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Last Updated: 10/10/18

Brain Tumor SPORE

University of California, Los Angeles

Principal Investigator
Linda M. Liau, MD, PhD, MBA, FAANS

Principal Investigator Contact Information

Linda M. Liau, MD, PhD, MBA, FAANS
University of California, Los Angeles
Department of Neurosurgery
300 Stein Plaza, Ste. 564
Los Angeles, California 90095-6901
Tel: (310) 267-9449
Fax: (310) 825-9385
Email: lliau@mednet.ucla.edu

Overall Goals and Research Strategies

The objectives of the UCLA SPORE in Brain Cancer are to contribute significantly to progress in the diagnosis, prognosis, and treatment of brain cancer. These goals will be accomplished through multiple and diverse research projects involving mechanistic pre-clinical work and innovative clinical studies, with a particular focus on developing novel strategies to overcome the problem of treatment resistance. The broad, long-term objectives and aims of our brain cancer SPORE are as follows: 1) to investigate mechanisms of immune evasion following active immunotherapy, and develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment; 2) to elucidate the alterations in metabolism associated with targeted therapy resistance, and exploit these metabolic vulnerabilities to induce intrinsic apoptosis of tumor cells; 3) to explore the concept of radiation-induced phenotype conversion of non-tumorigenic cells to glioblastoma-initiating cells as a mechanism for radiation resistance, and test new therapeutics to block such glioma stem cell conversion; and 4) to investigate the pathways of resistance to IDH inhibitors, and utilize novel epigenetic pathways to sensitize IDH-mutant gliomas to treatment. In order to achieve these translational research goals of our program, we propose four main projects involving: 1) active immunotherapy combined with immune checkpoint modulation for glioblastoma; 2) targeting metabolic vulnerabilities in glioblastoma cells; 3) inhibition of radiation-induced phenotype conversion to glioma-initiating stem cells; and 4) novel epigenetic treatment of IDH mutant gliomas. These translational research projects will be supported by shared resource cores in administration, biospecimen/pathology, neuroimaging, and biostatistics/bioinformatics/data management. Our program will also be responsive to SPORE themes by incorporating Developmental Research and Career Enhancement Programs in order to foster new approaches for assessing and treating brain cancer. Our diverse array of novel projects and state-of-the-art cores will likely make a significant impact on brain cancer patient care. Each project has been developed jointly by teams of basic and clinical researchers working together in a trans-disciplinary manner to address the most vexing problem in brain cancer – the development of treatment resistance.

To achieve the broad, long-term objectives and goals of our program, the Overall Specific Aims of the UCLA SPORE in Brain Cancer are:

Aim 1: Conduct innovative, high-impact research projects that represent a balance and diversity of translational approaches to the problem of brain cancer treatment resistance.

Aim 2: Create an organizational infrastructure designed to specifically support the translational research objectives of the SPORE.

Aim 3: Develop new brain cancer research areas and career enhancement initiatives to advance translational research.

Project 1: Active immunotherapy combined with checkpoint modulation for glioblastoma

Co-Leader: Robert M. Prins, PhD
Co-Leader: Linda M. Liau, MD, PhD, MBA

Immunotherapy is an appealing treatment strategy for glioblastoma (GBM) because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells in the brain. Pre-clinical studies and clinical trials of dendritic cell (DC) vaccination for GBM have shown some promising results, but also some treatment failures. The broad overall goals of this research project are to investigate mechanisms of immune evasion following active immunotherapy, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment. Our new preliminary data strongly suggests that active immunotherapy with DC vaccination may create a pro-inflammatory tumor microenvironment that induces the immigration of immunosuppressive antigen presenting cells (iAPC), which express high levels of PD-L1 and IL-10. We show that these cells are phenotypically similar to the iAPC that dominantly influence the T-cell response to chronic viral infection, and may act to counteract effective T-cell responses induced by DC vaccination via a mechanism involving PD-1/PD-L1. Furthermore, inhibition of iAPC using an anti-PD-1 mAb (Nivolumab, BMS) or a CNS penetrant inhibitor of CSF-1R (PLX-3397, Plexxikon), in conjunction with tumor lysate-pusled DC vaccination (DC-Vax-L), resulted in significantly prolonged survival in tumor-bearing animals with well-established intracranial (i.c.) gliomas. We therefore postulate that clinically relevant anti-tumor immunity to GBM must have two cellular components: 1) significant infiltration of tumor-specific tumor-infiltrating lymphocytes (TIL); and 2) blockade iAPC function within the tumor microenvironment. As such, our hypothesis is that the local cellular interactions between iAPC and T lymphocytes within the brain tumor microenvironment is a critical factor influencing the efficacy of immunotherapies in GBM patients. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor. The proposed studies span the continuum of translational research in brain tumor immunotherapy, and will likely provided informative new insights for the development of new, rational immune-based strategies for brain tumor patients. To test our hypotheses, we have devised a novel set of mechanistic studies in orthotopic pre-clinical murine glioma models, and then we will validate these immunological principles in humans using patient samples obtained from a Phase II clinical trial of DCVax-L +/- PD-1 mAb (Nivolumab, BMS). The Specific Aims of this Project are:

