Publications by authors named "William F Elmquist"

90 Publications

The influence of the blood-brain barrier in the treatment of brain tumours.

J Intern Med 2022 Jan 17. Epub 2022 Jan 17.

Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA.

Brain tumours have a poor prognosis and lack effective treatments. The blood-brain barrier (BBB) represents a major hurdle to drug delivery to brain tumours. In some locations in the tumour, the BBB may be disrupted to form the blood-brain tumour barrier (BBTB). This leaky BBTB enables diagnosis of brain tumours by contrast enhanced magnetic resonance imaging; however, this disruption is heterogeneous throughout the tumour. Thus, relying on the disrupted BBTB for achieving effective drug concentrations in brain tumours has met with little clinical success. Because of this, it would be beneficial to design drugs and drug delivery strategies to overcome the 'normal' BBB to effectively treat the brain tumours. In this review, we discuss the role of BBB/BBTB in brain tumour diagnosis and treatment highlighting the heterogeneity of the BBTB. We also discuss various strategies to improve drug delivery across the BBB/BBTB to treat both primary and metastatic brain tumours. Recognizing that the BBB represents a critical determinant of drug efficacy in central nervous system tumours will allow a more rapid translation from basic science to clinical application. A more complete understanding of the factors, such as BBB-limited drug delivery, that have hindered progress in treating both primary and metastatic brain tumours, is necessary to develop more effective therapies.
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http://dx.doi.org/10.1111/joim.13440DOI Listing
January 2022

Factors Influencing Luciferase-Based Bioluminescent Imaging in Preclinical Models of Brain Tumor.

Drug Metab Dispos 2021 Dec 9. Epub 2021 Dec 9.

Pharmaceutics, University of Minnesota, United States

Bioluminescent imaging (BLI) is a powerful tool in biomedical research to measure gene expression and tumor growth. The current study examined factors that influence the BLI signal, specifically focusing on the tissue distribution of two luciferase substrates, D-luciferin and CycLuc1. D-luciferin, a natural substrate of firefly luciferase, has been reported to have limited brain distribution, possibly due to the efflux transporter, breast cancer resistance protein (Bcrp), at the blood-brain barrier. CycLuc1, a synthetic analog of D-luciferin, has a greater BLI signal at lower doses than D-luciferin, especially in the brain. Our results indicate that limited brain distribution of D-luciferin and CycLuc1 is predominantly dictated by their low intrinsic permeability across the cell membrane, where the efflux transporter, Bcrp, plays relatively minor role. Both genetic ablation and pharmacological inhibition of Bcrp decreased the systemic clearance of both luciferase substrates, significantly increasing exposure in the blood and, hence, in organs and tissues. These data also indicate that the biodistribution of luciferase substrates can be differentially influenced in luciferase-bearing tissues, leading to a "tissue-dependent" BLI signal. The results of this study point to the need to consider multiple mechanisms that influence the distribution of luciferase substrates. Bioluminescence is used to monitor many biological processes, including tumor growth. This study examined the pharmacokinetics, brain distribution, and the role of active efflux transporters on the luciferase substrates, D-luciferin and CycLuc1. CycLuc1 has a more sustained systemic circulation time (longer half-life), that can provide an advantage for the superior imaging outcome of CycLuc1 over D-luciferin. The disparity in imaging intensities between brain and peripheral sites is due to low intrinsic permeability of these luciferase substrates across the blood-brain barrier.
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http://dx.doi.org/10.1124/dmd.121.000597DOI Listing
December 2021

Central Nervous System Distribution of an Opioid Agonist Combination with Synergistic Activity.

J Pharmacol Exp Ther 2022 Jan 18;380(1):34-46. Epub 2021 Oct 18.

Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota

Novel combinations of specific opioid agonists like loperamide and oxymorphindole targeting the - and -opioid receptors, respectively, have shown increased potency with minimized opioid-associated risks. However, whether their interaction is pharmacokinetic or pharmacodynamic in nature has not been determined. This study quantitatively determined whether these drugs have a pharmacokinetic interaction that alters systemic disposition or central nervous system (CNS) distribution. We performed intravenous and oral in vivo pharmacokinetic assessments of both drugs after discrete dosing and administration in combination to determine whether the combination had any effect on systemic pharmacokinetic parameters or CNS exposure. Drugs were administered at 5 or 10 mg/kg i.v. or 30 mg/kg orally to institute for cancer research (ICR) mice and 5 mg/kg i.v. to Friend leukemia virus strain B mice of the following genotypes: wild-type, breast cancer resistance protein ( ) (Bcrp knockout), [P-glycoprotein (P-gp) knockout], and (triple knockout). In the combination, clearance of oxymorphindole (OMI) was reduced by approximately half, and the plasma area under the concentration-time curve (AUC) increased. Consequently, brain and spinal cord AUCs for OMI in the combination also increased proportionately. Both loperamide and OMI are P-gp substrates, but administration of the two drugs in combination does not alter efflux transport at the CNS barriers. Because OMI alone shows appreciable brain penetration but little therapeutic efficacy on its own, and because loperamide's CNS distribution is unchanged in the combination, the mechanism of action for the increased potency of the combination is most likely pharmacodynamic and most likely occurs at receptors in the peripheral nervous system. This combination has favorable characteristics for future development. SIGNIFICANCE STATEMENT: Opioids have yet to be replaced as the most effective treatments for moderate-to-severe pain and chronic pain, but their side effects are dangerous. Combinations of opioids with peripheral activity, such as loperamide and oxymorphindole, would be valuable in that they are effective at much lower doses and have reduced risks for dangerous side effects because the -opioid receptor agonist is largely excluded from the CNS.
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http://dx.doi.org/10.1124/jpet.121.000821DOI Listing
January 2022

