CNS Malignancy/Brain and Nervous System


The OSUCCC – James CNS Malignancies Clinical Research Program evaluates state-of-the-art therapies for patients with cancer of the central nervous system (CNS). Neuro-oncology physician-researchers work closely with translational researchers and basic scientists who specialize in CNS malignancies to rapidly apply research results to patient care.

The ultimate goal is to rapidly and effectively translate research findings into treatments that will improve outcomes and quality of life for patients with CNS malignancies.

The CNS Malignancies Clinical Research Program also benefits from National Cancer Institute (NCI) funding to the OSUCCC – James that supports the cost of conducting phase I and phase II clinical trials and facilitates the movement of promising phase II studies into phase III national trials.

Clinical Research Strengths of the CNS Malignancies Program

  • OSUCCC – James investigators have shaped the current standards in the CNS field through their leadership in international clinical trials.
  • OSUCCC – James physicians hold national leadership positions in the CNS field. Our investigators hold positions such as:
    • Chairman of the NRG/RTOG Brain Tumor Translational Research Group
    • Chair on the Board of Directors of the International Society of Radiation Neuro-biology
    • Scientific Program Chair of American College of Radiation Oncology
    • Board of Directors for the Ohio Brain Tumor Consortium
    • Chairman of NIH/NCI Cancer Biomarkers Study Section
    • Board of Directors for American Association of Cancer Research (AACR)
    • Vice President and President-Elect for Society for Natural Immunity
    • Board of Directors for Pelotonia
    • Chief of Dardinger Laboratories for Neuro-Oncology and NeuroSciences
  • Superior outcome of CNS oncology patients treated at the James versus national averages (embed 2 graphs demonstrating Superior care).
  • Unparalleled track-record of NIH/Federal funding with a combined total of over $150,000,000 in funding over the past five years for the CNS team and relevant departments. (link to Grants section). For example:
    • Department of Health and Human Services Affordable Care Act Grant; Administrative PI: Schuller; Radiation Oncology PI: Arnab Chakravarti. Objective: Personalized Care Model in Radiation Oncology. Direct Costs = $100,000,000.00 (Funded, Active)
    • NIH/NCI R01 CA 188500 (PIs: Fen Xia and Arnab Chakravarti); The Novel Functions of Pyruvate Kinase M2 in DNA Double-Strand Break Repair. Objective: to examine the role of a newly-identified protein called PKM2 in mediating radiation resistance in glioblastoma. Direct Costs = $2,098,598.00
  • Unique technologies geared to eradicate CNS Malignancies at the OSUCCC – James:
    • Radiation Oncology: The department of Radiation Oncology is one of only two radiation departments located above ground in the country. The department includes cutting edge technologies such as gamma knife, Varian Edge, Varian True Beam and a state of the art Brachytherapy Suite. The radiation department also uses cutting edge imagining with the MRI-simulator, CT-simulator, and PET-CT.
    • Diagnostic Imaging: The Radiology Department provides complete diagnostic imaging services, which are vital in early diagnoses and in developing a treatment plan.
    • Neurosurgery: Our Neurosurgery team is led by highly specialized surgeons recruited from some of the country’s top programs. Our specialists are leaders in their fields in treatment and innovative management of new approaches for a wide spectrum of neurological malignancies. Expertise and advanced technology come together as they champion a personalized approach to medicine.
  • Various investigator-initiated trials as well as cooperative trials are open at the OSUCCC – James to offer personalized care for patients’ specific diseases.

Affiliated Programs

  • Dardinger Neuro-Oncology Center at Ohio State
  • Ohio State’s Minimally Invasive Surgery Program/Center for Minimally Invasive Surgery
  • Center for Clinical and Translational Science at Ohio State
  • National Institute of Neurological Disorders and Stroke at the National Institutes of Health
  • Nationwide Children’s Hospital, Columbus

Grants

Clinical research on promising investigational treatments for CNS malignancies at the OSUCCC – James is supported by numerous grants, both private and public, but particularly from the National Institutes of Health. Here are a few examples.

