Publications by authors named "Paul R Lockman"

66 Publications

Irradiator Commissioning and Dosimetry for Assessment of LQ α and β Parameters, Radiation Dosing Schema, and in vivo Dose Deposition.

J Vis Exp 2021 03 11(169). Epub 2021 Mar 11.

Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University;

Radiation dosimetry is critical in the accurate delivery and reproducibility of radiation schemes in preclinical models for high translational relevance. Prior to performing any in vitro or in vivo experiments, the specific dose output for the irradiator and individual experimental designs must be assessed. Using an ionization chamber, electrometer, and solid water setup, the dose output of wide fields at isocenter can be determined. Using a similar setup with radiochromic films in the place of the ionization chamber, dose rates for smaller fields at different depths can also be determined. In vitro clonogenic survival assays of cancer cells in response to radiation treatment are inexpensive experiments that provide a measure of inherent radio-sensitivity of cell lines by fitting these data with the traditional linear-quadratic model. Model parameters estimated from these assays, combined with the principles of biologic effective doses, allows one to develop varying fractionation schedules for radiation treatment that provide equivalent effective doses in tumor-bearing animal experiments. This is an important factor to consider and correct for in comparing in vivo radiation therapy schedules to eliminate potential confounding of results due to variance in the delivered effective doses. Taken together, this article provides a general method for dose output verification preclinical animal and cabinet irradiators, in vitro assessment of radio-sensitivity, and verification of radiation delivery in small living organisms.
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http://dx.doi.org/10.3791/61692DOI Listing
March 2021

Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis.

BMC Cancer 2020 Apr 7;20(1):292. Epub 2020 Apr 7.

Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 108 Biomedical Drive, Morgantown, WV, 26506, USA.

Background: Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~ 30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy.

Methods: Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis.

Results: A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50 > 2.5 μM at 48 h and 0.1 μM at 72 h) compared with parental PC-9 (IC50: 0.75 μM at 48 h and 0.027 μM at 72 h). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither a T790M mutation nor amplifications of MET and HER2 compared with parental PC-9.

Conclusion: Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.
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http://dx.doi.org/10.1186/s12885-020-06808-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137432PMC
April 2020

MiR-34a Interacts with Cytochrome c and Shapes Stroke Outcomes.

Sci Rep 2020 02 24;10(1):3233. Epub 2020 Feb 24.

Neuroscience, Center for Basic and Translational Stroke Research; West Virginia University, Morgantown, West Virginia, 26506, USA.

Blood-brain barrier (BBB) dysfunction occurs in cerebrovascular diseases and neurodegenerative disorders such as stroke. Opening of the BBB during a stroke has a negative impact on acute outcomes. We have recently demonstrated that miR-34a regulates the BBB by targeting cytochrome c (CYC) in vitro. To investigate the role of miR-34a in a stroke, we purified primary cerebrovascular endothelial cells (pCECs) from mouse brains following 1 h transient middle cerebral artery occlusion (tMCAO) and measured real-time PCR to detect miR-34a levels. We demonstrate that the miR-34a levels are elevated in pCECs from tMCAO mice at the time point of BBB opening following 1 h tMCAO and reperfusion. Interestingly, knockout of miR-34a significantly reduces BBB permeability, alleviates disruption of tight junctions, and improves stroke outcomes compared to wild-type (WT) controls. CYC is decreased in the ischemic hemispheres and pCECs from WT but not in miR-34a mice following stroke reperfusion. We further confirmed CYC is a target of miR-34a by a dural luciferase reporter gene assay in vitro. Our study provides the first description of miR-34a affecting stroke outcomes and may lead to discovery of new mechanisms and treatments for cerebrovascular and neurodegenerative diseases such as stroke.
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http://dx.doi.org/10.1038/s41598-020-59997-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040038PMC
February 2020

Improving CNS Delivery to Brain Metastases by Blood-Tumor Barrier Disruption.

Trends Cancer 2019 08 20;5(8):495-505. Epub 2019 Jul 20.

Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University HSC, Morgantown, West Virginia 26506, USA. Electronic address:

Brain metastases encompass nearly 80% of all intracranial tumors. A late stage diagnosis confers a poor prognosis, with patients typically surviving less than 2 years. Poor survival can be equated to limited effective treatment modalities. One reason for the failure rates is the presence of the blood-brain barrier (BBB) and blood-tumor barrier (BTB) that limit the access of potentially effective chemotherapeutics to metastatic lesions. Strategies to overcome these barriers include new small molecule entities capable of crossing into the brain parenchyma, novel formulations of existing chemotherapies, and disruptive techniques. Here, we review BBB physiology and BTB pathophysiology. Additionally, we review the limitations of routinely practiced therapies and three current methods being explored for BBB/BTB disruption for improved delivery of chemotherapy to brain tumors.
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http://dx.doi.org/10.1016/j.trecan.2019.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703178PMC
August 2019

Development of a Cx46 Targeting Strategy for Cancer Stem Cells.

Cell Rep 2019 04;27(4):1062-1072.e5

Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

Gap-junction-mediated cell-cell communication enables tumor cells to synchronize complex processes. We previously found that glioblastoma cancer stem cells (CSCs) express higher levels of the gap junction protein Cx46 compared to non-stem tumor cells (non-CSCs) and that this was necessary and sufficient for CSC maintenance. To understand the mechanism underlying this requirement, we use point mutants to disrupt specific functions of Cx46 and find that Cx46-mediated gap-junction coupling is critical for CSCs. To develop a Cx46 targeting strategy, we screen a clinically relevant small molecule library and identify clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuates proliferation, self-renewal, and tumor growth and synergizes with temozolomide to induce apoptosis. Although clofazimine does not cross the blood-brain barrier, the combination of clofazimine derivatives optimized for brain penetrance with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.
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http://dx.doi.org/10.1016/j.celrep.2019.03.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497083PMC
April 2019

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment.

J Cent Nerv Syst Dis 2019 9;11:1179573519840652. Epub 2019 Apr 9.

Graduate Programs in Neuroscience, Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA.

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB's role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors.
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http://dx.doi.org/10.1177/1179573519840652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456845PMC
April 2019

Long non-coding RNA FAM83H-AS1 is regulated by human papillomavirus 16 E6 independently of p53 in cervical cancer cells.

Sci Rep 2019 03 6;9(1):3662. Epub 2019 Mar 6.

Department of Microbiology, Immunology & Cell Biology, West Virginia University Cancer Institute, School of Medicine, West Virginia University, Morgantown, West Virginia, USA.

High-risk human papillomavirus (HPV) infection is one of the first events in the process of carcinogenesis in cervical and head and neck cancers. The expression of the viral oncoproteins E6 and E7 are essential in this process by inactivating the tumor suppressor proteins p53 and Rb, respectively, in addition to their interactions with other host proteins. Non-coding RNAs, such as long non-coding RNAs (lncRNAs) have been found to be dysregulated in several cancers, suggesting an important role in tumorigenesis. In order to identify host lncRNAs affected by HPV infection, we expressed the high-risk HPV-16 E6 oncoprotein in primary human keratinocytes and measured the global lncRNA expression profile by high-throughput sequencing (RNA-seq). We found several host lncRNAs differentially expressed by E6 including GAS5, H19, and FAM83H-AS1. Interestingly, FAM83H-AS1 was found overexpressed in HPV-16 positive cervical cancer cell lines in an HPV-16 E6-dependent manner but independently of p53 regulation. Furthermore, FAM83H-AS1 was found to be regulated through the E6-p300 pathway. Knockdown of FAM83H-AS1 by siRNAs decreased cellular proliferation, migration and increased apoptosis. FAM83H-AS1 was also found to be altered in human cervical cancer tissues and high expression of this lncRNA was associated with worse overall survival, suggesting an important role in cervical carcinogenesis.
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http://dx.doi.org/10.1038/s41598-019-40094-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403315PMC
March 2019

Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of metastatic brain tumor from breast cancer.

BMC Cancer 2018 Dec 7;18(1):1225. Epub 2018 Dec 7.

Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, School of Pharmacy, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.

Background: Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes.

Methods: Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28 days, after which animals were injected fluorescent tracers Texas Red (625 Da) or Texas Red dextran (3 kDa) or a chemotherapeutic agent C-paclitaxel. The accumulation of tracers and C-paclitaxel in BAT were determined by using quantitative fluorescent microscopy and autoradiography respectively. The effect of chemotherapy in BAT was determined by staining for activated astrocytes.

