Research Abstracts Online
2008 - March 2009
University of Minnesota Twin Cities
School of Pharmacy
Department of Pharmaceutics
PI: William F. Elmquist
Improving Delivery of Molecularly Targeted Therapy to Glioma Stem Cells
Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme (GBM), a devastating primary brain tumor, is due to a failure to effectively target cancer stem cells. An important question in targeting therapy to brain tumor stem cells (BTSCs) is whether treatment failure is due to inadequate delivery or ineffective drugs. Similar to hematopoietic stem cells, BTSCs may be protected from drug action by active efflux transport systems, including p-glycoprotein (MDR1) and breast cancer resistance protein (BCRP). The efficacy of molecularly targeted anti-tumor agents such as tyrosine kinase inhibitors (TKIs) may be limited by sequential barriers to delivery to their molecular target, including barriers to macroscopic distribution to the brain (active efflux at the blood-brain barrier (BBB)) and barriers to microscopic delivery to the cancer stem cell (active efflux from BTSCs). Therefore, drug delivery strategies that improve the delivery of selected "molecularly targeted” TKIs through the BBB, and improve TKI accumulation in BTSCs will significantly enhance the efficacy of molecularly targeted therapy against GBM.
These researchers hypothesize that TKIs can selectively target BTSCs through specific inhibition of active efflux at both the BBB and the tumor stem cell leading to improved efficacy in treating GBM and are testing their hypothesis. If successful, this information should be readily translatable to clinical trails and lead to eventual improvement in the treatment of gliomas and other tumors of the central nervous system. Currently, there are no effective treatments for malignant brain tumors. This represents a significant unmet medical need, and if active drug efflux is an important mechanism leading to therapeutic failure, then improved delivery of an effective agent is possible and should lead to improved patient outcomes, including longer progression free survival and possible cure.
Sagar Agarwal, Graduate Student
Ying Chen, Graduate Student
Li Li, Graduate Student
Ramola Sane, Graduate Student
Tianli Wang, Graduate Student