  • Department of Health and Human Services Affordable Care Act Grant; Administrative PI: Schuller; Radiation Oncology PI: Arnab Chakravarti. Objective: Personalized Care Model in Radiation Oncology. Direct Costs = $100,000,000.00 (Funded, Active)
  • NIH/NCI R01 CA 188500 (PIs: Fen Xia and Arnab Chakravarti); The Novel Functions of Pyruvate Kinase M2 in DNA Double-Strand Break Repair. Objective: to examine the role of a newly-identified protein called PKM2 in mediating radiation resistance in glioblastoma. Direct Costs = $2,098,598.00
  • Recipient of the American Cancer Society Scholar Award. (PI: Guo); Examine the vital contribution of cholesterol metabolism in promoting the malignant phenotype of Glioblastoma. Objective: Targeting the cholesterol metabolism to treat Glioblastoma. Direct Costs = $792,000.00
  • R01 CA163581-02 (PI: Denko); Decreasing oxygen metabolism to reduce hypoxia and radiosensitize tumors. Objective:  to examine the role of tumor hypoxia in radiosenstized tumors. Direct Costs = $254,489.00
  • R01 NS079701-01 (PI: Guo); Targeting the cholesterol metabolism to treat Glioblastoma. Objective: Targeting the cholesterol metabolism to treat Glioblastoma. Direct Costs = $218,750.00
  • American Society for Radiation Oncology Grant (PI: Williams); Elucidating and targeting intrinsic KRAS mutant Radioresistance with novel RAS targeted therapies. Objective: Elucidating and targeting intrinsic KRAS mutant Radioresistance with novel RAS targeted therapies. Direct Costs = $100,000.00

Circumventing barriers to effective oncolytic virotherapy of malignant gliomas (P01 CA163205)
PI: Michael A. Caligiuri, MD
Objectives:

  • Investigate the hypothesis that replication and dispersal of an oncolytic herpes simplex virus type 1 (oHSV) in glioblastoma are impeded by multiple viral- and host-based barriers and responses during initial phases of viral infection and replication.
  • Develop pharmacologic and genetic modalities that circumvent these barriers and responses and increase the efficacy of virotherapy for malignant glioma.

Patient-Oriented Research Program in Neuro-Oncology (CA160777)
PI: Vinay Puduvalli, MD
Objectives:

  • Enhance patient-oriented clinical and translational research for patients with neurological malignancies
  • Conduct a clinical trial based on Bayesian adaptive randomization methods to test the hypothesis that vorinostat (an epigenetic agent) can prevent development of resistance to bevacizumab in patients with recurrent glioblastoma, significantly delay tumor recurrence and improve survival
  • Measure changes in perfusion and diffusion within the tumor using DCE/DSC MR imaging as a noninvasive marker of treatment outcome
  • Measure serum biomarkers to determine their association with outcome
  • Mentor junior faculty, fellows and residents in neuro-oncology

Clinical Trials for CNS Malignancies

Examples of neuro-oncology clinical trials underway at the OSUCCC – James are below.

Newly Diagnosed Gliomas

OSU-13089: An Open Label Phase 1b/2 Study of Orally Administered PLX3397 in Combination with Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma
Site PI: Vinay Puduvalli, MD

OSU 12079: An International, Randomized, Double-Blind, Controlled Study of Rindopepimut/GM-CSF with Adjuvant Temozolomide in Patients with Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma
Site PI: Herb Newton, MD

Recurrent Gliomas

OSU-13072: Phase I/II Adaptive Randomized Trial of Bevacizumab versus Bevacizumab plus Vorinostat in Adults with Recurrent Glioblastoma
PI: Vinay Puduvalli, MD
NCT ID: NCT01266031
Objectives:

  • Determine the maximum tolerated dose (MTD) of vorinostat (an HDAC inhibitor) plus bevacizumab (an angiogenic inhibitor) in adult patients with malignant glioma
  • Determine the efficacy of vorinostat plus bevacizumab versus bevacizumab alone in patients with recurrent WHO grade IV glioma (glioblastoma and gliosarcoma)
  • Determine the progression-free survival rate using an adaptive randomization phase II trial design

OSU 11122: A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered to Subjects at the Time of Resection for Recurrent High Grade Glioma and Followed by Treatment with Toca FC, Extended-Release 5-FC
PI: Brad Elder, MD

OSU 10151: Intracerebral convection enhanced delivery of carboplatin for treatment of recurrent high-grade gliomas
PI: Brad Elder MD

Brain Metastases

OSU-13197: A Phase 1 Study of Trametinib in Combination with Radiation Therapy for Brain Metastases from KRAS-, BRAF-, NRAS- or HRAS- Mutant Malignancies
PI: Evan Wuthrick, MD
NCT ID: NCT02015117
Objectives:

  • Define the maximum dose level of trametinib
  • Assess overall tolerability and toxicity of the regimen
  • Assess the objective response rate per RECIST criteria
  • Describe the local control rate, neurological progression-free survival rate and overall survival rate

Translational Studies Under Way at the OSUCCC – James

The Tumor Microenvironmental Barrier to Effective Viral Oncolysis (CA163205)
PI: Balveen Kaur, PhD
Objective:

  • Understand extracellular barriers to efficient spread of oncolytic viruses
  • Develop a novel oncolytic virus with an extracellular-matrix modulating enzyme to enhance therapy of brain tumors

Enhancing Viral Oncolysis With Vasculostatin Gene Delivery (R01CA150153)
PI: Balveen Kaur, PhD
Objective: The ultimate goal of this proposal is to understand the contribution of Vstat120 expressing oncolytic viruses on OV propagation, tumor biology and anti-tumor efficacy. These results will lead to a better understanding of OV therapy-induced changes in tumor biology and will lead to the development of a dually-armed, cancer-killing OV. The OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Results from six clinical trials using replication competent OVs to treat patients with malignant glioma have shown the new modality to be relatively safe, but high expectations of efficacy remain unmet (1, 2). The tumor's microenvironment is increasingly recognized as an important determinant for its progression and its response to therapeutics. The Kaur laboratory has recently created two oncolytic viruses, armed with an anti-angiogenic gene. Researchers now propose to elucidate the role of this angiostatic protein in viral propagation, glioma biology and OV efficacy.

OV Therapy-Induced Changes In Tumor Secretome And Their Impact On Therapy (R01NS064607)
PI: Balveen Kaur, PhD
Objective: Researchers at the OSUCCC – James are investigating changes in the tumor microenvironment following oncolytic viral (OV) therapy, with the ultimate goal to devise better treatment strategies to combat brain tumors. In preliminary studies, investigators have uncovered a significant increase in the release of HMGB1. HMGB1 is normally a cellular protein that is released into the extracellular environment upon certain stimuli and can serve as a damage-associated molecular pattern. This study will evaluate the impact of this extracellular HMGB1 on tumor microenvironment, its impact on endothelial cells (Aim 1), macrophages (Aim 2) and antigen presentation to T cells (Aim 3).

Aurora-A Is A Novel Therapeutic Target In Glioblastoma (R01NS081125)
PI: Norm Lehman, MD
Objective: The goals of these studies are to test the potential efficacy of Aurora-A inhibition as a therapy for glioblastoma alone and in combination with other therapies. We will study the biological mechanisms and molecular determinants of the potential efficacy of Aurora-A inhibitors in vivo in order to both identify potential markers of patient drug response and to rationally design optimal combination therapies of Aurora-A inhibitors with other treatment modalities.

