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Last Updated: 08/15/19

SPORE: Targeted Therapies for Glioma

Brigham and Women’s Hospital

Principal Investigator:
Tracy Batchelor, MD

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Tracy Batchelor, MD
Chair, Department of Neurology
Brigham and Women’s Hospital
Hale Building for Transformative Medicine
60 Fenwood Road
Boston, MA 02115
Phone: 617-732-5355
Email: TBATCHELOR@BWH.HARVARD.EDU

OVERVIEW

The primary objective of the Dana-Farber/Harvard Cancer Center (DF/HCC) brain cancer SPORE is to improve the standard of care for adult and pediatric gliomas through the use of targeted therapies. Towards this end, basic scientists from Harvard Medical School have joined with clinical/translational investigators from Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital. This initiative is supported by central cores for Pathology, Biostatistics and Computational Biology, and Administration and includes career and developmental programs. The research program uses clinical materials and exploits a number of clinical trials to target gliomas on four distinct fronts:

Project 1: Targeted therapies for pediatric low-grade astrocytoma

Project Co-Leaders:
Michael J. Eck, MD, PhD
Daphne A. Haas-Kogan, MD
Karen D. Wright, MD

Project one is designed to develop potent, brain-penetrant, targeted therapies for pediatric Low-grade astrocytomas (PLGA), the most common brain tumor in children. Standard of care therapies have limited efficacy and treatment-related morbidity is significant. Towards this end, mutated, constitutively active forms of the BRAF protein kinase are expressed in ~75% of all PLGAs and are attractive targets for drug development. A minor cohort of PLGAs express V600E BRAF - a point mutation oncoprotein that is a frequent driver of malignant melanoma in adult patients. More commonly, PLGAs express a truncation/fusion oncoprotein known as KIAA1549:BRAF. Small molecule type 1 RAF inhibitors developed for melanoma have poor brain penetrance and are, moreover, ineffective antagonists of KIAA1549:BRAF. Against this backdrop, the project leaders have three specific aims. In Aim 1, we will examine the clinical activity of TAK-580 in progressive, BRAF-mutant PLGAs. Under auspices of this SPORE, we showed that TAK-580 (a clinical stage type 2 RAF inhibitor) has good brain penetrance and targets both forms of the BRAF oncoprotein. A phase 0/I/II trial of TAK-580 in children with BRAF-mutant low-grade gliomas tumors has been initiated. Using clinical materials from the phase I and II components of the trial we will establish the pharmacokinetics and pharmacodynamics of TAK-580 in children relative to adult patients where the drug has been previously evaluated. In the Phase 0 component of this trial, we will directly measure drug penetration into tumors. In Aim 2, we will define the impact of cellular and genetic modifiers on response of PLGAs to TAK-580. An “inconvenient truth” in precision medicine is that target expression does not guarantee responsiveness to a targeted therapeutic. For example, type 1 RAF antagonists are effective inhibitors of V600E BRAF in melanoma but are ineffective on the same oncoprotein in colon cancers. Accordingly, as the TAK-580 clinical trial goes forward, we will conduct a series of in vitro “avatar” trials on primary patient tumor cells grown in a synthetic hydrogel system developed in collaboration with a bioengineers at the Massachusetts Institute of Technology (MIT). This system is similar to “organoid” systems developed for other solid tumors. In Aim 3, we will develop second generation brain-penetrant drugs for BRAF-mutant PLGA with enhanced selectivity for KIAA1549:BRAF. TAK-580 targets both forms of the BRAF oncoprotein, but wild-type BRAF is also inhibited by the drug. Thus, TAK-580 is a “signal transduction inhibitor” but not a true targeted therapeutic. Although signal transduction inhibitors can be highly efficacious cancer medicines (e.g., imatinib or trastuzumab), a drug that is truly mutant-specific would be preferable for growing children. By far the most common form of a BRAF oncoprotein in PLGA is a truncation/fusion protein known as KIAA1549:BRAF. In this aim, we take a mechanism-based approach to development of a drug that selectively targets KIAA1549:BRAF.