Aim 1: To understand the mechanisms by which iAPC limit glioma-specific anti-tumor immune responses induced by active immunotherapy

Aim 2: To evaluate the efficacy of combining tumor lysate-pulsed DC vaccination (to induce TILs into the tumor) with immune checkpoint inhibition (to block iAPC function) in pre-clinical models in vivo, and explore the use of novel PET tracers as an imaging biomarker of response.

Aim 3: To develop predictive immunological and imaging biomarkers of response in recurrent glioblastoma patients enrolled in a Phase II clinical trial of DCVax-L +/- Nivolumab.

Project 2: Targeting metabolic vulnerabilities in glioblastoma

Co-Leader: David A. Nathanson, Ph.D.
Co-Leader: Steven J. Bensinger, V.M.D., Ph.D.
Co-Leader: Timothy F. Cloughesy, M.D.

Metabolic reprogramming is a key feature of glioblastoma (GBM) to accommodate the heightened energetic, nutrient, and redox requirements to support tumor growth and survival. The most prominent characteristic of this metabolic reprogramming is a shift to high glycolytic flux. Recent evidence suggests that oncogenic signaling regulates glycolytic flux in GBM. Accordingly, inhibition of oncogenic signaling or downstream signal transduction pathways with targeted therapies can induce rapid and specific alterations in glycolysis, resulting in reduced tumor energetic and biosynthetic capacity. These observations have led us to hypothesize that an induced "perturbed" metabolic state, resulting from targeted therapy, could be therapeutically exploited to achieve increased tumor control. However, the therapeutic potential of targeting oncogene-regulated glycolysis in GBM remains enigmatic. We present compelling preliminary data demonstrating that acute inhibition of epidermal growth factor receptor (EGFR) – the most frequently altered oncogene in GBM – can rapidly and potently attenuate glucose uptake and, consequently, glycolytic flux in GBM. As a result of this "altered" metabolic state, GBM models show synergistic lethality to pharmacological p53 activation. We also demonstrate that 18F-flurodeoxyglucose (FDG) and positron emission tomography (PET) can be used as a rapid (within hours), non-invasive biomarker that may predict sensitivity to this new combination approach. In this proposal, we expand on these exciting preliminary findings. The studies proposed in this application present a new combination strategy through specific manipulation of metabolism and apoptotic pathways in malignant glioma and have the long-term potential to shift current approaches in glioma therapy. In this SPORE Project, we propose three integrated translational aims to begin testing whether this novel therapeutic strategy could be effective in the treatment of GBM. The Specific Aims of this Project are:

Aim 1: To determine if a novel p53 activator (Idasanutlin) in combination with EGFR inhibition is effective in preclinical models and evaluate whether 18F-FDG PET is predictive of therapeutic response.

Aim 2: To determine the molecular mechanism underlying p53-dependent synergy with attenuating EGFR-regulated glycolysis.

Aim 3: To conduct a Phase I/II clinical trial of a p53 activator, Idasanutlin (provided by Roche®), in combination with pulsatile Erlotinib and determine whether 18F-FDG PET is predictive of therapeutic response.