Results: The mean permeability of texas Red (625 Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3 kDa) demonstrated mean permeability increase ranging from 1.0 to 1.8-fold compared to normal brain. The K values in the BAT for both Texas Red (625 Da) and Texas Red dextran (3 kDa) were found to be 4.32 ± 0.2 × 10 mL/s/g and 1.6 ± 1.4 × 10 mL/s/g respectively and found to be significantly higher than the normal brain. We also found that there is significant increase in accumulation of C-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10 mg/kg), erubilin (1.5 mg/kg) and docetaxel (10 mg/kg)) showed activated astrocytes in BAT.

Conclusions: Our data showed increased permeation of fluorescent tracers and C-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.
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http://dx.doi.org/10.1186/s12885-018-5115-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286543PMC
December 2018

Conditional knockout of SHP2 in ErbB2 transgenic mice or inhibition in HER2-amplified breast cancer cell lines blocks oncogene expression and tumorigenesis.

Oncogene 2019 03 22;38(13):2275-2290. Epub 2018 Nov 22.

Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, WV, 26506, USA.

Overexpression of the human epidermal growth factor receptor 2 (HER2) is the cause of HER2-positive breast cancer (BC). Although HER2-inactivating therapies have benefited BC patients, development of resistance and disease recurrence have been the major clinical problems, pointing to a need for alternative therapeutic strategies. For that to happen, proteins that play critical roles in the biology of HER2-induced tumorigenesis have to be identified and characterized. Here, we show that the Src homology phosphotyrosyl phosphatase 2 (Shp2) encoded by the Ptpn11 gene is a requisite for ErbB2-induced tumorigenesis. We report that conditional knockout of Shp2 alleles in the ErbB2 BC model mice abrogates mammary tumorigenesis by blocking the expression of the ErbB2 transgene. We also show that inhibition of SHP2 encoded by the PTPN11 gene in the HER2-amplified BC cells induces a normal-like cellular phenotype and suppresses tumorigenesis and metastasis by blocking HER2 overexpression. These findings demonstrate that ErbB2-induced tumors in mice or xenograft tumors induced by transplantation of HER2-amplified BC cells are vulnerable to SHP2 inhibition since it abrogates the expression of the very oncogene that causes of the disease. This report paves the way for developing SHP2-targeting therapies for BC treatment in the future.
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http://dx.doi.org/10.1038/s41388-018-0574-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440805PMC
March 2019

An Effective Approach to Teaching Pharmacogenomics in the First Year of Pharmacy Curriculum.

Am J Pharm Educ 2018 10;82(8):6345

School of Pharmacy, West Virginia University, Morgantown, West Virginia.

To develop an effective method in teaching pharmacogenomics as a part of a new course, Biopharmaceutics and Pharmacogenomics. Teaching effectiveness was measured by quizzes, retrospective pre- and post-surveys, team activities, and journal reflections. Four team activities were included in the course: genomic disease, patient case, genetic counselor and a debate about personalized medicine. Outcomes and course impact were evaluated at the end of the course. The evaluation methods included the assessment of knowledge, students' perceptions regarding the utility of team activities, the impact of the course on students' confidence to discuss pharmacogenomics with health care providers or patients, and long-term knowledge retention, measured in the following P2 semester. Seventy-six students were enrolled in the course. Multiple assessments during the course demonstrated that students' knowledge of pharmacogenomics improved. The team activities had a positive impact on student learning, and the course improved their confidence level to discuss pharmacogenomics with another health care provider or a patient. While 86% of the students considered themselves "unconfident," "somewhat unconfident" or "neither confident nor unconfident" at the beginning of the course, 91% reported being "confident" or "somewhat confident" by the end of the course. This increase in confidence was statistically significant. Furthermore, students showed knowledge retention six months after taking the course. Implementation of a new course in pharmacogenomics was effective and well received by the students. It also prepared students for system-based therapeutics courses later in the curriculum.
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http://dx.doi.org/10.5688/ajpe6345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221532PMC
October 2018

Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases.