PROJECT 2: Targeting IDH-mutant gliomas

Project Co-Leaders:
Dan P. Cahill, MD, PhD
William G. Kaelin, MD

Discovery of a recurrent hotspot IDH1 mutation in the vast majority of low-grade gliomas and secondary glioblastomas has revolutionized our understanding of the molecular pathogenesis of these malignancies. The canonical glioma-associated IDH1 mutation encodes a mutant isocitrate dehydrogenase enzyme, IDH1 R132H, that gains the neomorphic ability to convert 2-oxoglutarate (2-OG) to the ‘oncometabolite’ R-2-hydroxyglutarate (2-HG). Consequently, 2-HG accumulates to millimolar levels in IDH1-mutant gliomas, representing a 100- to 1000-fold increase relative to normal brain tissue. The structural similarity between 2-HG and 2-OG enables 2-HG to competitively modulate the activity of many 2-OG-dependent dioxygenases, including the JmjC family histone demethylases, the TET family DNA hydroxylases, and the hypoxia-responsive prolyl hydroxylase EglN1. Studies from our group and others demonstrate fundamental roles for epigenetic rewiring and HIF1alpha suppression in the oncogenic program induced by IDH1 mutations in glioma. Although our understanding of the function of the IDH1 R132H oncoprotein has expanded tremendously, successful exploitation of the inherent difference in 2-HG content between normal and malignant brain tissue to improve clinical outcomes has not yet been realized. Our proposal seeks to address this impediment with two specific aims. In Aim 1, we will use 2-HG as a biomarker of IDH mutational status and optimize methodology to quantify this metabolite in the brain using non-invasive magnetic resonance spectroscopy (MRS) imaging. We hypothesize that MRS-generated 3D maps of 2-HG concentration could be used as a complement to traditional T2/FLAIR imaging to enable more precise delineation of tumor boundaries and yield improvements in the efficiency of surgical resection, focal radiation, and the quantification of therapeutic responses in glioma patients. Furthermore, 2-HG 3D MRS imaging represents an ideal approach to assess pharmacodynamic responses in patients enrolled in ongoing clinical trials of IDH targeting therapeutics. In Aim 2, we will develop novel therapeutic strategies to preferentially eradicate IDH1-mutant glioma cells by targeting vulnerabilities engendered by high 2-HG accumulation. Pharmacological inhibitors of mutant IDH enzymes have shown remarkable activity in IDH-mutant leukemia but these inhibitors are considerably less active in IDH-mutant gliomas. An alternative approach to directly targeting mutant IDH enzymes employs the strategy of synthetic lethality with the IDH1-R132H oncogene. We have undertaken orthogonal hypothesis-driven and screening-based approaches to identify NAD+ metabolism and de novo pyrimidine synthesis as targetable vulnerabilities in IDH1-mutant glioma cells. We propose to evaluate the safety and efficacy of targeting these metabolic pathways in preclinical models of IDH1-mutant glioma to establish a rationale for clinical studies of these novel therapeutic strategies.

PROJECT 3: Targeting CDK4/6 to modulate immunogenicity in gliomas

Project Co-Leaders:
Jean J. Zhao, PhD
Patrick Y.C. Wen, MD

Glioblastoma (GBM), the most common primary malignant brain tumor of adults, is a significant cause of patient morbidity and mortality for which effective treatments are lacking. The cyclin D1-cyclin dependent kinase 4/6-retinoblastoma (cyclinD1-CDK4/6-Rb) signaling axis is genetically activated in the majority of GBM (~80%) via genomic loss of CDKN2A/B, amplification of CDK4/6 or deletion/mutation of RB1. CDK4/6 has been targeted based on the notion that suppressing the phosphorylation of pRB by CDK4/6 will lead to cell cycle arrest. Beyond suppressing cell cycle progression, we recently observed that CDK4/6 antagonists promote anti-tumor immunity. The molecular mechanisms underlying this are exerted at two levels: (i) a tumor cell autonomous enhancement of the antigen processing and presentation machinery and (ii) a non-tumor cell autonomous, systemic decrease of the Treg/CD8+ ratio. Collectively, these effects promote cytotoxic T cell mediated clearance of tumor cells, which is further enhanced by the addition of immune checkpoint inhibitors. Notably the actions of the combination of CDK4/6 inhibition and checkpoint blockade was much greater than additive in our preclinical models. CDK4/6 inhibitors are FDA-approved for the treatment of estrogen receptor (ER)-positive metastatic breast cancer, where they now present a well-tolerated, first-line therapy that improves progression-free survival. Their efficacy against GBM is unknown. However, early unpublished clinical data suggest that, like most targeted therapies, CDK4/6 inhibitors as single agents may have only modest benefit. Similarly, early data on immune checkpoint blockade as monotherapy have not been promising in recurrent GBM. Building upon our recent findings, we hypothesize that brain penetrant CDK4/6 inhibitors could augment immunotherapy approaches for GBM including PD-1 checkpoint inhibitors for recurrent GBM. This proposal has three specific aims designed to investigate the therapeutic approach of combined CDK4/6 inhibition and immune checkpoint blockade (ICB) in GBM in both preclinical and clinical settings. In Aim 1, we will assess the effects of CDK4/6 inhibition on GBM cell-intrinsic immune response. In Aim 2, we will assess the effects of CDK4/6 inhibition on enhancing immunotherapy in syngeneic models of GBM. In Aim 3, we will evaluate the impact of CDK4/6 inhibitors on immune function and clinical outcome for GBM patients. By using patient-derived GBM tumors and syngeneic mouse models of GBM, we will determine the preclinical efficacy of CDK4/6 inhibitors in combination with immunotherapy against GBM, further solidifying the preclinical rationale to design clinical trials for patients with GBM.

