De-escalation of Radiotherapy for Medulloblastoma by a Novel DNA Damage Checkpoint Inhibitor
Medulloblastoma is the most common malignant pediatric brain tumor. Radiotherapy is very 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.
We therefore 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 very 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.