Project 3: Inhibition of radiation-induced phenotype conversion in glioblastoma

Co-Leader: Frank Pajonk, MD, PhD
Co-Leader: Phioanh Leia Nghiemphu, MD

Radiation therapy (RT) is currently still one of the most effective treatment modalities against glioblastoma (GBM). However, while RT cures patients from many other cancers, all GBM eventually recur and are ultimately fatal. This data is in sharp contrast to the moderate radiosensitivity of GBM cells in vitro and in vivo, and the relatively high total radiation doses given to GBM patients clinically, thus indicating that RT failure in GBM is not easily explained by the intrinsic radioresistance of GBM cells. Recent experimental data support the view that GBM are organized hierarchically with a small number of radiation-resistant GBM-initiating cells (GICs) capable of re-growing a tumor and giving rise to all lineages of differentiated cells found in GBM, while their progeny lack these features. According to the cancer stem cell hypothesis, all tumor-initiating cells have to be eliminated to achieve cure. A competing model of GBM is based on the "clonal evolution" model and assumes that all cells in a tumor can stochastically acquire a cancer stem cell phenotype. This model is supported by recent studies demonstrating acquisition of stem cell traits by non-tumorigenic GBM cells under hypoxia, at low pH, upon nitric oxide exposure, and our recent report of radiation-induced generation of induced tumor initiating cells. Since each clinical radiation fraction of typically 2 Gy kills only a portion of the total cellular tumor mass, our data suggest that elimination of GICs alone will be insufficient for GBM cure unless non-tumorigenic GBM cells are eliminated in parallel, and phenotype conversion is prevented. Using an imaging system for cell populations enriched for tumor-initiating cells, we have screened chemical libraries of over 80,000 compounds and identified classes of compounds, including dopamine receptor antagonists, that interfere with radiation-induced phenotype conversion, eliminate non-stem GBM cells, and prolong survival in a mouse model of GBM. Results from the proposed studies could have a wider impact on cancer, as these principles may apply not only to GBM, but to many other solid tumors as well. Based on our exciting preliminary data, the Specific Aims of this Project are:

Aim 1: To study spontaneous and radiation-induced phenotype conversion in glioblastoma under different micro-environmental conditions and determine if this process generates tumorigenic GICs in vitro and in vivo.

Aim 2: To prevent radiation-induced phenotype conversion of non-tumorigenic cells into GICs using dopamine receptor antagonists (DRA).

Aim 3: To test whether inhibitors of phenotype conversion affect GICs clinically and prolong survival in recurrent GBM patients.

Project 4: Novel epigenetic treatment of IDH mutant gliomas

Co-Leader: Harley I. Kornblum, MD, PhD
Co-Leader: Albert Lai, MD, PhD

Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in the majority of low-grade gliomas, secondary glioblastomas (GBM) and other cancer types. Although their survival is relatively prolonged relative to patients with wild-type IDH, patients with IDH mutant gliomas still almost invariably succumb to their disease. Mutant IDH causes the aberrant production of the oncometabolite D-2-hydroxyglutarate (2HG). How 2HG contributes to glioma formation is not well-understood, but it is postulated that 2HG interferes with a number of a-ketoglutarate dependent enzymes, including those involved in DNA demethylation. A number of lines of evidence indicate that inactivation of the demethylator Tet methylcytosine dioxygenase (TET2) could result in the DNA hypermethylation phenotype displayed by IDH mutant gliomas. Treatment with selective inhibitors of mutant IDH have shown promise in acute myelogenous leukemia (AML), but results of pre-clinical studies in glioma have been mixed. Our preliminary data indicate that the transcription factor OLIG2 may be responsible for downregulating TET2 mRNA which, in combination with 2HG, potentially renders TET2 activity virtually non-existent in IDH1-mutant gliomas. As such, inhibition of mutant IDH alone would be insufficient to recoup TET2 function. It is our fundamental hypothesis that IDH mutant gliomas are dependent on repression of TET2 expression and function, and that a combined approach of inhibition of the enzymatic function of mutant IDH along with the suppression of OLIG2 will have a beneficial effect on the treatment of IDH mutant gliomas. By the end of the project period, we will have verified whether our therapeutic strategy is a viable option for patients with IDH mutant glioma. To test our hypotheses, this Project involves the following Specific Aims:

Aim 1: To determine the functional role of the OLIG2/IDH/TET2 axis in IDH mutant glioma.

Aim 2: To perform pre-clinical studies to determine the efficacy of combining panobinostat (LBH589) and a brain-penetrant inhibitor of mutant IDH (AG-881) as a therapy for IDH mutant gliomas.

Aim 3: To perform clinical trials to determine whether panobinostat suppresses OLIG2 expression, and whether panobinostat in combination with AG-881 (a brain-penetrant pan-IDH mutant inhibitor) has enhanced efficacy compared to AG-881 alone for patients with IDH1/2-mutated recurrent gliomas.