Brain Distribution of Berzosertib: An Ataxia Telangiectasia and Rad3-Related Protein Inhibitor for the Treatment of Glioblastoma.

J Pharmacol Exp Ther 2021 12 23;379(3):343-357. Epub 2021 Sep 23.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.T., W.Z., M.K., A.S.M., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.M.B., S.D., S.K.G., J.N.S.); and Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut (R.S.B.)

The effective treatment of brain tumors is a considerable challenge in part because of the presence of the blood-brain barrier (BBB) that limits drug delivery. Glioblastoma multiforme (GBM) is an aggressive and infiltrative primary brain tumor with an extremely poor prognosis after standard-of-care therapy with surgery, radiotherapy (RT), and chemotherapy. DNA damage response (DDR) pathways play a critical role in DNA repair in cancer cells, and inhibition of these pathways can potentially augment RT and chemotherapy tumor cell toxicity. The ataxia telangiectasia and Rad3-related protein (ATR) kinase is a key regulator of the DDR network and is potently and selectively inhibited by the ATR inhibitor berzosertib. Although in vitro studies demonstrate a synergistic effect of berzosertib in combination with temozolomide, in vivo efficacy studies have yet to recapitulate this observation using intracranial tumor models. In the current study, we demonstrate that delivery of berzosertib to the brain is restricted by efflux at the BBB. Berzosertib has a high binding affinity to brain tissue compared with plasma, thereby leading to low free drug concentrations in the brain. Berzosertib distribution is heterogenous within the tumor, wherein concentrations are substantially lower in normal brain and invasive tumor rim (wherein the BBB is intact) when compared with those in the tumor core (wherein the BBB is leaky). These results demonstrate that high tissue binding and limited and heterogenous brain distribution of berzosertib may be important factors that influence the efficacy of berzosertib therapy in GBM. SIGNIFICANCE STATEMENT: This study examined the brain delivery and efficacy of berzosertib in patient-derived xenograft models of glioblastoma multiforme (GBM). Berzosertib is actively effluxed at the blood-brain barrier and is highly bound to brain tissue, leading to low free drug concentrations in the brain. Berzosertib is heterogeneously distributed into different regions of the brain and tumor and, in this study, was not efficacious in vivo when combined with temozolomide. These factors inform the future clinical utility of berzosertib for GBM.
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http://dx.doi.org/10.1124/jpet.121.000845DOI Listing
December 2021

Changes in the vasculature of human brain tumors: Implications for treatment.

Neuro Oncol 2021 12;23(12):1995-1997

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

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http://dx.doi.org/10.1093/neuonc/noab220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643459PMC
December 2021

Preclinical Risk Evaluation of Normal Tissue Injury With Novel Radiosensitizers.

Int J Radiat Oncol Biol Phys 2021 12 14;111(5):e54-e62. Epub 2021 Aug 14.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Genotoxic damage induced by radiation triggers a highly coordinated DNA damage response, and molecular inhibitors of key nodes within this complex response network can profoundly enhance the antitumor efficacy of radiation. This is especially true for drugs targeting the catalytic subunit of DNA-dependent protein kinase, which is a core component of the nonhomologous end-joining DNA repair pathway, and ataxia telangiectasia mutated, which coordinates cell cycle arrest, apoptosis, and DNA repair functionalities after radiation exposure. Unlike the more modest in vitro radiosensitizing effects seen with classic sensitizing agents such as cisplatin, 5-fluorouracil, or taxanes, DNA-dependent protein kinase or ataxia telangiectasia mutated inhibitors provide much more robust sensitizing effects in vitro, as might be anticipated from targeting these key DNA repair modulators. However, patients with homozygous inactivating mutations of ataxia telangiectasia mutated or mice with homozygous defects in DNA-dependent protein kinase (severe combined immunodeficiency) have profoundly enhanced acute normal tissue radiation reactions. Therefore, there is significant potential that the combination of small molecule inhibitors of these kinases with radiation could cause similar dose-limiting acute normal tissue toxicities. Similarly, although less understood, inhibition of these DNA repair response pathways could markedly increase the risk of late radiation toxicities. Because these potent radiosensitizers could be highly useful to improve local control of otherwise radiation-resistant tumors, understanding the potential for elevated risks of radiation injury is essential for optimizing therapeutic ratio and developing safe and informative clinical trials. In this review, we will discuss 2 straightforward models to assess the potential for enhanced mucosal toxicity in the oral cavity and small intestine established in our laboratories. We also will discuss similar strategies for evaluating potential drug-radiation interactions with regard to increased risks of debilitating late effects.
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http://dx.doi.org/10.1016/j.ijrobp.2021.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764622PMC
December 2021

Methods for intratumoral microdialysis probe targeting and validation in murine brain tumor models.