Pharmacol Res 2018 06 28;132:47-68. Epub 2018 Mar 28.

West Virginia University, Health Sciences Center, School of Pharmacy, Department of Basic Pharmaceutical Sciences, Morgantown, WV 26506, USA. Electronic address:

In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2 BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM.
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http://dx.doi.org/10.1016/j.phrs.2018.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997530PMC
June 2018

Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer.

Pharm Res 2018 Jan 9;35(2):31. Epub 2018 Jan 9.

School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.

Purpose: The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain metastases relative to conventional irinotecan due to enhanced-permeation and retention (EPR) effect.

Methods: Female nude mice were intracardially or intracranially implanted with human brain seeking breast cancer cells (brain metastases of breast cancer model). Mice were administered vehicle, non-liposomal irinotecan (50 mg/kg), liposomal irinotecan (10 mg/kg and 50 mg/kg) intravenously starting on day 21. Drug accumulation, tumor burden, and survival were evaluated.

Results: Liposomal irinotecan showed prolonged plasma drug exposure with mean residence time (MRT) of 17.7 ± 3.8 h for SN-38, whereas MRT was 3.67 ± 1.2 for non-liposomal irinotecan. Further, liposomal irinotecan accumulated in metastatic lesions and demonstrated prolonged exposure of SN-38 compared to non-liposomal irinotecan. Liposomal irinotecan achieved AUC values of 6883 ± 4149 ng-h/g for SN-38, whereas non-liposomal irinotecan showed significantly lower AUC values of 982 ± 256 ng-h/g for SN-38. Median survival for liposomal irinotecan was 50 days, increased from 37 days (p<0.05) for vehicle.

Conclusions: Liposomal irinotecan accumulates in brain metastases, acts as depot for sustained release of irinotecan and SN-38, which results in prolonged survival in preclinical model of breast cancer brain metastasis.
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http://dx.doi.org/10.1007/s11095-017-2278-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884086PMC
January 2018

Trastuzumab distribution in an and model of brain metastases of breast cancer.

Oncotarget 2017 Oct 26;8(48):83734-83744. Epub 2017 Jul 26.

Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University HSC, Morgantown, West Virginia 26506, USA.

Background: Drug and antibody delivery to brain metastases has been highly debated in the literature. The blood-tumor barrier (BTB) is more permeable than the blood-brain barrier (BBB), and has shown to have highly functioning efflux transporters and barrier properties, which limits delivery of targeted therapies.

Methods: We characterized the permeability of I-trastuzumab in an , and fluorescent trastuzumab-Rhodamine123 (t-Rho123) in a novel microfluidic , BBB and BTB brain metastases of breast cancer model. : Human MDA-MB-231-HER2+ metastatic breast cancer cells were grown and maintained under static conditions. Cells were harvested at 80% confluency and prepped for intra-cardiac injection into 20 homozygous female Nu/Nu mice. : In a microfluidic device (SynVivo), human umbilical vein endothelial cells were grown and maintained under shear stress conditions in the outer compartment and co-cultured with CTX-TNA2 rat brain astrocytes (BBB) or Met-1 metastatic HER2+ murine breast cancer cells (BTB), which were maintained in the central compartment under static conditions.

Results: Tissue distribution of I-trastuzumab revealed only ~3% of injected dose reached normal brain, with ~5% of injected dose reaching brain tumors. No clear correlation was observed between size of metastases and the amount of I-trastuzumab localized . This heterogeneity was paralleled , where the distribution of t-Rho123 from the outer chamber to the central chamber of the microfluidic device was qualitatively and quantitatively analyzed over time. The rate of t-Rho123 linear uptake in the BBB (0.27 ± 0.33 × 10) and BTB (1.29 ± 0.93 × 10) showed to be significantly greater than 0 (p < 0.05). The BTB devices showed significant heterogenetic tendencies, as seen in .

Conclusions: This study is one of the first studies to measure antibody movement across the blood-brain and blood-tumor barriers, and demonstrates that, though in small and most likely not efficacious quantities, trastuzumab does cross the blood-brain and blood-tumor barriers.
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http://dx.doi.org/10.18632/oncotarget.19634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663550PMC
October 2017

A mouse Model of Focal Vascular Injury Induces Astrocyte Reactivity, Tau Oligomers, and Aberrant Behavior.

