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National Brain Tumor Society’s DNA Damage Response (DDR) Consortium is a collaboration of world-class researchers advancing an emerging and promising, but underdeveloped, area of cancer research: a tumor’s DDR network.
The consortium has the ability to cultivate this budding area of research and propel an entirely new class of treatments forward for both adults and children with multiple different types of malignant brain tumors.
National Brain Tumor Society’s flagship research initiative, the DNA Damage Response (DDR) Consortium, brings together a diverse team of renowned adult and pediatric researchers to rapidly advance a new class of promising potential treatments that can target a brain tumor’s DNA damage response network.
Research indicates that disrupted DDR networks are possibly an ‘Achilles’ heel’ for tumors, leaving them vulnerable to a new group of treatments currently being developed.
Unlike other, more traditional precision medicine strategies, targeting tumor DDR may be applicable to virtually all malignant brain tumor types, both in children and in adult patients.
With drugs designed to attack tumors’ DDR network already transforming the treatment of other cancers, like ovarian and breast cancer, this strategy needs to be quickly and expertly tested for patients with a brain tumor.
To bring forth a concerted effort to advance this strategy, NBTS has formed a consortium of leading experts in both pediatric and adult neuro-oncology research to go “all-in” in pursuit of making the promise of this approach a reality for patients.
The consortium will test different drugs in the laboratory, share data, and then bring the most promising drugs forward to evaluate in clinical trials that match the right drugs with the right patients. The consortium is made up of a diverse team of world-class researchers from across the United States with unparalleled expertise and the experience needed to rapidly develop and advance these drugs into clinical trials.
NBTS strongly believes that experimental drugs and treatments discovered and advanced by this consortium have the potential to revolutionize the treatment landscape for patients with brain tumors.
Project Lead:
Ranjit Bindra, MD, PhD
Description:
Dr. Ranjit Bindra, Harvey and Kate Cushing Professor of Therapeutic Radiology and Scientific Director of the Chênevert Family Brain Tumor Center at Smilow Cancer Hospital and Yale Cancer Center, is the co-principal investigator of the DDR-C. The Bindra lab brings years of experience and expertise in DNA Damage Response and biomarker-driven precision medicine approaches.
Project Lead:
Nathalie Agar, PhD
Project Focus:
Dr. Agar, Founding Director of the Surgical Molecular Imaging Laboratory, Daniel E. Ponton Distinguished Chair in the Department of Neurosurgery at Brigham and Women’s Hospital, and Associate Professor of Neurosurgery, Radiology at Harvard Medical School, will assume the role of the consortium’s co-principal investigator. Dr. Agar’s lab is a pioneer in the development and implementation of integrated biomolecular and drug imaging of tissue specimens through mass spectrometry. Dr. Agar brings critical skills in biomarker discovery, pharmacometabolomics, specimen preparation, and data analysis to the consortium.
Project Lead:
Patrick Wen, MD
Project Focus:
Dr. Wen, Professor of Neurology at Harvard Medical School and Director of the Center for Neuro-Oncology at Dana-Farber, will coordinate the multicenter clinical trials consortium that will evaluate the novel DDR targeting drugs, beginning with already enrolling surgical “window-of-opportunity” study of pembrolizumab, olaparib, and temozolomide in patients with recurrent glioblastoma.
Project Lead:
Jann Sarkaria, MD
Project Focus:
Dr. Sarkaria, radiation oncologist, and co-leader of the Mayo Clinic Comprehensive Cancer Center Neuro-oncology program, and his Translational Neuro-Oncology Laboratory are collaborating closely with the University of Minnesota group, led by Dr. William Elmquist, to study the effects and optimal dosing for treatments that target a core component of the DNA repair system in brain tumors. Dr. Sarkaria and his team are interested in understanding the basis of resistance to chemotherapy and radiation, identifying methods to overcome therapy resistance, and using innovative approaches to develop targeted therapies and combination treatment strategies. They also are developing methods to improve delivery of drugs into brain tumors, and are known for modeling brain tumors for use in laboratory studies
Project Lead:
Erik Sulman, MD, PhD
Project Focus:
Dr. Sulman is an expert in radiation oncology and his lab uses innovative cell line barcoding and glioma stem cell models to assess the potential effectiveness of different DDR-targeting drug combinations. Dr. Sulman and his team are evaluating promising treatments across all the types of aggressive gliomas, including, glioblastoma, astrocytoma, and the notoriously difficult-to-culture oligodendroglioma. His lab is also evaluating the combination of the antidepressant Prozac with standard of care chemotherapy, building from a recent NBTS-funded discovery of possible glioblastoma survival benefits found by Dr. Paul Mischel at Stanford University.
Project Leads:
Anang Shelat, PhD; Chris Tinkle, MD, PhD; Stephen Mack, PhD
Project Focus:
The team from St. Jude has expertise in DDR, chemical biology, developmental neurobiology, and screening and bioinformatics. Together, they will focus on the toughest types of pediatric brain tumors, including diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG), atypical teratoid/rhabdoid tumors (AT/RT), and childhood ependymomas. The pediatric ependymoma work will be funded through the Collaborative Ependymoma Research Network, a program of NBTS. Specifically, the team will test multiple types of DDR-inhibiting drugs like ATR, ATM, and PARP, inhibitors in addition to others in combination, with different DNA damaging agents, like chemotherapy and radiation, in laboratory models.
Project Lead:
William Elmquist, PhD, PharmD
Project Focus:
Dr. Elmquist is a world-renowned leader in examining and modeling mechanisms that the brain’s protective barrier, known as the blood-brain barrier (BBB), uses to limit the delivery and hence, the efficacy of drugs for brain tumors. He will help consortium teams understand if promising drugs are able to cross the BBB to reach and engage their targets at appropriate therapeutic levels with pharmacokinetic/pharmacodynamic (PK/PD) testing.
Project Lead:
John de Groot, MD
Project Focus:
Dr. de Groot is a leader in translational medicine and in developing clinical trials of new brain tumor therapies. As part of the consortium, his lab will also bring new expertise in drug delivery methods. Specifically, Dr. de Groot’s team will compare three different methods of drug delivery: intravenous (IV), convection-enhanced delivery, and IV + low-intensity focused ultrasound.