Dr. Mahapatra grant to fund medulloblastoma research 

A new grant will help cancer researchers explore how to lessen toxicity in drugs that are used to fight brain cancer in children.

The Child Health Research Institute announced the new National Cancer Institute research grant awarded to a team led by Sidharth Mahapatra, MD, PhD, associate professor, UNMC Departments of Pediatrics and Biochemistry and Molecular Biology, and critical care physician with Children’s Nebraska.

Awarded as part of the NCI Small Grants Program for Cancer Research, the two-year R03 grant will advance Dr. Mahapatra’s research on Group 3 medulloblastoma (G3MB), the most lethal form of medulloblastoma. 

Dr. Mahapatra said G3MBs are the most aggressive form of medulloblastoma, with survival rates of less than 50% after five years.

“The challenge with current treatment strategies lies in their overall toxicity to growing children,” said Dr. Mahapatra, chair of the Nebraska Children’s Brain Tumor Collaborative and co-chair of the Brain Tumor Working Group at the Fred & Pamela Buffett Cancer Center. “Chemotherapy drugs often have to be given in lower doses to minimize side effects in children, which can lead to cancer returning even more aggressively.”

This new funding will allow Dr. Mahapatra and his team to explore treating G3MB with a novel strategy that targets B7-H3 signaling.

B7-H3 is part of a family of B7 proteins that are expressed at levels that normally regulate the immune system, Dr. Mahapatra said. However, in G3MB, these molecules are expressed at much higher levels and allow tumors to hide from the immune system and grow unchecked, he said.

Dr. Mahapatra’s previous research showed that blocking B7-H3 slows down the growth and spread of G3MB cancer cells in lab experiments.

Dr. Mahapatra acknowledges that aggressive cancers in adults already are being treated with therapies targeting B7-H3. However, these treatments, like antibody-based drugs or CAR T-cell therapy, are expensive, can precipitate serious side effects or have difficulty crossing into the brain. Small-molecule inhibitors of B7-H3 may provide several tangible advantages.

“First, their small size and solubility allow ready penetration into the brain. Second, their manufacturing cost is low, and storage conditions are less stringent than antibody- or CAR-based therapies,” Dr. Mahapatra said. “A library of inhibitors can be generated and efficiently screened to identify the best therapeutic compounds based on safety profiles, tissue and tumor penetration, half-life in the body and oral bioavailability.”

The goal of this research is to prove that targeting B7-H3 is an effective and safe way to treat G3MB. If successful, the team hopes to combine these new lead compounds with existing treatments to create therapies that remain toxic to cancer cells but are easier on young patients.

“The ultimate goal is to develop a therapeutic approach that mitigates current toxicities while maintaining a high index of anti-cancer effect,” Dr. Mahapatra said. “This could lead to better survival rates and improved quality of life for children and their families who are suffering from this devastating disease.”

Dr. Mahapatra is collaborating with Paul Trippier, PhD, associate professor at the UNMC College of Pharmacy. Dr. Trippier’s research focuses on small-molecule drug discovery for cancer and neurodegenerative diseases. His lab employs synthetic, medicinal chemistry, chemical biology and molecular pharmacology techniques to design, optimize and employ biologically active compounds for probing human disease pathways and to be lead compounds for novel drug discovery.

“His team was instrumental in identifying the first small-molecule drug that targets B7-H3, which will be a key part of this project,” Dr. Mahapatra said.

Joann Sweasy, PhD, director of the Fred & Pamela Buffett Cancer Center and the Eppley Institute for Research in Cancer and Allied Diseases, said, “Dr. Mahapatra’s work in testing a novel therapeutic target for Group 3 medulloblastoma has the potential to transform how we treat this aggressive cancer, especially in children, bringing us closer to safer and more effective therapies.”

“We are proud to support and be part of such critical research at the Fred & Pamela Buffett Cancer Center,” Dr. Sweasy said.