J Neurosci Methods 2021 11 12;363:109321. Epub 2021 Aug 12.

Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Microdialysis is a well validated sampling technique that can be used for pharmacokinetic studies of oncological drugs targeting the central nervous system. This technique has also been applied to evaluate tumor metabolism and identify pharmacodynamic biomarkers of drug activity. Despite the potential utility of microdialysis for therapeutic discovery, variability in tumor size and location hamper routine use of microdialysis as a preclinical tool. Quantitative validation of microdialysis membrane location relative to radiographically evident tumor regions could facilitate rigorous preclinical studies. However, a widely accessible standardized workflow for preclinical catheter placement and validation is needed.

New Method: We provide methods for a workflow to yield tailored placement of microdialysis probes within a murine intracranial tumor and illustrate in an IDH1-mutant patient-derived xenograft (PDX) model. This detailed workflow uses a freely available on-line tool built within 3D-slicer freeware to target microdialysis probe placement within the tumor core and validate probe placement fully within the tumor.

Results: We illustrate use of this workflow to validate microdialysis probe location relative to implanted IDH1-mutant PDXs, using the microdialysis probes to quantify levels of extracellular onco-metabolite D-2 hydroxyglutarate.

Comparison With Existing Methods: Previous methods have used 3D slicer to reliably measure tumor volumes. Prior microdialysis studies have targeted expected tumor locations without validation.

Conclusions: The new method offers a streamlined and freely available workflow in 3D slicer to optimize and validate microdialysis probe placement within a murine brain tumor.
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http://dx.doi.org/10.1016/j.jneumeth.2021.109321DOI Listing
November 2021

Lisdexamfetamine Pharmacokinetic Comparison Between Patients Who Underwent Roux-en-Y Gastric Bypass and Nonsurgical Controls.

Obes Surg 2021 10 21;31(10):4289-4294. Epub 2021 Jul 21.

Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Introduction/purpose: The objective of this research was to characterize the impact of Roux-en-Y gastric bypass (RYGB) on the pharmacokinetic properties of the pro-drug lisdexamfetamine and its active metabolite, d-amphetamine.

Materials And Methods: A case-control design was used where patients who had undergone RYGB 9-24 months prior were matched on sex, age, and body mass index (BMI) to nonsurgical controls who had no history of weight loss surgery. Each participant received a single 50 mg dose of lisdexamfetamine, and plasma samples were collected over a 24-h period following dosing. Noncompartmental analyses were used to compare pharmacokinetic measures between groups.

Results: There were no significant differences between the RYGB (n = 10) and NSC groups (n = 10) on sex (70% female), age (40.9 ± 9.6 vs. 41.3 ± 8.9 years), BMI (30.3 ± 5.2 vs. 31 ± 5.9 kg/m), or ethnicity (100% vs. 80% White). The pharmacokinetic parameters between the RYGB and NCS groups were found to be equivalent for lisdexamfetamine and d-amphetamine, including maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC).

Conclusion: These data suggest that there is no need to routinely adjust lisdexamfetamine dosing following RYGB. However, given the potential for inter-individual differences, patients who undergo RYGB should be clinically monitored and individualized dosing strategies should be considered for concerns surrounding efficacy or toxicity.
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http://dx.doi.org/10.1007/s11695-020-04969-4DOI Listing
October 2021

Preclinical modeling in GBM PDX xenografts to guide clinical development of lisavanbulin - a novel tumor checkpoint controller targeting microtubules.

Neuro Oncol 2021 Jul 7. Epub 2021 Jul 7.

Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Background: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts.

Methods: Mice bearing intracranial tumors received lisavanbulin +/- RT +/- TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis.

Results: Lisavanbulin monotherapy showed significant benefit (p<0.01) in 9 of 14 PDXs tested (median survival extension 9-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours post-dose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, p=0.0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, p=0.06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, p=0.0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, p=0.04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (p=0.01).

Conclusions: Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.
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http://dx.doi.org/10.1093/neuonc/noab162DOI Listing
July 2021

Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma.

Neuro Oncol 2021 12;23(12):2042-2053

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important.

Methods: PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH, and phosphoproteomics.

Results: Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment.

Conclusions: Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.
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http://dx.doi.org/10.1093/neuonc/noab133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643472PMC
December 2021

Efficacy of Tesevatinib in -Amplified Patient-Derived Xenograft Glioblastoma Models May Be Limited by Tissue Binding and Compensatory Signaling.