Arch Neurosci 2017 Apr 30;4(2). Epub 2017 Apr 30.

Department of Pharmaceutical Sciences, West Virginia University School of Medicine, Morgantown, WV 26506-9530, USA.

Neuropsychiatric symptom development has become more prevalent with 270,000 blast exposures occurring in the past 10 years in the United States. How blast injury leads to neuropsychiatric symptomology is currently unknown. Preclinical models of blast-induced traumatic brain injury have been used to demonstrate blood-brain barrier disruption, degenerative pathophysiology, and behavioral deficits. Vascular injury is a primary effect of neurotrauma that can trigger secondary injury cascades and neurodegeneration. Here we present data from a novel scaled and clinically relevant mouse blast model that was specifically developed to assess the outcome of vascular injury. We look at the biochemical effects and behavioral changes associated with blast injury in young-adult male BALB/c mice. We report that blast exposure causes focal vascular injury in the Somatosensory Barrel Field cortex, which leads to perivascular astrocyte reactivity, as well as acute aberrant behavior. Biochemical analysis revealed that mild blast exposure also invokes tauopathy, neuroinflammation, and oxidative stress. Overall, we propose our model to be used to evaluate focal blood-brain barrier disruption and to discover novel therapies for human neuropsychiatric symptoms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529099PMC
http://dx.doi.org/10.5812/archneurosci.44254DOI Listing
April 2017

Inhibition of VEGF and Angiopoietin-2 to Reduce Brain Metastases of Breast Cancer Burden.

Front Pharmacol 2017 11;8:193. Epub 2017 Apr 11.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, AmarilloTX, USA.

For metastases in the central nervous system, angiogenesis enhances metastatic potential and promotes progression. Primary factors which drive vessel growth are vascular endothelial growth factor (VEGF) and angiopoietin-2. Preclinical models show inhibition of either factor reduces metastases spread and inhibits growth. This work sets out to answer two questions in a preclinical mouse model. First, whether the combined inhibition of VEGF and angiopoietin-2, reduces passive permeability and limits drug uptake into brain metastases; and second, whether this inhibition reduces metastases burden in brain. We observed combinatorial inhibition of VEGF and angiopoietin-2, decreased ( < 0.05) angiogenesis and vascular branching in an aortic ring assay and decreased ( < 0.05) endothelial wound closure times. Using a brain metastases of breast cancer model (induced by intracardiac injections of brain seeking MDA-MB-231Br cells or 4T1Br cells), we observed, similar to VEGF, angiopoetin-2 expression correlates to increased angiogenesis ( < 0.05) and increased lesion permeability. To determine efficacy, animals were administered bevacizumab plus L1-10 (angiopoietin inhibitor) twice per week until neurological symptoms developed. Lesion permeability significantly decreased by ∼50% ( < 0.05) compared to untreated lesions, but remained ∼25% greater ( < 0.0%) than brain. In subsequent experiments, animals were administered similar regimens but sacrificed on day 32. The number of metastatic lesions developed was significantly ( < 0.001) reduced in the bevacizumab group (56%) and combination group (86%). Lesions' size was reduced in bevacizumab treated lesions (∼67%) and bevacizumab and L1-10 treated lesions (∼78%) developing area < 0.5 mm. In summary, combinatorial inhibition of VEGF and angiopoietin reduces lesion permeability and brain metastatic burden.
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http://dx.doi.org/10.3389/fphar.2017.00193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387068PMC
April 2017

Permeability across a novel microfluidic blood-tumor barrier model.

Fluids Barriers CNS 2017 Jan 23;14(1). Epub 2017 Jan 23.

Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University HSC, 1 Medical Center Dr., Morgantown, WV, 26506, USA.

Background: The lack of translatable in vitro blood-tumor barrier (BTB) models creates challenges in the development of drugs to treat tumors of the CNS and our understanding of how the vascular changes at the BBB in the presence of a tumor.

