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Last Updated: 09/10/21

Targeted Therapies for Glioma

Brigham and Women’s Hospital

Principal Investigator(s):

Tracy T. Batchelor, MD
Tracy T. Batchelor, MD

Principal Investigator(s) Contact Information

Tracy T. Batchelor, MD
Chair, Department of Neurology
Brigham and Women’s Hospital
Hale Building for Transformative Medicine
60 Fenwood Road
Boston, MA 02115
(617) 732-5355

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. To this end, basic scientists from Harvard Medical School have joined clinical and 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.

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Project 1: Targeted therapies for pediatric low-grade astrocytoma

Project Co-Leaders:
Michael J. Eck, MD, PhD (Basic Co-Leader)
Daphne A. Haas-Kogan, MD (Clinical Co-Leader)
Karen D. Wright, MD (Clinical Co-Leader)

This project aims to develop potent, brain-penetrant, targeted therapies for pediatric low-grade astrocytomas (hereafter termed “PLGAs). Two oncogenic variants of the BRAF protein kinase serve as drivers for roughly 75% of all PLGAs. The less frequent of these is BRAF:V600E — a variant that is also commonly found in adult melanomas. Far more frequently, PLGAs express a truncation/fusion BRAF oncoprotein known as KIAA1549:BRAF. Despite their efficacy in melanoma, type 1 RAF inhibitors developed for BRAF:V600E are ineffective (and, in fact, counterproductive) on KIAA1549:BRAF. During the prior funding period of this SPORE grant, we identified a brain-penetrant type 2 RAF inhibitor (TAK-580) that targets both forms of the BRAF oncoprotein. Building upon this work, we have three specific aims:

  • Aim 1: Examine the clinical activity of TAK-580 (a brain penetrant type II RAF inhibitor) in progressive BRAF mutant PLGAs.
  • Aim 2: Define the impact of cellular and genetic modifiers of PLGA response to TAK-580.
  • Aim 3: Develop second generation, brain-penetrant drugs for BRAF-mutant PLGA with enhanced selectivity for KIAA1549:BRAF.
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Project 2: Targeting IDH-mutant gliomas

Project Co-Leaders:
Dan P. Cahill, MD, PhD (Clinical Co-Leader)
William G. Kaelin, MD (Basic Co-Leader)

Up to 90% of low-grade gliomas and secondary glioblastomas harbor mutations in the metabolic isocitrate dehydrogenase enzymes encoded by the IDH1/2 genes. These mutations, now recognized as the genetic hallmark of these cancers, result in enzymatic overproduction of the oncometabolite 2-hydroxyglutarate (2-HG), leading to profound reprogramming of the tumor cell epigenome and cellular metabolism. During the current funding period, we have focused on (i) new imaging technologies for IDH-mutant gliomas and (ii) the development of novel therapeutic approaches. 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. We have three specific aims:

  • Aim 1: Test the hypotheses that 2-HG imaging maps can complement traditional T2/FLAIR signal to generate more accurate assessments of tumor burden in IDH-mutant glioma patients.
  • Aim 2: Test the hypothesis that 2HG-mediated NAD+ depletion can be exploited in a synthetic lethal therapeutic protocol that draws upon clinical stage PARP inhibitors.
  • Aim 3: Evaluate pyrimidine synthesis inhibitors as synthetic lethal therapies for IDH-mutant glioma.
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Project 3: Targeting CDK4/6 to modulate immunogenicity in gliomas

Project Co-Leaders:
Jean J. Zhao, PhD (Basic Co-Leader)
Patrick Y.C. Wen, MD (Clinical Co-Leader)

The cyclin D1-cyclin dependent kinase 4/6-retinoblastoma (cyclinD1-CDK4/6-Rb) signaling axis is genetically activated in approximately 80% of glioblastomas (GBM) via genomic loss of CDKN2A/B, amplification of CDK4/6, or deletion/mutation of RB1. CDK4/6 has been targeted by major pharma predicated on the notion that suppressing phosphorylation of RB by CDK4/6 will lead to cell cycle arrest. The broad objective of this project is to capitalize on a recent discovery by Dr. Zhao and her colleagues under the auspices of our DF/HCC breast cancer program. Briefly, Goel et al. show that, beyond its anti-proliferative effects, CDK4/6 antagonists promote anti-tumor immunity. Mechanistically, CDK4/6 inhibition results in (i) a tumor cell-intrinsic enhancement of the antigen processing and presentation machinery, and (ii) a tumor cell-extrinsic, systemic decrease of the Treg/CD8+ ratio. Together, these effects promote cytotoxic T cell-mediated clearance of tumor cells, which can be further enhanced by the addition of immune checkpoint blockade (ICB). Building upon these findings and similar preclinical observations by the Project team in glioma, we propose to test the hypothesis that brain penetrant CDK4/6 inhibitors can unleash anti-tumor immunity and synergize with immunotherapy to achieve a therapeutic breakthrough for GBM, a tumor characterized by its immunosuppressive microenvironment. We have three specific aims:

  • Aim 1: To assess the effects of CDK4/6 inhibition on GBM cell-intrinsic immune response.
  • Aim 2: To assess the effects of CDK4/6 inhibition on enhancing immunotherapy in syngeneic models of GBM.
  • Aim 3: To evaluate the impact of CDK4/6 inhibitors on immune function and clinical outcome for GBM patients.
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Project 4: Targeting the neuronal microenvironment in gliomas

Project Co-Leaders:
Mario L. Suva, MD, PhD (Basic Co-Leader)
Michelle Monje-Deisseroth, MD, PhD (Clinical Co-Leader)

Glioblastoma (GBM) hijacks cellular mechanisms of neural development and plasticity (Suva et al., 2014 Cell; Tirosh et al., Nature 2016; Neftel et al., Cell 2019; Hara et al., Cancer Cell 2021; Venkatesh et al., Cell 2015; Qin et al., Cell 2017). Because the neuronal activity is a key regulator of neural development and plasticity, we have tested the hypothesis that it may similarly influence glioma growth and discovered that neuronal activity robustly regulates the growth of both pediatric and adult high-grade gliomas (HGG) through activity-regulated secretion of neuroligin-3 (NLGN3) and brain-derived neurotrophic factor (BDNF) in the tumor microenvironment (Venkatesh Cell 2015). More recently, we have xenografted multiple different subtypes of patient-derived HGG cells into the brains of Nlgn3+/+ or Nlgn3-/- mice. The xenograft studies document strong dependency of both pediatric and adult HGGs upon microenvironmental NLGN3 (Venkatesh et al., Nature 2017, 2019), findings that raise numerous mechanistic questions and highlight a promising therapeutic opportunity. The broad objectives of this research are to define the molecular mechanisms whereby microenvironmental NLGN3 modulates the formation (Aim 1) and progression (Aim 2) of HGGs. In Aim 3, we explore a therapeutic opportunity embedded within the NLGN3 requirement. Details are as follows:

  • Aim 1: Determine the effects of NLGN3 expression on GBM interactions with its microenvironment.
  • Aim 2: Determine the mechanisms by which GBM cells progress to circumvent NLGN3 dependencies.
  • Aim 3: Test the therapeutic efficacy of ADAM10 inhibition to block NLGN3 release into the tumor microenvironment.
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Pathology Core

Core Directors:
Keith L. Ligon, MD, PhD
Anat Stemmer-Rachmaninov, MD

The goal of the Pathology Core is to collect, profile, and distribute human glioma tissues, patient-derived xenografts, and cell lines for the research projects of this SPORE. In addition, the Core will provide centralized expert neuropathology and genomic analysis and clinical trial support to all projects. As such, the Pathology Core services are essential for the success of the SPORE. In addition to its biorepository and service functions, the Core will strive to improve its services by developing emerging tissue technologies. This Core will facilitate and ensure the safe and effective use of finite, clinically annotated glioma tissue resources. It will aid in the prioritization of resource utilization across collaborative translational research at Dana-Farber/Harvard Cancer Center (DF/HCC) institutions and other SPORE programs.

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Biostatistics and Computational Biology Core

Core Director:
Steven Piantadosi, MD, PhD

This Glioma SPORE will require statistical and bioinformatics collaboration on various research, ranging from pre-clinical models to human studies. The Biostatistics and Computational Biology Core mission of this glioma SPORE is to foster rigor and reproducibility. Towards this end, the core will work with project leaders to ensure statistical integrity in the design of their experiments and interpretation of their data. The Biostatistics and Computational Biology Core will function as a scientific hub to facilitate inter-and intra- SPORE collaborations between all Projects and the Pathology Core. The core will advise on all issues related to data collection, analysis, and interpretation.

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Administration Core

Core Directors:
Tracy T. Batchelor, MD
Mario L. Suva, MD, PhD

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 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 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 program oversight. Each of the committees consists of collaborative, complementary members who have worked together in the current funding period of this SPORE or on previous projects. A series of regular Glioma SPORE meetings involving both administrative and scientific SPORE personnel will continue to facilitate close collaboration, troubleshooting, and monitoring the SPORE program.

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Developmental Research Program

Program Director:
Tracy T. Batchelor, MD

The Glioma SPORE Developmental Research Program (DRP) objective 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 with 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 pilots or collaborative studies that will generate feasibility data and their ultimate potential to emerge as complete projects in future years of the SPORE program. The DRP employs a monitoring process to measure the progress and outcomes of DRP projects, including the possible elevation of successful DRP awards to complete 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.

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Career Enhancement Program

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 the 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.

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