Nanoparticle-formulated drug combination is effective in
medulloblastoma, a pediatric brain tumor
Date:
January 26, 2022
Source:
UNC Lineberger Comprehensive Cancer Center
Summary:
Researchers have demonstrated that a novel combination of two
drugs that act as targeted inhibitors, delivered in a nanoparticle
formulation, extend the survival of mice with medulloblastoma. The
research team believes this laboratory success could be translated
into a less toxic treatment for medulloblastoma, the most common
malignant pediatric brain tumor.
FULL STORY ==========================================================================
UNC Lineberger Comprehensive Cancer Center researchers have demonstrated
that a novel combination of two drugs that act as targeted inhibitors, delivered in a nanoparticle formulation, extend the survival of mice
with medulloblastoma. The research team believes this laboratory success
could be translated into a less toxic treatment for medulloblastoma, the
most common malignant pediatric brain tumor. Advances such as this are
crucial because current treatments, while effective for many patients,
often result in potentially disabling 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," 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 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." The researchers'
finding appeared January 26, 2022, inScience Advances.
Medulloblastoma is an aggressive brain tumor that can spread to other
parts 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 each year in the U.S.,
often before the age of 10. Overall, the survival rate for children with medulloblastoma that has not spread is close to 80%, and the survival
rate drops to about 60% if the cancer has spread. For patients whose
tumor recurs -- or returns -- after treatment, there is no effective established therapy.
The current standard of care for medulloblastoma includes surgery,
radiation and chemotherapy. This therapeutic approach, though
often effective, can produce disabling side effects. Therefore, the investigators wanted to develop a drug to complement radiation so
that clinicians could lower the dose of radiation and cause less brain
injury. Of special interest to the researchers were the 20% of patients
whose experience cancer recurrence; this is the group of patients where
the new dual nanoparticle drug could provide the greatest benefit.
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, as well as being more effective than combinations of
other drugs with palbociclib.
These data show that targeting the mTOR pathway, which affects cell growth
and blood flow to tumors, makes palbociclib markedly more effective. This finding may be relevant 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,"
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." Gershon noted that
if drug approval and production plans proceed quickly, the investigators
look forward to opening a clinical trial for patients with recurrent medulloblastoma in collaboration with multiple institutions, optimizing
the chance of gathering enough patients and allowing patients to be
treated near their homes.
In addition to Gershon and Sokolsky-Papkov, the paper's other authors
at UNC include Chaemin Lim, PhD, Taylor Dismuke, MS, Daniel Malawsky,
Jacob D. Ramsey, PhD, Duhyeong Hwang, PhD, Virginia L. Godfrey, DVM,
PhD, and Alexander V.
Kabanov, PhD, DrSci.
Kabanov is an inventor on U.S. Patent No. 9,402,908 and is a cofounder of DelAQUA Pharmaceuticals Inc., having intent of commercial development of
POx- based drug formulations. Sokolsky-Papkov has a potential interest
in DelAQUA as a spouse of the cofounder. The authors declare that they
have no other competing interests.
This work was supported by the NCI Alliance for Nanotechnology in
Cancer grant (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence), National Institute of Neurological Disorders and Stroke
grants (R01NS088219, R01NS102627, and R01NS106227), and the St. Baldrick's Foundation.
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========================================================================== Journal Reference:
1. Chaemin Lim, Taylor Dismuke, Daniel Malawsky, Jacob D. Ramsey,
Duhyeong
Hwang, Virginia L. Godfrey, Alexander V. Kabanov, Timothy
R. Gershon, Marina Sokolsky-Papkov. Enhancing CDK4/6 inhibitor
therapy for medulloblastoma using nanoparticle delivery and
scRNA-seq-guided combination with sapanisertib. Science Advances,
2022; 8 (4) DOI: 10.1126/sciadv.abl5838 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/01/220126144237.htm
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