Core A: Administrative Core

Core Leader: Linda M. Liau, MD, PhD, MBA
Co-Leader: Timothy F. Cloughesy, MD
Co-Leader: Robert M. Prins, PhD

The Administrative Core (Admin Core) will be responsible for the oversight and daily functions of the SPORE and provide organizational leadership for the overall successful conduct of the program. It will provide organizational leadership and administrative support for all of the aspects of the SPORE, including coordination and communication between all investigators and committee members. It will provide scientific management, including ongoing management and scientific review of all projects and cores to ensure that the stated scientific goals of the SPORE are met. The Core has ultimate responsibility for the overall financial management of the budget and appropriate filing of budgetary information. It will organize regularly scheduled meetings and seminars, and provide commitment of SPORE investigators to attend the annual NCI Translational Science Meeting and other relevant workshops. The scheduling and organization of an annual UCLA Brain Cancer SPORE Symposium, including participation of the External Advisory Board, will be the responsibility of the Admin Core. This core will oversee the administration of the SPORE Developmental Research and Career Enhancement Programs, while providing oversight of all the established policies for recruitment of women and minorities. It will be the liaison between the SPORE and the NCI-designated Jonsson Comprehensive Cancer Center, other UCLA academic and administrative bodies, NIH/NCI staff, IAB/EAB members, and patient advocacy groups. It will ensure that appropriate regulatory approvals are maintained and will complete necessary documentation with regulatory agencies. The Admin Core will also ensure that data and resources are shared appropriately in order to promote intra- and inter-SPORE collaboration, including maintenance and updating of a UCLA Brain SPORE website. The leadership of the Admin Core of this SPORE is well-integrated in many ways to the higher administration levels of the institution, and has developed a thoughtful plan for oversight, integration, and evaluation of SPORE activities with a strong leadership team and dedicated administrative support. The overall Specific Aims of the Administrative Core are to:

Aim 1: Provide organizational leadership for the overall successful conduct of the SPORE.

Aim 2: Provide administrative support for the daily activities of the SPORE, including coordination and communication between all investigators and committee members.

Aim 3: Provide scientific management of the SPORE program, including mechanisms for ongoing monitoring and scientific review of all projects and cores to ensure that the stated scientific goals of the SPORE are met.

Aim 4: Assume responsibility for financial management of the SPORE, including maintenance of fiscal functions and timely submission of all budgetary filings.

Aim 5: Organize regularly scheduled meetings and seminars, including planning an annual UCLA Brain Cancer Symposium and attending the annual NCI Translational Science Meeting and other relevant NIH/NCI/NINDS workshops.

Aim 6: Oversee administration of the Developmental Research Program and Career Enhancement Program.

Aim 7: Interact with the Internal and External Advisory Boards, patient advocates, NIH staff, cooperative groups, and industry representatives.

Aim 8: Ensure that appropriate human subjects approvals are maintained for all projects and cores, and monitor policies for inclusion of women and minorities.

Aim 9: Ensure that appropriate animal subjects approvals are maintained for all projects and cores.

Aim 10: Ensure that there is a data/resource sharing plan implemented by each of the research projects that promotes inter-SPORE collaboration with other brain SPORE programs, integration with intra-institutional SPORE programs in other organ sites, and other scientific collaborations.

Core 1: Biospecimen and Pathology Core (BiPC)

Co-Director: William H. Yong, MD
Co-Director: Harley I. Kornblum, MD, PhD
Co-Investigator: David A. Nathanson, PhD
Co-Investigator: Harry V. Vinters, MD

The Biospecimen and Pathology Core (BiPC), a biorepository and multi-faceted research resource led by experienced neuropathologists and cell biologists with ongoing active research expertise, will provide critical support for the translational prognostic, diagnostic, and therapeutic studies proposed in the UCLA SPORE in Brain Cancer. Working closely with the Biostatistics, Bioinformatics, and Data Management Core (BBD, Core 3), BiPC will maximize optimal biospecimen collection/storage and efficient disbursement of consented, clinically annotated, and molecularly characterized biospecimens. This Core will support all four SPORE projects with 24/7 tissue procurement, clinical and family history annotation, and molecular characterization of tissues, plus research support in gliomasphere/neurosphere cultures, tissue microarray, and patient-derived orthotopic xenografts (PDOX). The Biospecimen and Pathology Core Co-Directors and Investigators have a long collaboration history with each other and with all the SPORE Project Leaders, as shown in joint publications, grants, and consortia. In addition to an excellent program for the collection, processing, storage, and dissemination of important biospecimens in support of the proposed SPORE research projects, the BiPC agenda goes well beyond these core functions to the innovative development of new scientific approaches for the maximization of rare/sparse specimen collection and the development of new animal models for therapeutic drug discovery. As part of this core, brain cancer cells grown in animals will be specially adapted to have a fluorescent label so that growth or shrinkage of the tumor can be serially followed in vivo when experimental treatments are given to the animals. The BiPC will develop and provide these materials, resources, and information to SPORE investigators and others, both inside and outside of UCLA. We anticipate that this outstanding team approach will flexibly and robustly provide biobanking, neuropathology expertise, cell culture, xenograft, and clinical trial resources critical for the success of the UCLA SPORE in Brain Cancer projects. Core 1 focuses on the following Specific Aims:

Aim 1: To optimally collect, store, and distribute high-quality human brain tumor biospecimens and their detailed clinical and molecular annotations.

