SPORE in Brain (Gliomas)
Brigham and Women’s Hospital University
Principal Investigator(s):
Tracy Batchelor, MD
- Principal Investigator Contact Information
- Overview
- Project 1: Targeted therapeutics for pediatric low-grade glioma
- Project 2: Druggable dependencies in diffuse midline gliomas
- Project 3: Targeting IDH mutant gliomas
- Administrative Core
- Biostatistics Core
- Pathology Core
- Developmental Research Program
- Career Enhancement Program
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
(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, Boston Children’s Hospital, and Massachusetts General Hospital. This initiative is supported by central cores for pathology, biostatistics and computational biology, and administration, and it includes career and developmental programs.
Project 1: Targeted therapeutics for pediatric low-grade glioma
Project Co-Leaders:
Mike Eck, MD, PhD (Basic Co-Lead)
Benjamin Kann, MD (Clinical Co-Lead)
Project one targets pediatric low-grade gliomas (pLGGs), the most common subtype of glioma in children. Nearly 75% of pLGGs are driven by truncation/fusion variants of the BRAF protein kinase. Type 1 RAF inhibitors (developed for the amino acid substitution mutations of BRAF commonly expressed in malignant melanoma) are ineffective on these truncation/fusion variants. With standard of care, only about one third of pLGGs progress to become candidates for RAF inhibitors such as tovorafenib. However, almost all pLGG patients undergo long term follow up with MRIs that are stressful for children and parents alike. We have three specific aims:
Aim 1: Enhanced efficacy and tolerability of targeted inhibition for pLGG.
Aim 2: A genomic “audit” of RAF expression in pLGG.
Aim 3: Non-invasive “child friendly” predictors of children with pLGG most likely to require and respond to RAF antagonists.
Project 2: Druggable dependencies in diffuse midline gliomas
Project Co-Leaders:
Mariella G. Filbin, MD, PhD (Basic Co-Lead)
Daphne A. Haas-Kogan, MD (Clinical Co-Lead)
Project two targets diffuse midline gliomas (DMGs) — the deadliest brain tumor of children. DMGs are unresectable and refractory to conventional therapeutic modalities. Moreover, the prevalent oncogenic drivers (a set of recurrent H3K27M substitutions) are undruggable. Various workarounds and surrogate targets for drug development has thus far shown no clear clinical benefit. Against this backdrop, the project two team has conducted a genome-wide CRISPR screen for DMG-specific metabolic vulnerabilities. The screen reveals that DMGs are critically dependent on the alternative end-joining (alt-EJ) pathway for repair of DNA double-strand breaks (DSBs). Three separate components of the alt EJ pathway are viable targets for drug development and the team have identified brain-penetrant, clinical-stage antagonists for each of these three components. One of the drugs identified by the team is orludodstat — a brain-penetrant inhibitor of de novo pyrimidine biosynthesis that was identified. We have three specific aims:
Aim 1: Brain penetrance and target engagement in phase 0, target validation clinical trial of orludodstat for DMG.
Aim 2: Pre-clinical development of POLQ and ATR kinase antagonists.
Aim 3: A 3-Dimensional (3D) reference map of DMG architecture.
Project 3: Targeting IDH mutant gliomas
Project Co-Leaders:
Samuel McBrayer, PhD (Basic Co-Lead)
Dan P. Cahill, MD, PhD (Basic Co-Lead)
Luis Nicholas Gonzalez Castro, MD, PhD (Clinical Co-Lead)
Patrick Wen, MD (Clinical Co-Lead)
Project three addresses the early-stage (lower-grade) IDH mutant gliomas (IDHM) of young adults. We have demonstrated that the IDHM oncoprotein sensitizes progressive (WHO grade 4) IDHM gliomas to inhibitors of de novo pyrimidine synthesis or NAD+ metabolism — a pair of “synthetic lethal” vulnerabilities created by the IDHM-generated (R)-2HG oncometabolite. Importantly, these vulnerabilities can be exploited by orludodstat, a clinical stage, brain penetrant inhibitor of the de novo pathway for pyrimidine biosynthesis, or with temozolomide and poly (ADPribose) glycohydrolase (PARG) inhibitor combination therapy, respectively. IDH-mutant gliomas eventually progress to high grade disease and become refractory to these treatments. As such, there is an unmet clinical need for new therapies tailored to the unique pathobiology and clinical course of IDH-mutant gliomas. Recently, pharmacological inhibitors of mutant IDH (IDHi) have been tested in several clinical trials for brain tumor therapy.
We have three specific aims:
Aim 1: Define the impact of IDHi acquired resistance on orludodstat activity in IDH-mutant glioma.
Aim 2: Define the impact of IDHi acquired resistance on the activity of PARG inhibitor and TMZ combination therapy in IDH-mutant glioma.
Aim 3: Evaluate orludodstat activity in patients who have progressed on IDHi therapy.
Administrative Core
Core Directors:
Tracy Batchelor, MD
Mario L. Suva, MD, PhD
Dan P. Cahill, 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.
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 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.
An effective internal and external committee structure provides multidisciplinary expertise, advice, and program oversight. These committees consist of collaborative members who have worked together on the current and previous SPORE projects. Regular Glioma SPORE meetings with both administrative and scientific personnel will continue to facilitate collaboration, troubleshooting, and monitoring of the SPORE program.
Biostatistics Core
Core Director:
Wendy B. London, PhD
This Glioma SPORE will require statistical and bioinformatics collaboration on various research, ranging from pre-clinical models to human studies. The Biostatistics 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 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.
Pathology Core
Core Directors:
Keith L. Ligon, MD, PhD
Anat Stemmer-Rachamimov, 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.
Developmental Research Program
Program Director:
Tracy 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 leverages an established, extensive Dana-Farber/Harvard Cancer Center (DF/HCC) communications infrastructure to widely disseminate an annual Request for Proposals (RFP). The review process employs an experienced panel of DF/HCC glioma scientists. The DRP provides limited-duration funding for innovative projects with ultimate translational potential and aims to synergize with existing SPORE projects and cores. DF/HCC institutions match DRP funding from this SPORE to expand the pool of DRP awardees.
DRP applications are judged for their potential as pilot or collaborative studies that will generate feasibility data and their ultimate potential to evolve into 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.
Career Enhancement Program
Program Director:
Tracy 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.