers discovered with the use of mass spectrometry could be applied to improve multiple aspects of treatment including: early detection of cancer, diagnosis, prognosis, response to therapy options, and cancer recurrence. Biomarker identification, however, has several challenges due to biological and technical limitations4 and continues to evolve as clinical specimen pipelines and technologies are optimized. Tumors, including GBM, are heterogeneous and evolve over time in response to current treatments.


PI: Jenna Rickus, PhD; Melissa L. Fishel, PhD

Title: Multi-cellular, Multi-niche 3D Culture Model of Glioblastoma

Abstract

Glioblastoma multiforme (GBM) is a highly invasive type of brain cancer with low prognosis and overall median survival of 1-2 years. Invariably tumors reappear in surrounding tissue following treatment by surgical resection, radiation, and chemotherapy. Synergistic relationships and signaling with other cell types and with the extracellular environment play important roles in resistance, migration and colonization strategies. A critical barrier in the cancer field is that most of the pathway analyses and drug screens are initially conducted in 2D cultures that fail to recapitulate important microenvironment-induced cell responses. GBM cells when extracted from the tumor and cultured under traditional 2D, monoculture conditions lose native interactions and change their behavior; therefore, their ability to predict in vivo outcomes is reduced. Direct passage of human tumor cells into xenograft mice models is increasingly preferred as a way to preserve the in vivo characteristics, nevertheless, the microenvironment of xenografts are difficult to systematically manipulate and interrogate. To dissect mechanistic understanding, 3D in vitro culture systems that are both tunable and able to reflect the multi-cellular, multi-niche human tumor microenvironment are required to compliment in vivo xenograft and organotypic model systems.


PI: Maria Teresa Rizzo, MD

Title: Targeting the Microsomal Prostaglandin E Synthase-1 for the Prevention of Recurrent Glioblastoma Multiforme

Abstract

Despite the current multimodal therapy, the majority of patients with glioblastoma multiforme (GBM) die of recurrent disease in less than 9-12 months. There is, therefore, an urgent and unmet clinical need to develop new therapeutic approaches aimed at preventing recurrent GBM. Our previous studies demonstrated constitutive expression of the microsomal prostaglandin E synthase (mPGES-1) in the established GBM cell line U87-MG and implicated the enzyme as a critical regulator of GBM growth. During the course of recent studies, unexpectedly we detected loss of mPGES-1 protein expression in U87-MG cells cultured under stem like-cell conditions (neurospheres). However, U87-MG-derived neurospheres acquired mPGES-1 expression when exposed to differentiation-inducing conditions. Against this background, the objective of this pilot study is to test the novel hypothesis that mPGES-1 contributes to regulation of GBM stem like-cell (GBM-SC) differentiation. mPGES-1 protein expression and activity will be measured in neurospheres derived from GBM cell lines, xenografts and surgical specimens of GBM patients following differentiation with all-trans-retinoic acid (ATRA) or arsenic trioxide. Differentiation will be assessed by monitoring stemness and lineage-specific markers. Retroviral transduction of mPGES-1 and RNAi-mediated gene silencing will be employed to establish the requirement of mPGES-1 for GBM-SC differentiation.  


PI: Ahmad Safa, PhD

Title: Selective targeting of histone deacetylase 6 (HDAC6) for glioblastoma multiforme (GBM) treatment

Abstract:

Resistance to apoptosis and chemotherapy is a common feature of glioblastoma multiforme (GBM) tumors. Temozolomide (TMZ) is the only chemotherapeutic agent shown to slightly benefit GBM patients, and the combination of temozolomide (TMZ) and radiotherapy has increased the survival of patients with GBM. However, the median survival of GBM patients remains about 14.6 months (1). Another major problem limiting our ability to treat GBM is the existence of rare populations of GBM stem cells (GSCs) or cancer-initiating cells in GBM tumors. Hence, there is an urgent need to identify new agents and design rational strategies to counter drug and apoptosis resistance in GBM.  Our long-term goal is to develop therapeutic strategies that sensitize drug-resistant PC tumors to therapy.  Our long-term goal is to develop therapeutic strategies that sensitize drug-resistant GBM tumors to therapy. We have found that a histone deacetylase 6 (HDAC6) effectively triggered cell death in the GBM cell lines and primary cultures.  We also have isolated CD133+ GBM stem cells and neurospheres, and plan to determine the molecular mechanism of the HDAC6 inhibitor-triggered inhibition of cell survival in GBM cell lines, primary cultures, and GSCs.  Our overall hypothesis is that inhibition of HDAC6 prevents the growth and proliferation of GBM and improvements in the treatment of GBM can be achieved by inhibition of HDAC6 alone or in combination with TMZ.  We will (1) determine the molecular mechanisms of the HDAC6 inhibitor-triggered cell death in GBM tumor cells and GSCs, and (2) determine the pharmacodynamic (PKD) and pharmacokinetic (PK) as well as assess in vivo target validation and toxicity profile of the inhibitor of HDAC6 through the Clinical Pharmacology Analytical Core (CPAC), and the In Vivo Therapeutics Core (IVTC). Our innovative strategies will provide significant information on how to apply these findings to the translational context, eliminate GSCs, and help develop rational approaches to more specifically and effectively treat GBM patients.