Methods: In this study, we characterize a novel microfluidic model of the BTB (and BBB model as a reference) that incorporates flow and induces shear stress on endothelial cells. Cell lines utilized include human umbilical vein endothelial cells co-cultured with CTX-TNA2 rat astrocytes (BBB) or Met-1 metastatic murine breast cancer cells (BTB). Cells were capable of communicating across microfluidic compartments via a porous interface. We characterized the device by comparing permeability of three passive permeability markers and one marker subject to efflux.

Results: The permeability of Sulforhodamine 101 was significantly (p < 0.05) higher in the BTB model (13.1 ± 1.3 × 10, n = 4) than the BBB model (2.5 ± 0.3 × 10, n = 6). Similar permeability increases were observed in the BTB model for molecules ranging from 600 Da to 60 kDa. The function of P-gp was intact in both models and consistent with recent published in vivo data. Specifically, the rate of permeability of Rhodamine 123 across the BBB model (0.6 ± 0.1 × 10, n = 4), increased 14-fold in the presence of the P-gp inhibitor verapamil (14.7 ± 7.5 × 10, n = 3) and eightfold with the addition of Cyclosporine A (8.8 ± 1.8 × 10, n = 3). Similar values were noted in the BTB model.

Conclusions: The dynamic microfluidic in vitro BTB model is a novel commercially available model that incorporates shear stress, and has permeability and efflux properties that are similar to in vivo data.
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http://dx.doi.org/10.1186/s12987-017-0050-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260004PMC
January 2017

Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer.

Curr Cancer Drug Targets 2017 ;17(5):479-485

Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV. United States.

Background: Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases.

Method: In this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma.

Results: From our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB).

Conclusion: The results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers.
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http://dx.doi.org/10.2174/1568009617666161121123948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438904PMC
March 2018

Quantitative Fluorescence Microscopy Measures Vascular Pore Size in Primary and Metastatic Brain Tumors.

Cancer Res 2017 01 4;77(2):238-246. Epub 2016 Nov 4.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.

Tumors residing in the central nervous system (CNS) compromise the blood-brain barrier (BBB) via increased vascular permeability, with the magnitude of changes dependent on the tumor type and location. Current studies determine penetrability of a cancer therapeutic by administering progressively larger molecules until cutoff is observed where little to no tumor accumulation occurs. However, decades-old experimental work and mathematical modeling document methods to calculate both the size of the vascular opening (pore) with solute permeability values. In this study, we updated this classic mathematical modeling approach with quantitative fluorescence microscopy in two preclinical tumor models, allowing simultaneous administration of multiple sized tracers to determine vascular permeability at a resolution of nearly one micron. We observed that three molecules ranging from 100 Da to 70 kDa permeated into a preclinical glioblastoma model at rates proportional to their diffusion in water. This suggests the solutes freely diffused from blood to glioma across vascular pores without steric restriction, which calculates to a pore size of >140 nm in diameter. In contrast, the calculated pore size of a brain metastasis of breast cancer was approximately 10-fold smaller than glioma vasculature. This difference explains why antibodies are effective against glioblastoma but generally fail in brain metastases of breast cancer. On the basis of our observations, we hypothesize that trastuzumab most likely fails in the treatment of brain metastases of breast cancer because of poor CNS penetration, while the similar sized antibody bevacizumab is effective in the same tumor type not because it penetrates the CNS degree better, but because it scavenges VEGF in the vascular compartment, which reduces edema and permeation. Cancer Res; 77(2); 238-46. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267930PMC
January 2017

Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain: an In-Vivo Study.

Pharm Res 2016 12 15;33(12):2930-2942. Epub 2016 Aug 15.

School of Pharmacy, West Virginia University Health Sciences Center, Morgantown, West Virginia, USA.

Purpose: The ability of human melanotransferrin (hMTf) to carry a therapeutic concentration of trastuzumab (BTA) in the brain after conjugation (in the form of trastuzumab-melanotransferrin conjugate, BT2111 conjugate) was investigated by measuring the reduction of the number and size of metastatic human HER breast cancer tumors in a preclinical model of brain metastases of breast cancer.

Methods: Human metastatic brain seeking breast cancer cells were injected in NuNu mice (n = 6-12 per group) which then developed experimental brain metastases. Drug uptake was analyzed in relation to metastasis size and blood-tumor barrier permeability. To investigate in-vivo activity against brain metastases, equimolar doses of the conjugate, and relevant controls (hMTf and BTA) in separate groups were administered biweekly after intracardiac injection of the metastatic cancer cells.