Mol Cancer Ther 2021 06 30;20(6):1009-1018. Epub 2021 Mar 30.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Tesevatinib is a potent oral brain penetrant EGFR inhibitor currently being evaluated for glioblastoma therapy. Tesevatinib distribution was assessed in wild-type (WT) and triple knockout (TKO) FVB mice after dosing orally or via osmotic minipump; drug-tissue binding was assessed by rapid equilibrium dialysis. Two hours after tesevatinib dosing, brain concentrations in WT and TKO mice were 0.72 and 10.03 μg/g, respectively. Brain-to-plasma ratios (Kp) were 0.53 and 5.73, respectively. With intraperitoneal infusion, brain concentrations were 1.46 and 30.6 μg/g (Kp 1.16 and 25.10), respectively. The brain-to-plasma unbound drug concentration ratios were substantially lower (WT mice, 0.03-0.08; TKO mice, 0.40-1.75). Unbound drug concentrations in brains of WT mice were 0.78 to 1.59 ng/g. cytotoxicity and EGFR pathway signaling were evaluated using -amplified patient-derived glioblastoma xenograft models (GBM12, GBM6). pharmacodynamics and efficacy were assessed using athymic nude mice bearing either intracranial or flank tumors treated by oral gavage. Tesevatinib potently reduced cell viability [IC GBM12 = 11 nmol/L (5.5 ng/mL), GBM6 = 102 nmol/L] and suppressed EGFR signaling However, tesevatinib efficacy compared with vehicle in intracranial (GBM12, median survival: 23 vs. 18 days, = 0.003) and flank models (GBM12, median time to outcome: 41 vs. 33 days, = 0.007; GBM6, 44 vs. 33 days, = 0.007) was modest and associated with partial inhibition of EGFR signaling. Overall, tesevatinib efficacy in -amplified PDX GBM models is robust but relatively modest , despite a high brain-to-plasma ratio. This discrepancy may be explained by drug-tissue binding and compensatory signaling.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172524PMC
June 2021

Efflux Limits Tumor Drug Delivery Despite Disrupted BBB.

Trends Pharmacol Sci 2021 06 15;42(6):426-428. Epub 2021 Mar 15.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA. Electronic address:

Apparent blood-brain barrier (BBB) disruption is common in glioblastoma (GBM), but has not translated to improved drug delivery efficacy. Recently, de Gooijer et al. demonstrated that efflux transporters can have a prominent role in limiting drug delivery. These transport systems contribute to ineffective drug delivery to tumor cells in the brain.
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http://dx.doi.org/10.1016/j.tips.2021.03.001DOI Listing
June 2021

Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors.

Pharmaceutics 2020 Dec 11;12(12). Epub 2020 Dec 11.

Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.

Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood-brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of brain tumors, which results in what is referred to as the blood-tumor barrier (BTB). Herein, we discuss this heterogeneity, how it contributes to the failure of novel pharmaceutical treatment strategies, and why a "whole brain" approach to the treatment of brain tumors might be beneficial. We discuss various methods by which these obstacles might be overcome and assess how these strategies are progressing in the clinic. We believe that by approaching brain tumor treatment from this perspective, a new paradigm for drug delivery to brain tumors might be established.
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http://dx.doi.org/10.3390/pharmaceutics12121205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763839PMC
December 2020

Comments on: "Synergistic activity of mTORC1/2 kinase and MEK inhibitors suppresses pediatric low-grade glioma tumorigenicity and vascularity".

Neuro Oncol 2020 09;22(9):1404-1405

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

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http://dx.doi.org/10.1093/neuonc/noaa112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523448PMC
September 2020

High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model.

J Neurosurg Pediatr 2020 May 1:1-9. Epub 2020 May 1.

2Neurosurgery.

Objective: Chemotherapy infusions directly into the fourth ventricle may play a role in treating malignant fourth-ventricular tumors. This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma) into the fourth ventricle of nonhuman primates.

Methods: Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In group I (n = 2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was infused into the fourth ventricle daily for 5 consecutive days. Serial CSF and serum panobinostat levels were measured. In group II (n = 2), fourth-ventricle catheters were connected to a subcutaneously placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions (0.5 ml of 300 μM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and postmortem histological analyses.

Results: No neurological deficits occurred after intraventricular MTX110 infusions. MRI scans showed catheter placement within the fourth ventricle in all 4 animals, with extension to the cerebral aqueduct in 1 animal and into the third ventricle in 1 animal. There were no MRI signal changes in the brainstem, cerebellum, or elsewhere in the brains of any of the animals. Histologically, normal brain cytoarchitecture was preserved with only focal mild postsurgical changes in all animals. Panobinostat was undetectable in serum samples collected 2 and 4 hours after infusions in all samples in both groups. In group I, the mean peak panobinostat level in the fourth-ventricle CSF (6242 ng/ml) was significantly higher than that in the lumbar CSF (9 ng/ml; p < 0.0001). In group II, the mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than the mean trough CSF panobinostat level (33 ng/ml; p < 0.0001).

