Medulloblastoma is a malignant pediatric brain tumor that starts in the cerebellum. It can occur in adults, but is less common. Overall, the survival rate for children with medulloblastoma that has not spread is about 70 to 80%. The survival rate if the medulloblastoma has spread to the spinal cord is about 60%. A new study by researchers at the UNC Lineberger Comprehensive Cancer Center demonstrates that a novel combination of two drugs that act as targeted inhibitors, delivered in a nanoparticle formulation, extend the survival of mice with medulloblastoma.

Their findings are published in the journal Science Advances in a paper titled, “Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq–guided combination with sapanisertib.”

“The therapeutic potential of CDK4/6 inhibitors for brain tumors has been limited by recurrence,” the researchers wrote. “To address recurrence, we tested a nanoparticle formulation of CDK4/6 inhibitor palbociclib (POx-Palbo) in mice genetically-engineered to develop SHH-driven medulloblastoma, alone or in combination with specific agents suggested by our analysis.”

“We showed that palbociclib, an FDA-approved drug for breast cancer, may be effective for medulloblastoma, but as a single agent it is not curative because it does not stay in the brain for long enough, and because tumors can become resistant to it,” said Timothy R. Gershon, MD, PhD, professor and vice-chair for research, UNC School of Medicine department of neurology, and co-corresponding author of the article. “In our mouse studies, we addressed the limited brain penetration by developing a nanoparticle formulation that delivers the therapeutics into the brain more effectively. We then studied why resistance developed over the long-term and ultimately, we found a mechanism of resistance that we could target by adding another drug, sapanisertib.”

The current standard of care for medulloblastoma includes surgery, radiation, and chemotherapy. Although this therapeutic approach is often effective, it can produce disabling side effects.

The researchers were determined to develop a drug to complement radiation so that clinicians could lower the dose of radiation and cause less brain injury.

The researchers focused on the drug palbociclib, which disrupts the proliferation cycle of cancer cells and has been effective in breast cancer. Because palbociclib’s ability to get into the brain is limited, the researchers turned to nanoparticle carriers to help increase medulloblastoma drug exposure and reduce off-target toxicity. The method they used to formulate the nanoparticle has proven effective and works for other drugs.

By analyzing gene expression patterns of medulloblastoma cells that were able to grow in mice treated with palbociclib, the authors identified a resistance mechanism that could be targeted by the mTOR inhibitor sapanisertib. The authors then showed that the combination of palbocicbib and sapanisertib, delivered in nanoparticles, was more effective than either drug alone.

“The nanoparticle formulation incorporating palbociclib plus sapanisertib may also combine well with standard radiation, potentially enabling lower, less toxic doses of radiation without increasing recurrence risk,” said Marina Sokolsky-Papkov, PhD, co-corresponding author and associate professor and director of the Translational Nanoformulation Research Core Facility at the UNC Eshelman School of Pharmacy. “Our next steps are getting the nanoparticle approved for use in people and also finding ways to ramp up production for potential use in humans.”

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