De-escalation of Radiotherapy for Medulloblastoma by a Novel DNA Damage Checkpoint Inhibitor

Background
Medulloblastoma is the most common malignant pediatric brain tumor. Radiotherapy is effective for a large number of medulloblastoma patients, but it often has devastating life-long side effects that severely limit the quality of life of these patients. Thus, safer therapies are urgently needed. 

Project Goal
We propose to test a novel approach that should strongly reduce the unwanted side effects of radiation using a drug that makes the tumors more sensitive to radiotherapy in a process called radiosensitization. This drug, named M443, has recently been designed and characterized by our group, in collaboration with other researchers at The Feinstein Institute for Medical Research. We previously showed that M443 can reduce the radiation dose needed to kill medulloblastoma cells by about half. Importantly, M443 does not make normal brain cells more sensitive to radiation. However, like most drugs, M443 does not effectively cross the blood-brain barrier, a defense mechanism that protects the brain from toxic insults. To overcome this challenge, we will use a peptide that can open up the intercellular junctions of the blood-brain barrier. The action of this peptide is short-lived, to leave just enough time for M443 to reach the tumor, without causing additional damage to the normal brain. In summary, we expect the preclinical studies that we propose here will accomplish a number of critical steps that promise to lead to a new, effective and safer approach to treat patients with medulloblastoma.

Project Update - June 2020
Over the past year, we have implemented and optimized a genetic model of the most aggressive form of this disease. We are now examining whether minocycline, an anti-inflammatory drug, can sensitize medulloblastoma tumors to radiation. This should allow us to treat children with lower doses of radiation, thereby protecting their brains. Minocycline already is in clinical use as a neuroprotective drug, and we expect that this would further diminish the side effects caused by radiation. In addition, our recent results showed that minocycline also strongly diminishes the spread of medulloblastoma cells into the surrounding normal brain, and we, therefore, expect to see that minocycline also will prevent or diminish medulloblastoma metastasis.

Project Update - March 2021
Effective treatment of brain tumors is strongly limited by the presence of the blood-brain barrier, a feature of the brain vasculature that protects the brain against soluble insults, but also prevents access of most drugs to these tumors. In collaboration with Dr. Robert Mitchell (University of Louisville, KY), we have identified a blood-brain barrier permeable drug that makes glioblastoma tumors more sensitive to temozolomide chemotherapy. Current efforts are geared toward translating these findings into clinical benefit.