Conclusions: MTX110 can be safely infused into the fourth ventricle in nonhuman primates at supratherapeutic doses. Postinfusion CSF panobinostat levels peak immediately in the fourth ventricle and then rapidly decrease over 24 hours. Panobinostat is detectable at low levels in CSF measured from the lumbar cistern up to 4 hours after infusions. These results will provide background data for a pilot clinical trial in patients with recurrent medulloblastoma.
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http://dx.doi.org/10.3171/2020.2.PEDS19786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104457PMC
May 2020

Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma.

Sci Rep 2020 04 16;10(1):6524. Epub 2020 Apr 16.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Glioblastoma, the most lethal primary brain cancer, is extremely proliferative and invasive. Tumor cells at tumor/brain-interface often exist behind a functionally intact blood-brain barrier (BBB), and so are shielded from exposure to therapeutic drug concentrations. An ideal glioblastoma treatment needs to engage targets that drive proliferation as well as invasion, with brain penetrant therapies. One such target is the mitotic kinesin KIF11, which can be inhibited with ispinesib, a potent molecularly-targeted drug. Although, achieving durable brain exposures of ispinesib is critical for adequate tumor cell engagement during mitosis, when tumor cells are vulnerable, for efficacy. Our results demonstrate that the delivery of ispinesib is restricted by P-gp and Bcrp efflux at BBB. Thereby, ispinesib distribution is heterogeneous with concentrations substantially lower in invasive tumor rim (intact BBB) compared to glioblastoma core (disrupted BBB). We further find that elacridar-a P-gp and Bcrp inhibitor-improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers.
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http://dx.doi.org/10.1038/s41598-020-63494-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162859PMC
April 2020

Localized Metabolomic Gradients in Patient-Derived Xenograft Models of Glioblastoma.

Cancer Res 2020 03 25;80(6):1258-1267. Epub 2019 Nov 25.

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Glioblastoma (GBM) is increasingly recognized as a disease involving dysfunctional cellular metabolism. GBMs are known to be complex heterogeneous systems containing multiple distinct cell populations and are supported by an aberrant network of blood vessels. A better understanding of GBM metabolism, its variation with respect to the tumor microenvironment, and resulting regional changes in chemical composition is required. This may shed light on the observed heterogeneous drug distribution, which cannot be fully described by limited or uneven disruption of the blood-brain barrier. In this work, we used mass spectrometry imaging (MSI) to map metabolites and lipids in patient-derived xenograft models of GBM. A data analysis workflow revealed that distinctive spectral signatures were detected from different regions of the intracranial tumor model. A series of long-chain acylcarnitines were identified and detected with increased intensity at the tumor edge. A 3D MSI dataset demonstrated that these molecules were observed throughout the entire tumor/normal interface and were not confined to a single plane. mRNA sequencing demonstrated that hallmark genes related to fatty acid metabolism were highly expressed in samples with higher acylcarnitine content. These data suggest that cells in the core and the edge of the tumor undergo different fatty acid metabolism, resulting in different chemical environments within the tumor. This may influence drug distribution through changes in tissue drug affinity or transport and constitute an important consideration for therapeutic strategies in the treatment of GBM. SIGNIFICANCE: GBM tumors exhibit a metabolic gradient that should be taken into consideration when designing therapeutic strategies for treatment..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073296PMC
March 2020

Brain Distributional Kinetics of a Novel MDM2 Inhibitor SAR405838: Implications for Use in Brain Tumor Therapy.

Drug Metab Dispos 2019 12 16;47(12):1403-1414. Epub 2019 Oct 16.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (M.K., J.K.L., G.G., K.E.P., W.F.E.); Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota (R.B.); and Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.)

Achieving an effective drug concentration in the brain is as important as targeting the right pathway when developing targeted agents for brain tumors. SAR405838 is a novel molecularly targeted agent that is in clinical trials for various solid tumors. Its application for tumors in the brain has not yet been examined, even though the target, the MDM2-p53 interaction, is attractive for tumors that could occur in the brain, including glioblastoma and brain metastases. In vitro and in vivo studies indicate that SAR405838 is a substrate of P-glycoprotein (P-gp). P-gp mediated active efflux at the blood-brain barrier plays a dominant role in limiting SAR405838 brain distribution. Even though the absence of P-gp significantly increases the drug exposure in the brain, the systemic exposure, including absorption and clearance processes, were unaffected by P-gp deletion. Model-based parameters of SAR405838 distribution across the blood-brain barrier indicate the CL of the brain was approximately 40-fold greater than the CL The free fraction of SAR405838 in plasma and brain were found to be low, and subsequent Kp values were less than unity, even in P-gp/Bcrp knockout mice. These results indicate additional efflux transporters other than P-gp and Bcrp may be limiting distribution of SAR405838 to the brain. Concomitant administration of elacridar significantly increased brain exposure, also without affecting the systemic exposure. This study characterized the brain distributional kinetics of SAR405838, a novel MDM2 inhibitor, to evaluate its potential in the treatment of primary and metastatic brain tumors. SIGNIFICANCE STATEMENT: This paper examined the brain distributional kinetics of a novel MDM2-p53 targeted agent, SAR405838, to see its possible application for brain tumors by using in vitro, in vivo, and in silico approaches. SAR405838 is found to be a substrate of P-glycoprotein (P-gp), which limits its distribution to the brain. Based on the findings in the paper, manipulation of the function of P-gp can significantly increase the brain exposure of SAR405838, which may give an insight on its potential benefit as a treatment for primary and metastatic brain cancer.
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http://dx.doi.org/10.1124/dmd.119.088716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042719PMC
December 2019

Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and -Deficient Mice.

