Browsing by Subject "active efflux"

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    Distribution of DNA Damage Response Inhibitors to the Central Nervous System for Brain Tumor Therapy
    (2022-04) Talele, Surabhi
    Brain tumors are associated with a grim prognosis despite the aggressive treatment strategy of surgery, radiation, and chemotherapy. Therefore, there is a need to develop strategies to enhance efficacy of chemo-radiation treatments. DNA damage response (DDR) signaling pathways play a critical role of DNA repair in cancer cells and resistance to radiation and chemotherapy. Inhibition of these pathways can augment tumor kill. Berzosertib, peposertib and AZD1390 are potent small molecule inhibitors of three critical DDR pathways. We evaluated mechanisms limiting central nervous system (CNS) distribution of these molecules and identified their potential for chemo/radiosensitization in brain tumors. CNS distribution of all three molecules is restricted by active efflux mediated by P-gp and/or Bcrp. Moreover, high tissue binding to plasma, brain, and spinal cord, restricts partitioning of unbound drug across the blood-brain barrier (BBB). Additionally, peposertib concentrations in different anatomical regions of the brain were similar, however lower accumulation was observed in the spinal cord. Impact of efflux inhibition using elacridar demonstrated similar increase in peposertib concentrations within each of these regions, indicating that inhibition of efflux activity was functionally similar across these regions. Similarly, no differences were observed in AZD1390 distribution within different anatomical regions of the CNS, and the functional activity of P-gp and Bcrp also remained the same across brain regions. These molecules show heterogeneous tumor distribution in patient-derived xenograft models of brain tumors with drug accumulation maximum within tumor core, slightly lower in adjacent tumor rim, but significantly lower in surrounding normal brain. Berzosertib did not achieve effective chemosensitizing brain and tumor concentrations in vivo. Peposertib, despite its limited CNS delivery, showed potential as a safe yet effective radiosensitizer for brain metastases. Effective radiosensitizing concentrations of AZD1390 were achieved in brain and tumor despite its restricted CNS delivery. Combined, these CNS pharmacokinetic evaluations can guide dosing in pre-clinical efficacy studies and enable future clinical trial design to test these innovative chemo/radiosensitizers with the eventual goal of improving therapy for brain tumors. Integrating knowledge from these studies will aid in determining the potential of DDR inhibitors as effective chemo-radiosensitizing agents in brain tumors.
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    Influence of active efflux transport on the distribution of targeted agents to brain tumors
    (2014-07) Oberoi, Rajneet Kaur
    Glioblastoma multiforme (GBM) is a lethal disease of the whole brain. Despite complete surgical resection of the tumor, recurrence is inevitable and leads to patient death. Several molecularly-targeted agents have shown promising results preclinically, although clinical results have been disappointing. One plausible explanation for clinical failure of drugs is their inability to effectively target the invasive glioma cells that reside in areas away from the tumor core. These regions of the brain have an intact blood brain barrier (BBB), which through a combination of endothelial tight junctions and active efflux transporters restricts brain penetration of several drugs. The objective of this thesis was to investigate the influence of active efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) on the brain distribution of molecularly targeted agents. To enhance our understanding of brain distribution with statistical certainty, we proposed a population-based analysis method to estimate variability around the brain partition coefficient (Kp). We showed that the brain distribution of sunitinib (a tyrosine-kinase inhibitor) is limited by active efflux mediated by P-gp and Bcrp at the BBB. We further demonstrated that brain distribution could be enhanced by administration of a dual P-gp/Bcrp inhibitor. To statistically ascertain the variability associated with Kp in a serial sacrifice design, we developed a pharmacokinetic model to simultaneously describe plasma and brain concentration time profile data. We further evaluated the influence of study design features such as between subject variability (BSV) and sample size at each time point on bias and precision of estimation of Kp. Our results show that bias is unaffected by the assumptions regarding the magnitude of BSV and sample size, however, precision improves with sample size.We further examined the influence of BBB on delivery and efficacy of dual PI3K/mTOR inhibitors, GNE-317 (higher BBB permeability) and GDC-0980 (restricted BBB penetration) using three glioma mouse models, GL261-luc-GFP model, GBM10 and U87. Disruption of the BBB in the tumor core resulted in higher drug concentrations for GDC-0980. However, intact BBB in the areas adjacent to the core restricted the brain concentrations of GDC-0980. Contrary to this, the brain concentrations of GNE-317 were similar in all the three regions of the brain. Furthermore, results from survival studies indicated that although both GNE-317 and GDC-0980 significantly improved survival compared to placebo, the treatment groups were not significantly different from each other. Therefore, it is important to consider that effective treatment of GBM relies not only on effective delivery across the BBB to invasive glioma cells but also on an effective drug.