Targeting The Cholesterol Metabolism To Treat Glioblastoma (R01NS079701)
PI: Deliang Guo, PhD
Objective: The hypothesis of this application is that GBM cells are dependent on cholesterol uptake for rapid growth, and that its high levels are maintained by EGFR/PI3K/Akt signaling through upregulation of the SREBP-1/LDLR pathway to promote LDL uptake. Investigators predict that LDLR and LXR are novel molecular targets in GBM, and depriving cells of cholesterol alone or in combination with inhibition of fatty acid synthesis, will significantly inhibit GBM growth. This study aims to identify a novel, therapeutically targetable tumor survival pathway, and to investigate the efficacy of targeting LDLR or activating LXR by its synthetic agonists GW3965 and T9091317, separately or in combination with the FASN inhibitor C75, on GBM xenograft tumor growth. Objectives: 1) determine the molecular mechanism by which EGFR/PI3K signaling upregulates LDLR and LDL uptake, and test atorvastatin treatment in GBM cells in Aim 1; 2) investigate the role of LDLR on GBM tumor growth in Aim 2; 3) determine the mechanism and efficacy of activating LXR by GW3965, T9091317 alone or in combination with FASN inhibitor C75 on GBM tumor growth and evaluate the translational potential of these drugs to treat GBM in Aim 3.

Targeting Melk-Mediated Ezh2 Signaling In Glioma Stem Cells (R01 NS083767)
PI: Ichiro Nakano, MD, PhD
Objective: The major goals of this project are to determine the MELK signaling in glioma stem cells and develop novel therapeutic approaches for malignant glioma by targeting the MELK signals.

Determination Of Musashi1/Cd44v6 Signaling In Mesenchymal Glioma Stem Cells (R21 CA175875)
PI: Ichiro Nakano, MD, PhD
Objective: This proposal will molecularly define GSCs by characterization of the key mechanism underlying proliferation of GSCs. It will further determine whether elimination of GSCs attenuates growth of tumors with the pre-clinical patient-derived GBM models. 

Metabolism Informs Intertumoral And Intratumoral Heterogeneity (R01 NS087913) 
PI: Ichiro Nakano, MD, PhD
Objectives: The goal of this project is to translate our findings to develop therapeutics targeting the dysregulated metabolic signaling in GBM. 

Elucidate And Modulate Tgf-B Signaling In Nk Cells For Glioma Treatment (CA155521)
PI: Jianhua Yu, PhD
Objectives:

  • Understand an important negative signaling initiated by a cytokine, TGF-?.
  • Either inhibit or enhance this signaling especially in NK cells at different contexts to treat GBM in an animal models.
  • Ultimately, apply these studies in patients once they are proven effective and safe.

Recent Clinical Research Accomplishments That Have Shaped Current Standard of Care in CNS Malignancies

Ohio State investigators use the information from clinical studies to guide them to the most cutting edge standard of care therapies in patients who suffer from CNS malignancies. Large randomized trials provide the highest levels of data analysis, and this data analysis allows our investigators to make appropriate improvements in the care they provide to our patients.

A Phase II Study of Observation in Favorable Low-Grade Glioma and Phase III Study of Radiation with or without PCV Chemotherapy in Unfavorable Low-Grade Glioma. (RTOG 9802) The RTOG 9802 study determined that radiation therapy plus chemotherapy improved progression-free survival in patients with low-grade gliomas compared to treatment with radiation therapy alone.

A Phase I/II Study of an Oral Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitor (EGFR-TKI), ZD 1839 (IRESSA) [NCS# 715055] with Radiation Therapy in Glioblastoma Multiforme. (RTOG 0211) The RTOG 0211 study demonstrated safety but not efficacy of gefitinib therapy when combined with radiation therapy (RT) for newly diagnosed glioblastoma (GBM) patients. The analysis of epidermal growth factor receptor (EGFR) expression did not identify a patient subset that benefited from RT with concurrent and adjuvant gefitinib.