Drug Metab Dispos 2019 04 31;47(4):393-404. Epub 2019 Jan 31.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy (M.K., J.K.L., A.S.M., S.T., W.F.E.) and Clinical Pharmacology and Analytical Services Laboratory, Department of Experimental and Clinical Pharmacology (J.F.), University of Minnesota, Minneapolis, Minnesota; and Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.)

Tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR) have had success in treating EGFR-positive tumors, including non-small-cell lung cancer (NSCLC). However, developing EGFR inhibitors that can be delivered to the brain remains a challenge. To identify optimal compounds for brain delivery, eight EGFR inhibitors [afatinib, 6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]--(1-phenylethyl)-7H-pyrrolo[2,3-day]pyrimidin-4-amine (AEE788), [4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] (2R)-2,4-dimethylpiperazine-1-carboxylate (AZD3759), erlotinib, dacomitinib, gefitinib, osimertinib, and vandetanib] were evaluated for distributional kinetics using cassette dosing with the ultimate goal of understanding the brain penetrability of compounds that share the same molecular target in an important oncogenic signaling pathway for both primary brain tumors (glioblastoma) and brain metastases (e.g., NSCLC). Cassette dosing was validated by comparing the brain-to-plasma ratios obtained from cassette-dosing to discrete-dosing studies. The brain-to-blood partition coefficients (K) were calculated following cassette dosing of the eight EGFR inhibitors. The comparison of K in wild-type and transporter-deficient mice confirmed that two major efflux transporters at the blood-brain barrier (BBB), P-glycoprotein and breast cancer resistance protein, play a crucial role in the brain distribution of seven out of eight EGFR inhibitors. Results show that the prediction of brain distribution based on physicochemical properties of a drug can be misleading, especially for compounds subject to extensive efflux transport. Moreover, this study informs the choice of EGFR inhibitors, i.e., determining BBB permeability combined with a known target potency, that may be effective in future clinical trials for brain tumors.
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http://dx.doi.org/10.1124/dmd.118.084210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408736PMC
April 2019

Brain Distribution and Active Efflux of Three panRAF Inhibitors: Considerations in the Treatment of Melanoma Brain Metastases.

J Pharmacol Exp Ther 2019 03 8;368(3):446-461. Epub 2019 Jan 8.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G., M.K., A.S.M., K.E.P., W.F.E.); and Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., J.N.S.)

Targeted inhibition of RAF and MEK by molecularly targeted agents has been employed as a strategy to block aberrant mitogen-activated protein kinase (MAPK) signaling in melanoma. While the use of BRAF and MEK inhibitors, either as a single agent or in combination, improved efficacy in BRAF-mutant melanoma, initial responses are often followed by relapse due to acquired resistance. Moreover, some BRAF inhibitors are associated with paradoxical activation of the MAPK pathway, causing the development of secondary malignancies. The use of panRAF inhibitors, i.e., those that target all isoforms of RAF, may overcome paradoxical activation and resistance. The purpose of this study was to perform a quantitative assessment and evaluation of the influence of efflux mechanisms at the blood-brain barrier (BBB), in particular, Abcb1/P-glycoprotein (P-gp) and Abcg2/breast cancer resistance protein (Bcrp), on the brain distribution of three panRAF inhibitors: CCT196969 [1-(3-(-butyl)-1-phenyl-1-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea], LY3009120 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido(2,3-d)pyrimidin-6-yl)phenyl)urea, and MLN2480 [4-pyrimidinecarboxamide, 6-amino-5-chloro--[(1)-1-[5-[[[5-chloro-4-(trifluoromethyl)-2-pyridinyl]amino]carbonyl]-2-thiazolyl]ethyl]-]. In vitro studies using transfected Madin-Darby canine kidney II cells indicate that only LY3009120 and MLN2480 are substrates of Bcrp, and none of the three inhibitors are substrates of P-gp. The three panRAF inhibitors show high nonspecific binding in brain and plasma. In vivo studies in mice show that the brain distribution of CCT196969, LY3009120, and MLN2480 is limited, and is enhanced in transgenic mice lacking P-gp and Bcrp. While MLN2480 has a higher brain distribution, LY3009120 exhibits superior in vitro efficacy in patient-derived melanoma cell lines. The delivery of a drug to the site of action residing behind a functionally intact BBB, along with drug potency against the target, collectively play a critical role in determining in vivo efficacy outcomes.
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http://dx.doi.org/10.1124/jpet.118.253708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374543PMC
March 2019

Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma.

