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DNA Damage Response (DDR) Consortium

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.

What is DNA Damage Response (DDR)?

Doctors traditionally use chemotherapy, radiation, and surgery to treat brain tumors. Unfortunately, these often aren’t fully capable of killing all the cancerous cells in a tumor. While these treatments damage the cancer cells’ DNA, tumors can sometimes repair their DNA and grow back stronger than ever.

This process of repairing broken DNA is called “DNA Damage Response (DDR).”

This video explains more:

Targeting the DDR networks in brain tumors with an emerging class of promising drugs – which have already proved effective in other difficult-to-treat cancer types – could transform the treatment landscape for many types of malignant brain tumor, both in children and adult patients.

NBTS’s DNA Damage Response Consortium has the ability to cultivate this budding area of drug development.

About the Consortium

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 drugs and treatments discovered and advanced by this consortium have the potential to revolutionize the treatment landscape for patients with brain tumors.

Consortium Partners

Project Lead: 
Ranjit Bindra, MD, PhD

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.

Manmeet Ahluwalia, MD, MBA, FASCO: Clinical Advisor

In his role as Clinical Advisor, Dr. Ahluwalia will partner with various members of the DDR-C to support the consortium’s efforts to rapidly translate laboratory findings into an early-phase clinical trials platform that matches the right treatments with the right patients and learns quickly from each patient.

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