Aim 2: To centrally create, molecularly characterize, and provide human biospecimen derivatives and sGluc-GFP reporter patient-derived orthotopic xenograft (PDOX) models to support SPORE projects.

Core 2: Neuro-Imaging Core (NIC)

Co-Director: Benjamin M. Ellingson, PhD
Co-Director: Whitney B. Pope, MD, PhD

The Neuro-Imaging Core (NIC) is fully committed to provide quantitative, advanced MRI and PET imaging support with established reliability and consistency to the SPORE project investigators for their respective projects. Specifically, we will use quantitative μMR and μPET for preclinical imaging and state-of-the-art MR and PET imaging acquisition, advanced post-processing, and novel analysis tools to better understand the underlying metabolic, physiologic, and traditional radiographic changes within the tumor in order to address specific objectives of each SPORE project. Since many of the novel therapies explored within the proposed UCLA SPORE in Brain Cancer may result in radiographic changes that are challenging to differentiate from non-responsive or growing tumor, a secondary goal of this core is also to understand the link between metabolic or physiologic imaging and tumor biology. It is our goal to utilize state-of-the-art non-invasive imaging techniques to reliably delineate treatment response from recurrent tumor. Additionally, the NIC will leverage our extensive clinical MR-PET imaging experience in order to maximize the possibility of immediate translation of novel MR-PET biomarkers in these new therapeutic paradigms. We anticipate that this approach will provide non-invasive insight into the physiological changes that accompany the novel therapies proposed in the respective SPORE projects. Furthermore, the current approach will allow for direct translation of new MR-PET companion biomarkers and techniques to the clinic for evaluation of treatment response in ongoing or new therapeutic clinical trials resulting from the UCLA SPORE in Brain Cancer. The Specific Aims of Core 2 are:

Aim 1: To provide expertise and resources for the acquisition, post-processing, and image analysis of pre-clinical anatomic and physiologic μMR and μPET imaging information for individual SPORE projects.

Aim 2: To provide professional expertise and resources for traditional radiographic response assessment in clinical trials for individual SPORE projects.

Aim 3: To quantify anatomic, physiologic, and metabolic changes in human gliomas as a result of novel therapies using advanced MR-PET imaging.

Core 3: Biostatistics, Bioinformatics & Data Management (BBD)

Co-Director: Gang Li, PhD
Co-Director: Matteo Pellegrini, PhD

The overall goal of the Biostatistics, Bioinformatics and Data Management (BBD) Core is to provide comprehensive support in the areas of biostatistics, bioinformatics, and data management for all research Projects, Developmental Research and Career Enhancement programs, and Cores in the UCLA SPORE in Brain Cancer. The BBD Core is comprised of multiple faculty members from the departments of Biostatistics, Biomathematics, Molecular, Cell & Developmental Biology, and the UCLA Institute of Quantitative & Computational Biosciences, as well as staff statisticians/database managers, bioinformaticians, database and applications development programmers, and web designers. Faculty members include nationally respected biostatisticians and bioinformaticians with broad expertise in general biostatistics, design and analysis of clinical trials, analysis and interpretation of high-dimensional tissue arrays and gene expression data, and next generation sequencing (NSG) and genomic data analysis, which are needed by the SPORE research projects. The BBD Core aims to foster an outstanding environment to conduct translational research in brain cancer by providing the UCLA Brain SPORE investigators with leading edge biostatistics, bioinformatics, and data management support, and develop innovative solutions/methodology required by the SPORE projects. The BBD Core has three Specific Aims:

Aim 1: Biostatistics Support: Provide SPORE investigators broad-based statistical support for the individual SPORE projects. This includes statistical advice on study design, analysis and interpretation of experimental results, preparation of manuscripts, and development and submission of new grant applications. Statistical methodology research is also conducted as needed by the projects.

Aim 2: Bioinformatics Support: Provide infrastructure and bioinformatics leadership to design and carry out projects using high-throughput technologies, such as NGS data analysis of RNA sequencing, CHIPseq, BS-seq, and variant callilng. Up-to-date bioinformatics software and pipelines are provided.

Aim 3: Data Management Support: Develop and maintain an on-line central data repository and provide data management, data sharing, and quality control activities for all SPORE projects and cores.