Glioblastoma multiforme (GBM) is a disease of the entire brain. Even complete surgical resection of the tumor-bearing hemisphere inevitably leads to recurrence and has been abandoned. Nonetheless, the majority of clinical trials employing small molecule drugs have focused their measurements of efficacy (both clinical outcome and biomarkers) on the bulk tumor mass that can be surgically removed. This is done in spite of mounting evidence that suggests the inevitable relapse and lethality of GBM is due to a failure to effectively target invasive glioma cells. Brain tumor cells overexpress protective active efflux transport systems, including p-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). The blood-brain barrier (BBB) in the tumor core is "leaky", allowing systemic drug delivery, but glioma cells infiltrate normal brain structures centimeters away from the margin of surgical resection where the BBB is intact and has functional efflux transport systems. Molecularly- targeted anti-tumor agents such as tyrosine kinase inhibitors (TKIs, e.g., imatinib, erlotinib, dasatinib) have their efficacy limited by sequential barriers to delivery to the actual target, including barriers to macroscopic distribution (active efflux at the BBB) and barriers to microscopic delivery (active efflux from invasive glioma cell). Therefore, drug delivery strategies that (1) improve the delivery of selected "molecularly-targeted" chemotherapeutic agents through the BBB, and (2) improve the intracellular drug accumulation in invasive glioma cells, will significantly enhance the efficacy of molecularly-targeted therapy. Our central hypothesis is that invasive glioma cells can be targeted through specific inhibition of active efflux at the level of both the BBB and the invasive tumor cell leading to improved efficacy of molecularly-targeted tyrosine kinase inhibitors. We propose three specific aims to test this hypothesis.
Aim 1 will characterize strategies to improve TKI delivery and efficacy in both human and mouse primary glioma cell lines.
Aim 2 will determine the influence of active efflux, and optimize strategies to overcome efflux, on TKI efficacy in a novel spontaneous mouse model of glioma that grows invasively.
Aim 3 will determine the influence of inhibiting active efflux transport using a novel prodrug targeting Pgp and BCRP on the efficacy of TKIs in a primary human glioma xenograft model that grows invasively relative to traditional xenografts. Completion of these aims will indicate if active efflux transport at the BBB, the invasive glioma cell barrier, or both is an important mechanism that can influence the efficacy of molecularly-targeted therapy by limiting drug delivery to the invasive glioma cell. If successful, this information should be readily translatable to clinical trials and lead to eventual improvement in the treatment of gliomas, and other tumors of the central nervous system.

Public Health Relevance

Currently, there are no effective treatments for malignant brain tumors. This represents a significant unmet medical need, and if active drug efflux limits drug delivery to the brain leading to therapeutic failure, then improved delivery of an effective agent is possible through inhibiting drug efflux. Improving drug delivery could lead to improved patient outcomes, including longer progression free survival and possible cure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138437-03
Application #
8215833
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Alley, Michael C
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$306,972
Indirect Cost
$76,751
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Vaidhyanathan, Shruthi; Mittapalli, Rajendar K; Sarkaria, Jann N et al. (2014) Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab Dispos 42:1292-300
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Mittapalli, Rajendar K; Vaidhyanathan, Shruthi; Sane, Ramola et al. (2012) Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther 342:33-40

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