Medulloblastoma (MB) is a highly aggressive brain tumor in childhood that accounts for 20-25% of all pediatric tumors. Post-surgical radiotherapy, in combination with chemotherapy, is used to inhibit the growth of highly chemoresistant tumor cells and cancer stem-like cells (CSCs) and prevent tumor recurrence. Unfortunately, the use of high doses of chemo/radiation leads to neurotoxicity and progressive hearing loss, which affect the quality of life of childhood cancer survivors, highlighting the need for novel therapeutic targets to increase the efficacy of current therapy. The other main challenge in MB treatment is the delivery of drugs to the brain tumor cells through the blood-brain barrier (BBB). Further, brain tumor cells show relatively low uptake of non-targeted nanoparticles (NP) after extravasation into the central nervous system. Therefore, the development of new nanocarriers that cross BBB and preferably target MB is needed urgently.
We design both, new drug therapeutics and innovative drug carriers for safe and effective treatment.
Phosphatidylinositol 3-kinase (PI3K) is a family of intracellular enzymes that transduce signals from outside to inside of the cell. PI3K activation turn on the crucial oncogenic signaling. Because of which, PI3K is a highly desirable target for treating cancer. BRD4 is a member of the bromo and extra C-terminal (BET) family of proteins, which promotes cancer cell growth and proliferation in different cancer types including meduloblastoma. We are developing small molecules dual inhibitors of PI3K and BRD4 signaling. One of the compound named MDP5 showed promising anticancer effects in preclinical studies. We expect MDP5 may not only increase the the efficacy, but also decrease the major side effects arising from the the current MB therapies.
MB treatment is challenging also due to blood brain barrier (BBB) which hinder the reach of enough drugs to the cancer cell. Therefore, we are developing biodegradable polymeric nanoparticles decorate suitable targeting legends to facilitate drug delivery to the brain.