PROJECT 4: Targeting the neuronal microenvironment in gliomas

Project Co-Leaders:
Mario L. Suva, MD, PhD
Michelle Monje-Deisseroth, MD, PhD

High-grade gliomas are a leading cause of brain tumor-related death in young adults, underscoring the urgent need for a deeper understanding of high-grade glioma pathobiology and novel avenues for therapy. We have recently discovered that neuronal activity robustly promotes high-grade glioma growth and that a synaptic molecule, neuroligin-3, is a crucial activity-regulated mechanism for glioma growth. Activity-regulated cleavage and release of neuroligin-3 from synapses, mediated by the protease ADAM10, is required for glioma growth, although it is not yet clear what mediates this striking dependency. Further, we have observed that a subset of xenografted gliomas evolve in vivo to circumvent neuroligin-3 dependency over a period of 6 months in the context of a neuroligin-3 deficient brain microenvironment. In the present proposal we have 3 specific aims. In Aim 1, we seek to leverage single cell genomics together with patient-derived GBM orthotopic xenografts and immunocompetent murine GBM allografts in neuroligin-3 knockout or wild type mice to dissect neuroligin-3 signaling within the intact glioma ecosystem. Using a similar strategy, in Aim 2, we will also uncover the mechanisms by which some xenografted gliomas circumvent neuroligin-3 dependency, findings that will inform not only neuron-glioma interactions but also fundamental mechanisms of glioma progression. Finally, in Aim 3, we will perform preclinical efficacy and safety testing of ADAM10 inhibition to block neuroligin-3 release into the tumor microenvironment in an effort to provide sufficient preclinical evidence to bring this novel therapeutic strategy to a clinical trial for adult high-grade gliomas. This future trial will complement our Pediatric Brain Tumor Consortium-sponsored phase 1 clinical trial of ADAM10 inhibition for pediatric high-grade glioma. Taken together, the proposed experiments will elucidate fundamental mechanisms of glioma growth and progression and advance a promising new therapeutic approach for these lethal brain cancers.

CORE A: Pathology Core

Core Directors:
David N. Louis, MD
Keith L. Ligon, MD, PhD

The overall goal of this SPORE application is to develop more effective targeted molecular for adult and pediatric gliomas. The four proposed projects of the SPORE focus on 1) targeted therapeutics to treat BRAF-mutant pediatric gliomas; 2) development of improved targeted therapies for IDH-mutant gliomas; 3) combining targeted CDK4/6 inhibitors with immunotherapies to treat glioblastoma; and 4) evaluation of Nlgn3 as a novel therapeutic target in gliomas. The Pathology Core will support the goals of these SPORE Projects by providing expert neuropathologic review, specimen banking, genomic analysis and clinical trial support. In addition, the Pathology Core will be a centralized resource for validated patient-derived cell lines and xenografts of gliomas. The Core will also offer innovative CyTOF slide multiplex imaging (MIBI), mass spectrometry imaging of drug distribution within tissue sections, and liquid biopsy of circulating tumor cells (CTC) to determine responses to targeted therapies in clinical trials. By centralizing these activities, the Pathology Core will ensure the reproducibility of data and effective use of finite glioma tissue resources essential to the collaborative translational research of the SPORE program.

CORE B: Biostatistics and Computational Biology Core

Core Director:
Dianne M. Finkelstein, PhD

This Glioma SPORE will require statistical and bioinformatics collaboration on a wide variety of research, ranging from pre-clinical models to human studies. The mission of the Biostatistics and Computational Biology Core of this glioma SPORE is to foster rigor and reproducibility. Towards this end, the core will work with project leaders to insure statistical integrity in the design of their experiments and interpretation of their data. The Biostatistics and Computational Biology Corewill function as a scientific hub to facilitate inter- and intra- SPORE collaborations between all Projects and with the Pathology Core. The core will advise on all issues related to data collection, analysis and interpretation. The core will provide 1) ready and dedicated resources for database and computing requirements, 2) consultation and expertise on the development and implementation of plans for data collection, particularly the coding convention and variable format required for statistical analysis, 3) advice on the data management plan, including form design and database requirements, during development of the SPORE-related clinical trials, 4) expertise and resources for data transfer, merging, sharing and security while maintaining the confidentiality of all patient-related protected health information, 5) statistical expertise for the design, planning and conduct of preclinical experiments, clinical trials and correlative tissue and biomarker studies, 6) analysis of the clinical trials and interim monitoring and analysis, if necessary, including the stopping rules for safety and futility, 7) statistical and bioinformatics expertise for inference and interpretation of research studies, including manuscript preparation.