Nat Commun 2018 11 21;9(1):4904. Epub 2018 Nov 21.

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling.
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http://dx.doi.org/10.1038/s41467-018-07334-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249307PMC
November 2018

E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases.

Invest New Drugs 2019 08 28;37(4):636-645. Epub 2018 Sep 28.

Honor Health Research Institute, 10510 N. 92nd Street, #200, Scottsdale, AZ, 85258, USA.

Malignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 years. Whole exome and transcriptome sequencing revealed a high mutational burden tumor (22 mutations/Megabase) with homozygous BRAF V600E mutation. Correlative preclinical studies demonstrated broad activity for E6201 across BRAF V600E mutant melanoma cell lines and effective BBB penetration in vivo. Together, these results suggest that E6201 may represent a potential new treatment option for BRAF-mutant MM patients with BM.
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http://dx.doi.org/10.1007/s10637-018-0668-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519637PMC
August 2019

Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine.

Pharm Res 2018 Jul 12;35(9):177. Epub 2018 Jul 12.

University of Minnesota, Minneapolis, Minnesota, USA.

The treatment of metastatic lesions in the brain represents a serious unmet medical need in the field of neuro-oncology. Even though many effective compounds have demonstrated success in treating peripheral (non-CNS) tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. Many factors can influence the brain delivery of these agents, but one key barrier is a heterogeneously "leaky" BBB that expresses efflux transporters that limit the BBB permeability for many targeted agents. Future success in therapeutics for brain metastases must take into account the adequate delivery of "active, free drug" to the target, and may include combinations of targeted drugs that are appropriate to address each individual patient's tumor type. This review discusses some issues that are pertinent to precision medicine for brain metastases, using specific examples of tumor types that have a high incidence of brain metastases.
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http://dx.doi.org/10.1007/s11095-018-2455-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700736PMC
July 2018

Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood-Brain Barrier.

Mol Cancer Ther 2018 09 3;17(9):1893-1901. Epub 2018 Jul 3.

Mayo Clinic, Rochester, Minnesota.

Controversy exists surrounding whether heterogeneous disruption of the blood-brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. efficacy of SAR405838 was evaluated in PDX models with varying MDM2 expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3 kDa dextran, was significantly increased in GBM108 through VEGFA overexpression. Drug delivery, MRI, and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison with MDM2 control lines in both and heterotopic models. In contrast with profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125211PMC
September 2018

Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier.

J Pharmacol Exp Ther 2018 05 12;365(2):249-261. Epub 2018 Feb 12.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (J.K.L., M.K., K.E.P., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.)

A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [] compared with the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared with single knockout mice [ or ], suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15-fold higher in the wild-type compared with mice, resulting in a significant increase in the mean transit time (the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain, a process that reduces the duration and extent of ponatinib exposure in the brain and has critical implications for the use of targeted drug delivery for brain tumors.
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http://dx.doi.org/10.1124/jpet.117.246116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878676PMC
May 2018

Brain Distribution of a Novel MEK Inhibitor E6201: Implications in the Treatment of Melanoma Brain Metastases.

Drug Metab Dispos 2018 05 2;46(5):658-666. Epub 2018 Feb 2.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G., M.K., N.C.-R., J.K.L., W.F.E.); Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.); and Strategia Therapeutics Inc., Spring, Texas (L.P., L.D.)

Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and mitogen-activated protein/extracellular signal-regulated kinase (MEK) has been identified to be an important target. E6201 is a potent synthetic small-molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the blood-brain barrier on the central nervous system (CNS) exposure of E6201. In vitro studies utilizing transfected Madin-Darby canine kidney II (MDCKII) cells indicate that E6201 is not a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp). In vivo studies also suggest a minimal involvement of P-gp and Bcrp in E6201's brain distribution. The total concentrations in brain were higher than in plasma, resulting in a brain-to-plasma AUC ratio (Kp) of 2.66 in wild-type mice. The brain distribution was modestly enhanced in and knockout mice. The nonspecific binding of E6201 was higher in brain compared with plasma. However, free-drug concentrations in brain following 40 mg/kg intravenous dose reach levels that exceed reported in vitro half-maximal inhibitory concentration (IC) values, suggesting that E6201 may be efficacious in inhibiting MEK-driven brain tumors. The brain distribution characteristics of E6201 make it an attractive targeted agent for clinical testing in MBM, glioblastoma, and other CNS tumors that may be effectively targeted with inhibition of MEK signaling.
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http://dx.doi.org/10.1124/dmd.117.079194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896365PMC
May 2018

Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data.

Neuro Oncol 2018 01;20(2):184-191

Mayo Clinic, Rochester, Minnesota (J.N.S., I.F.P., D.H.P., D.H.B., N.N.L., C.G., T.C.B., S.H.K., T.J.K., P.D.B., E.G., J.C.B.).

