Browsing by Subject "Active efflux"

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    Improving The Delivery Of Novel Molecularly-Targeted Therapies For The Treatment Of Primary And Metastatic Brain Tumors
    (2019-01) Gampa, Gautham
    Tumors in the brain are challenging to diagnose and are associated with poor survival outcomes. Brain tumors are difficult to treat, in part, due to restricted drug delivery across the blood-brain barrier (BBB). Although the BBB is compromised in some regions of brain tumors, the degree of disruption is not uniform and certain tumor locations have a functionally intact BBB. A critical component of BBB that restricts entry of therapeutics into brain is active efflux. The objective of this work is to examine brain distribution of novel molecularly-targeted therapies, including evaluation of influence of P-gp and Bcrp-mediated efflux at the BBB, assessment of spatial heterogeneity in drug distribution to brain tumors, and comparison of unbound (active) drug exposures with in vitro efficacy. Ispinesib is a KIF11 inhibitor that inhibits both tumor proliferation and invasion in glioblastoma (GBM). We demonstrate that ispinesib has a limited brain delivery due to efflux by P-gp and Bcrp, and ispinesib delivery is heterogeneous to areas within a tumor in a GBM model. Furthermore, predicted unbound-concentrations in brain were less than in vitro cytotoxic concentrations, suggesting that delivery may limit in vivo efficacy. Also, pharmacological inhibition of efflux transport (elacridar co-administration) improves brain delivery of ispinesib, and future studies will evaluate if enhanced delivery will improve efficacy. CCT196969, LY3009120 and MLN2480 are panRAF inhibitors with minimal paradoxical activation of MAPK pathway and may overcome resistance observed with BRAF inhibitor therapy in melanoma. MEK inhibition is used in combination with BRAF inhibitors to delay resistance. E6201 is a potent MEK inhibitor with a unique macrocyclic structure. While brain distribution of panRAF inhibitors is limited by efflux, E6201 has a favorable brain distribution profile and interacts minimally with P-gp and Bcrp. The delivery of E6201 is variable to regions of tumor in an intracranial melanoma model. However, predicted unbound-concentrations in brain achieve levels higher than in vitro cytotoxic concentrations for LY3009120 and E6201, suggesting possible efficacy in melanoma brain metastases. Future studies evaluating in vivo efficacy in preclinical models will reveal the utility of selected compounds in brain tumor treatment, and if improved delivery translates to superior efficacy.
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    Metabolism and CNS Distribution of Selected Histone Deacetylase Inhibitors
    (2024-03) Zhang, Wenqiu
    Brain tumors are the leading cause of cancer-related death in children and efficacious treatment remains a critical unmet need. The blood-brain barrier (BBB) is a major hurdle for effective delivery of treatments for tumors in the central nervous system (CNS). While the paracellular transport of large, hydrophilic molecules is largely limited by tight junctions, efflux transporter systems are a key element of the BBB that can limit the penetration of lipophilic drugs. Histone deacetylase inhibitors (HDACIs) have been widely explored for their application in oncology, including the field of neuro-oncology. Despite their high in vitro potency and CNS-penetration-favorable physicochemical properties, the in vivo efficacy of HDACIs has been poor for CNS tumor treatment. This lack of in vitro-in vivo correlation may be in part attributed to poor CNS distribution. In this thesis project, we investigated the CNS distribution of three potent HDACIs, panobinostat, vorinostat, and quisinostat, following systemic administration. We characterized the systemic pharmacokinetics and CNS distributional kinetics of these compounds in wild-type and transgenic mice lacking p-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp), two major efflux transporters expressed at the BBB. The in vitro stability studies show that all three hydroxamic acid-based HDACIs are enzymatically metabolized in mouse plasma, highlighting the need for careful sample handling to have accurate measurements of in vivo drug concentrations. In vivo experiments in the different mouse genotypes show that the CNS distribution of panobinostat and quisinostat is moderately limited by P-gp, but not Bcrp. Although the CNS penetration of vorinostat was not restricted by P-gp and Bcrp, its small unbound CNS tissue-to-plasma partition coefficients suggest that other efflux transporters could be involved. In addition, our results show that a tolerable dosing regimen of panobinostat would not result in adequate CNS exposure of unbound panobinostat in patients. In summary, our data show that the lack of adequate exposure of the active moieties can be a major reason for the lack of efficacy of these HDACIs in the CNS when systemically delivered. This result indicates that alternative approaches to improve delivery (e.g., convection-enhanced delivery or focused ultrasound) should be considered.