CORE C: Administration Core

Core Director: 
Tracy T. Batchelor, MD

This Specialized Program of Research Excellence (SPORE) grant is intended to support multi-project, interdisciplinary, and multi-institutional translational research in glioma. The governance structure of this Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE grant provides the foundation for the implementation, execution and ultimate success of all the projects and cores. The Administration Core serves as the “hub” for this governance structure and aims to achieve a number of specific objectives as defined below. We will execute a plan that provides experienced, centralized program leadership and administration. The Glioma SPORE Director and Co-Director are senior administrators, institutional leaders, and researchers who have worked together on the current funding period for this SPORE and on prior DF/HCC initiatives and, consequently, provide consistent, strong, complementary leadership for the grant. The trans-institutional administrative team consists of senior personnel at DF/HCC institutions who have worked together effectively in the current funding period of this grant. We will expand our management to an external, funded component (Project Four) of the SPORE at Stanford University Medical Center and to both adult and pediatric patient populations. We maintain two senior clinical and imaging scientists in the Administration Core to supervise Glioma SPORE-specific clinical trials and Glioma SPORE-specific imaging studies, respectively, and to enable this Glioma SPORE to capitalize on existing DF/HCC P30 Cores to support these types of studies. We have established and utilized an effective internal and external committee structure to provide multidisciplinary expertise, advice, and oversight of the program. Each of the committees consists of collaborative, complementary members who have worked together in the current funding period of this SPORE or on prior projects. A series of regular Glioma SPORE meetings involving both administrative and scientific SPORE personnel will continue to facilitate close collaboration, troubleshooting, and monitoring of the SPORE program. We will continue and expand an effective internal and external communications program, which includes a Glioma SPORE-specific component. An established and extensive DF/HCC communications infrastructure is utilized to promote open, regular, trans-institutional communication regarding SPORE opportunities and activities. We will reinforce an active SPORE program to enhance participation by underrepresented minorities and women.

DEVELOPMENTAL RESEARCH PROGRAM

Director:
Tracy T. Batchelor, MD

The objective of the Glioma SPORE Developmental Research Program (DRP) is to identify innovative pilot research projects in glioma that have translational potential. The DRP utilizes a solicitation and review process to select meritorious pilot projects for funding. The solicitation process capitalizes on an established, extensive Dana-Farber/Harvard Cancer Center (DF/HCC) communications infrastructure to widely disseminate an annual Request for Proposals (RFP). The review process utilizes an experienced panel of DF/HCC glioma scientists. The DRP provides limited-duration funding for innovative projects that have ultimate translational potential and could synergize with existing SPORE projects and cores. DF/HCC institutions match DRP funding from this SPORE to expand the pool of DRP awardees. The DRP applications are judged for their potential as pilot or collaborative studies that will generate feasibility data and for their ultimate potential to emerge as full projects in future years of the SPORE program. The DRP employs a monitoring process to measure progress and outcomes of DRP projects including the possible elevation of successful DRP awards to full projects. The program is closely monitored through clearly established metrics and oversight by the DRP Awards Committee. DRP awardees are required to present biannual progress reports.

CAREER ENHANCEMENT PROGRAM

Director:
Tracy T. Batchelor, MD

The primary objective of the Glioma SPORE Career Enhancement Program (CEP) is to attract talented new investigators to translational glioma research. Potential CEP awardees include junior faculty beginning their careers or established faculty members in other fields who wish to redirect their interests and efforts to glioma research. We will maintain a comprehensive, system-wide process for solicitation of CEP applications and an expert-based review process to select the most meritorious applicants. The CEP program faculty consists of a multidisciplinary cohort of experienced, senior mentors for CEP awardees. The CEP provides limited-duration funding for promising, junior translational investigators who are focused on glioma research. The program will provide support, mentoring and monitoring for CEP awardees. We will maintain a monitoring process to measure progress and outcomes of CEP awardees and the CEP program. We carefully monitor the progress of CEP awardees through clearly enumerated metrics. The overall CEP is assessed on an annual basis by the internal and external advisory boards. The CEP leverages institutional resources to support and enhance the success of the program.