Phase III Double-Blind, Placebo-Controlled Trial of Conventional Concurrent Chemoradiation and Adjuvant Temozolomide Plus Bevacizumab versus Conventional Concurrent Chemoradiation and Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma. (RTOG 0825) The RTOG 0825 study demonstrated no benefit in overall survival with early administration of bevacizumab in newly diagnosed glioblastoma (GBM) patients. Progression-free survival was prolonged for the patients receiving first-line bevacizumab but did not reach the pre-defined improvement target.

Use of false pedicles to construct a load-bearing pelvic and spine structure that supports and protects the spine after complex cancer surgeries. Ehud Mendel, MD FACS, and a multidisciplinary team at the OSUCCC – James created false pedicles and a neo-pelvis for lumbopelvic reconstruction following en bloc resection of iliosacral chondrosarcoma with lumbar spine. Published in the Journal of Neurosurgery: Spine.

Implications of bevacizumab discontinuation in adults with recurrent glioblastoma. Bevacizumab discontinuation unrelated to disease progression does not appear to cause rebound recurrence or worsen PFS in patients who benefit from bevacizumab. Additionally, Bev-D patients had an improved response to salvage therapy, findings which provide a strong basis for a prospective study. Published in Neuro-Oncology.

Adult pilocytic astrocytomas: clinical features and molecular analysis. This was the largest single institution series of adult PA. A significant proportion of adult PAs follow an aggressive clinical course. The results support a period of observation following biopsy or surgical resection. B-K fusion in adult PA does not influence outcome, and BRAF V600E mutation appears to be a very rare event. Further study of tumor biology and optimal treatment is needed, given a more aggressive clinical behavior. Published in Neuro-Oncology.

Tumor derived vasculogenesis in von Hippel-Lindau disease. This study demonstrate that isolated vascular structures and blood vessels within VHL-associated hemangioblastomas are a result of tumor-derivedvasculogenesis. Further, similar to hemangioblastomas, we demonstrate that other VHL-associated lesions possess vascular tissue of tumor origin and that tumor-derived endothelial cells emerge within implanted VHL deficient UMRC6 RCC murine xenografts. These findings further establish the embryologic, developmentally arrested, hemangioblast as the tumor cell of origin for VHL-associated hemangioblastomas and indicate that it is also the progenitor cell for other VHL-associated tumors. Published in Nature.

Proteostasis modulators prolong missense VHL protein activity and halt tumor progression. This study found a quantitative reduction of missense mutant VHL protein (pVHL) in tumors associated with physiologic mRNA expression. Although mutant pVHL is unstable and degraded contemporarily with translation, it retains its E3 ligase function, including hypoxia-inducible factor degradation. The premature pVHL degradation is due to misfolding and imbalance of chaperonin binding. Histone deacetylase inhibitors (HDACIs) can modulate this pathway by inhibiting the HDAC-Hsp90 chaperone axis, stabilizing pVHL, and restoring activity comparable to wild-type protein, both in vitro and in animal models. Furthermore, HDACI-mediated stabilization of missense pVHL significantly attenuates the growth of 786-O rodent tumor model. These findings provide direct biological insight into VHL-associated tumors and elucidate a treatment paradigm for VHL. Published in Cell Reports.

Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas. Magnetic resonance imaging of a coinfused Gd-DTPA surrogate tracer provided direct insight into the properties of CED in a clinical application. While clinically relevant Vds can be achieved by convective delivery, specific tissue properties can affect distribution volume and pattern, including Gd-DTPA concentration, preferential flow patterns, and infusion rate. Understanding of these properties of CED can enhance its clinical application. Published in Journal of Nuerosurgery: Pediatrics.

Trends in central nervous system tumor incidence relative to other common cancers in adults, adolescents and children in the United States, 2000 to 2010. Surveillance of IR trends is an important way to measure the changing public health and economic burden of cancer. In the current study, there were significant decreases noted in the incidence of adult cancer, whereas adolescent and childhood cancer IR were either stable or increasing. Published in Cancer.

