Repurposing Quinolines for Pediatric Glioma Therapy
Abstract
Childhood brain tumors are the second most common type of pediatric cancer, with overall survival and treatment related long-term side effects far worse compared to other children with solid tumors and haematological malignancies. The prognosis of brain tumors in children has improved over the past decades; however, one-third of these patients cannot be cured. For high-grade gliomas such as diffuse intrinsic pontine gliomas (DIPG), a rare but aggressive brain tumor in children, the prognosis is in fact even worse. Despite intensive multimodality treatment (surgery, chemo, and radiotherapy), refractory disease and relapse are frequent events. Thus, there is a clear need for improved therapy. Through a repurposing drug screen aiming at recycling old drugs for DIPG therapy, we identified a subset of anti-malaria drugs to have significant DIPG-killing properties. Among them, the Food and Drug Administration-approved compound mefloquine had high efficacy and potency in killing DIPG. Mefloquine was developed by the Walter Reed Army Institute of Research (WRAIR), the largest biomedical research facility by the Department of Defense, to prevent and treat malaria and it remains to be the drug of choice for U.S military deployed overseas and travelers such as the Peace Corps. In their search for novel antimalarial drugs with lower toxicity, researchers at WRAIR have amassed a large collection of mefloquine-like compounds. In this proposal, by teaming with investigators at WRAIR, we will screen their library collection of antimalarial drugs and will evaluate for the first time their potential use for the treatment of DIPG. We will test the potency of these drugs against DIPG cells obtained from patient-tumor specimens and will select the best analog and test it in animal models. If successful, this proposal could provide a novel and improved therapeutic strategy for our young patients with malignant brain cancer leading to an increase in their overall survival and improved quality of life. Since mefloquine is currently being used to treat malaria, it can have a very fast translation to the clinic, while just being a minor addition to the current treatment protocol.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010711
Entities
People
- Bakhos A Tannous
Organizations
- Massachusetts General Hospital
- United States Army