Researchers from the Lineberger Comprehensive Cancer Center of the University of North Carolina (UNC) have shown that a unique combination of two drugs that serve as targeted inhibitors, supplied in a nanoparticle formulation, prolong the survival of mice with medulloblastoma.
“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, Ph.D., 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.” (Image Credit: UNC Lineberger Comprehensive Cancer Center).
The researchers believe this success in the laboratory could be translated into a less toxic treatment for medulloblastoma, the most frequently occurring malignant pediatric brain tumor. Advances such as this are important because existing treatments, while effective for a number of patients, frequently result in potentially incapacitating brain injury.
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.
Timothy R. Gershon, MD, PhD, Professor and Vice-Chair for Research, Department Of Neurology, School of Medicine, UNC
Timothy R. Gershon is the 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 we 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.
Timothy R. Gershon, MD, PhD, Professor and Vice-Chair for Research, Department Of Neurology, School of Medicine, UNC
The researchers’ findings were reported in the journal Science Advances on January 26, 2022.
Medulloblastoma is an aggressive brain tumor that can spread to other areas of the brain as well as the spinal cord. According to the Central Brain Tumor Registry of the U.S. Statistical Report, between 250 and 500 children are diagnosed with medulloblastoma annually in the United States mostly before the age of 10.
Generally, the survival rate for children with medulloblastoma that has not spread is close to 80%, and the survival rate declines to around 60% if the cancer has spread. For patients whose tumor relapses — or returns — after treatment, there is no effective proven therapy.
The existing standard of care for medulloblastoma includes surgery, chemotherapy and radiation. This therapeutic technique, though mostly effective, can create disabling side effects. Therefore, the researchers were keen to create a drug to complement radiation so that clinicians could reduce the dose of radiation and cause less brain damage.
The 20% of patients who experienced cancer relapse were of particular interest to the scientists as this new dual nanoparticle drug could offer them the most benefit.
The scientists concentrated on the drug palbociclib, which interrupts the proliferation cycle of cancer cells and has been successful in breast cancer. Since palbociclib’s ability to reach into the brain is narrow, the scientists looked to nanoparticle carriers to help boost medulloblastoma drug exposure and decrease off-target toxicity. The technique they employed to formulate the nanoparticle has proven operational and works for other drugs.
By examining gene expression patterns of medulloblastoma cells that were able to form in mice treated with palbociclib, the researchers detected a resistance mechanism that could be targeted by the mTOR inhibitor sapanisertib.
The researchers then demonstrated that the combination of sapanisertib and palbocicbib, delivered in nanoparticles, was more effective than either drug in isolation, as well as being more effective than mixtures of other drugs with palbociclib. This data reveals that targeting the mTOR pathway, which impacts blood flow to tumors and cell growth, makes palbociclib significantly more effective. This finding could be applicable to palbociclib in other cancers.
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. 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.
Marina Sokolsky-Papkov, PhD, Co-Corresponding Author and Associate Professor and Director, Translational Nanoformulation Research Core Facility, Eshelman School of Pharmacy, UNC
Gershon observed that if drug approval and manufacturing plans progress rapidly, the team aims to open a clinical trial for patients with recurrent medulloblastoma in partnership with several institutions, augmenting the chance of gathering sufficient patients and facilitating patients to be treated closer to their homes.
Authors and disclosures
Besides Gershon and Sokolsky-Papkov, the study’s other authors at UNC include Chaemin Lim, Ph.D., Taylor Dismuke, MS, Daniel Malawsky, Jacob D. Ramsey, Ph.D., Duhyeong Hwang, Ph.D., Virginia L. Godfrey, DVM, Ph.D., and Alexander V. Kabanov, Ph.D., DrSci.
Kabanov is an inventor on U.S. Patent No. 9,402,908 and is a co-founder of DelAQUA Pharmaceuticals Inc., having the aim to commercialize POx-based drug formulations. Sokolsky-Papkov has a potential interest in DelAQUA as the cofounder’s spouse. The authors state that they have no other competing interests.
This work received support from the NCI Alliance for Nanotechnology in Cancer grant (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence), the National Institute of Neurological Disorders and Stroke grants (R01NS088219, R01NS102627, and R01NS106227), and the St. Baldrick’s Foundation.
Journal Reference:
Lim, C., et al. (2022) Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq–guided combination with sapanisertib. Science Advances. doi.org/10.1126/sciadv.abl5838.
Source: https://unclineberger.org