The blood-brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.
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http://dx.doi.org/10.1093/neuonc/nox175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777482PMC
January 2018

Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma.

Mol Cancer Ther 2017 Dec 25;16(12):2735-2746. Epub 2017 Sep 25.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1-3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G-M arrest cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated. This talazoparib/temozolomide regimen prolonged tumor stasis more than temozolomide alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days versus 50 days temozolomide ( = 0.005), 11 days placebo ( < 0.001)]. However, talazoparib/temozolomide did not accentuate survival beyond that of temozolomide alone in corresponding orthotopic xenografts [median survival 37 vs. 30 days with temozolomide ( = 0.93), 14 days with placebo, < 0.001]. Average brain and plasma talazoparib concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49 ± 0.07 ng/g and 25.5±4.1 ng/mL, respectively. The brain/plasma distribution of talazoparib in Bcrp versus wild-type (WT) mice did not differ, whereas the brain/plasma ratio in Mdr1a/b mice was higher than WT mice (0.23 vs. 0.02, < 0.001). Consistent with the brain distribution, overexpression of MDR1 decreased talazoparib accumulation in MDCKII cells. These results indicate that talazoparib has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of talazoparib-mediated temozolomide sensitization in orthotopic versus heterotopic GBM xenografts. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716902PMC
December 2017

Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma.

J Pharmacol Exp Ther 2017 11 28;363(2):136-147. Epub 2017 Aug 28.

Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (J.K.L., M.K., K.E.P., S.Z., W.F.E.) and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (S.K.G., K.K.B., B.L.C., A.C.M., D.J.M., J.N.S.)

This study investigated how differences in drug distribution and free fraction at different tumor and tissue sites influence the efficacy of the multikinase inhibitor ponatinib in a patient-derived xenograft model of glioblastoma (GBM). Efficacy studies in GBM6 flank (heterotopic) and intracranial (orthotopic) models showed that ponatinib is effective in the flank but not in the intracranial model, despite a relatively high brain-to-plasma ratio. In vitro binding studies indicated that flank tumor had a higher free (unbound) drug fraction than normal brain. The total and free drug concentrations, along with the tissue-to-plasma ratio (Kp) and its unbound derivative (Kp,uu), were consistently higher in the flank tumor than the normal brain at 1 and 6 hours after a single dose in GBM6 flank xenografts. In the orthotopic xenografts, the intracranial tumor core displayed higher Kp and Kp,uu values compared with the brain-around-tumor (BAT). The free fractions and the total drug concentrations, hence free drug concentrations, were consistently higher in the core than in the BAT at 1 and 6 hours postdose. The delivery disadvantages in the brain and BAT were further evidenced by the low total drug concentrations in these areas that did not consistently exceed the in vitro cytotoxic concentration (IC). Taken together, the regional differences in free drug exposure across the intracranial tumor may be responsible for compromising efficacy of ponatinib in orthotopic GBM6.
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http://dx.doi.org/10.1124/jpet.117.243477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625285PMC
November 2017

Drug delivery to melanoma brain metastases: Can current challenges lead to new opportunities?

Pharmacol Res 2017 Sep 17;123:10-25. Epub 2017 Jun 17.

Brain Barriers Research Center, Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA. Electronic address:

Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease. While these studies are encouraging, there remains significant room for improvement in the treatment of MBM, given the lack of durable response and the development of resistance to current therapies. Critical questions remain regarding mechanisms that lead to this lack of durable response and development of resistance, and how those mechanisms may differ in systemic sites versus brain metastases. One issue that may not be fully appreciated is that the delivery of several small molecule molecularly-targeted therapies to the brain is often restricted due to active efflux at the blood-brain barrier (BBB) interface. Inadequate local drug concentrations may be partially responsible for the development of unique patterns of resistance at metastatic sites in the brain. It is clear that there can be local, heterogeneous BBB breakdown in MBM, as exemplified by contrast-enhancement on T1-weighted MR imaging. However, it is possible that the successful treatment of MBM with small molecule targeted therapies will depend, in part, on the ability of these therapies to penetrate an intact BBB and reach the protected micro-metastases (so called "sub-clinical" disease) that escape early detection by contrast-enhanced MRI, as well as regions of tumor within MRI-detectable metastases that may have a less compromised BBB. The emergence of resistance in MBM may be related to several diverse, yet interrelated, factors including the distinct microenvironment of the brain and inadequate brain penetration of targeted therapies to specific regions of tumor. The tumor microenvironment has been ascribed to play a key role in steering the course of disease progression, by dictating changes in expression of tumor drivers and resistance-related signaling mechanisms. Therefore, a key issue to consider is how changes in drug delivery, and hence local drug concentrations within a metastatic microenvironment, will influence the development of resistance. Herein we discuss our perspective on several critical questions that focus on many aspects relevant to the treatment of melanoma brain metastases; the answers to which may lead to important advances in the treatment of this devastating disease.
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http://dx.doi.org/10.1016/j.phrs.2017.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565722PMC
September 2017
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