Intraoperative neurophysiologic monitoring and neurologic outcomes in patients with epidural spine tumors. These cases are often long with significant blood loss, and stability of multiple IOM modalities provides reassurance that spinal cord function remains intact. Signal changes should result in scrutiny of blood pressure, surgical technique and anesthesia. Preserved IOM signals are suggestive of preserved neurologic outcome. Published in Clinical Neurology and Neurosurgery.

Methylation markers of malignant potential in meningiomas. A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas. Published in Journal of Nuerosurgery.

Translational Research Accomplishments

Low-dose bortezomib might improve effectiveness of oncolytic virus therapy. A study led by OSUCCC – James researchers suggests that combining low doses of the drug bortezomib with an oncolytic virus might significantly improve oncolytic virus therapy with little added toxicity. The findings support testing this combination therapy in a clinical trial. Published in Clinical Cancer Research.

Novel signaling pathway drives growth of glioblastoma subtype. This study showed that the mesenchymal subtype of glioblastoma is the most aggressive subtype; that genes involved in glycolysis and gluconeogenesis, particularly ALDH1A3, were significantly up-regulated in mesenchymal glioma stem cells and drive tumor growth; and that inhibiting ALDH1A3-mediated pathways might provide a promising therapeutic approach for glioblastomas with a mesenchymal signature. Published in the Proceedings of the National Academy of Sciences.

Cytomegalovirus Might Speed Brain Cancer Growth. This study by researchers at the OSUCCC – James and at Dana Farber Cancer Institute suggests that cytomegalovirus (CMV) might significantly accelerate the development and progression of glioblastoma. The findings suggest that CMV speeds tumor development following the silencing of the p53 and Nf1 tumor suppressor genes in the neural stem cells of the brain. The study used a mouse model and a mouse CMV, and suggests that anti-viral therapy might benefit glioblastoma patients. Published in Cancer Research.

Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells. This study revealed that the mechanism by which piperlongumine preferentially kills HGG cells involves PRDX4 inactivation, thereby inducing ER stress. Therefore, piperlongumine treatment could be considered as a novel therapeutic option for HGG treatment. Published in Neuro-Oncology.

Role of CCN1 in macrophage mediated OV clearance. This study revealed that CCN1 plays a novel role in pathogen clearance; increasing macrophage infiltration and activation resulting in increased virus clearance in tumors. Published in Molecular Therapy.

SapC-DOPS-induced lysosomal cell death synergizes with TMZ in glioblastoma. This study suggests that SapC-DOPS induces lysosomal cell death in GBM cells, providing a new approach for treating tumors resistant to traditional apoptosis-inducing agents. Published in Oncotarget.

Aurora-A inhibition offers a novel therapy effective against intracranial glioblastoma. This study offers preclinical proof-of-concept for alisertib as a new therapeutic for glioma treatment. Published in Cancer Research.

Team

Arnab Chakravarti, MD

Vinay Puduvalli, MBBS

Robert Cavaliere, MD

Herbert Newton, MD

Russell Lonser, MD

Fen Xia, MD, PhD

Delian Guo, PhD

Nicholas Denko, PhD

Erica Bell, PhD

Kamalakannan Palanichamy, PhD

Naduparambil Jacob, PhD

Ehud Mendel, MD

Michael Knopp, PhD

Timothy Cripe, MD, PhD

Peter Houghton, MD

Jonathan Finlay, MD

Balveen Kaur, PhD

Ichiro Nakano, PhD

Norman Lehman, MD, PhD

Jose Otero, PhD

Robert Baiocchi, MD, PhD

Bradley Elder, MD

Jeff Leonard, MD

Lance Governale, MD

Daniel Boue, MD, PhD

Christopher Pierson, MD, PhD

Nick Zumberge, MD

Jerome Rusin, MD

Robert Johnson, PhD

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