Results: The trastuzumab-melanotransferrin conjugate (BT2111) reduced the number of preclinical human HER breast cancer metastases in the brain by 68% compared to control groups. Tumors which remained after treatment were 46% smaller than the control groups. In contrast, BTA alone had no effect on reducing number of metastases, and was associated with only a minimal reduction in metastasis size.

Conclusions: The results suggest the novel trastuzumab-melanotransferrin conjugate (BT2111) may have utility in treating brain metastasis and validate hMTf as a potential vector for antibody transport across the Blood Brain Barrier (BBB).
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http://dx.doi.org/10.1007/s11095-016-2015-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267937PMC
December 2016

Alterations in Pericyte Subpopulations Are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer.

Clin Cancer Res 2016 Nov 31;22(21):5287-5299. Epub 2016 May 31.

Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.

Purpose: The blood-brain barrier (BBB) is modified to a blood-tumor barrier (BTB) as a brain metastasis develops from breast or other cancers. We (i) quantified the permeability of experimental brain metastases, (ii) determined the composition of the BTB, and (iii) identified which elements of the BTB distinguished metastases of lower permeability from those with higher permeability.

Experimental Design: A SUM190-BR3 experimental inflammatory breast cancer brain metastasis subline was established. Experimental brain metastases from this model system and two previously reported models (triple-negative MDA-231-BR6, HER2 JIMT-1-BR3) were serially sectioned; low- and high-permeability lesions were identified with systemic 3-kDa Texas Red dextran dye. Adjoining sections were used for quantitative immunofluorescence to known BBB and neuroinflammatory components. One-sample comparisons against a hypothesized value of one were performed with the Wilcoxon signed-rank test.

Results: When uninvolved brain was compared with any brain metastasis, alterations in endothelial, pericytic, astrocytic, and microglial components were observed. When metastases with relatively low and high permeability were compared, increased expression of a desmin subpopulation of pericytes was associated with higher permeability (231-BR6 P = 0.0002; JIMT-1-BR3 P = 0.004; SUM190-BR3 P = 0.008); desmin pericytes were also identified in human craniotomy specimens. Trends of reduced CD13 pericytes (231-BR6 P = 0.014; JIMT-1-BR3 P = 0.002, SUM190-BR3, NS) and laminin α2 (231-BR6 P = 0.001; JIMT-1-BR3 P = 0.049; SUM190-BR3 P = 0.023) were also observed with increased permeability.

Conclusions: We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin pericytes and laminin α2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy. Clin Cancer Res; 22(21); 5287-99. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093086PMC
November 2016

Semi-automated rapid quantification of brain vessel density utilizing fluorescent microscopy.

J Neurosci Methods 2016 09 16;270:124-131. Epub 2016 Jun 16.

Texas Tech University Health Sciences Center, School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, TX 79106-1712, USA; West Virginia University Health Sciences Center, School of Pharmacy, Department of Pharmaceutical Sciences, Morgantown, WV 26506, USA. Electronic address:

Background: Measurement of vascular density has significant value in characterizing healthy and diseased tissue, particularly in brain where vascular density varies among regions. Further, an understanding of brain vessel size helps distinguish between capillaries and larger vessels like arterioles and venules. Unfortunately, few cutting edge methodologies are available to laboratories to rapidly quantify vessel density.

New Method: We developed a rapid microscopic method, which quantifies the numbers and diameters of blood vessels in brain. Utilizing this method we characterized vascular density of five brain regions in both mice and rats, in two tumor models, using three tracers.

Results: We observed the number of sections/mm(2) in various brain regions: genu of corpus callosum 161±7, hippocampus 266±18, superior colliculus 300±24, frontal cortex 391±55, and inferior colliculus 692±18 (n=5 animals). Regional brain data were not significantly different between species (p>0.05) or when using different tracers (70kDa and 2000kDa Texas Red; p>0.05). Vascular density decreased (62-79%) in preclinical brain metastases but increased (62%) a rat glioma model.

Comparison With Existing Methods: Our values were similar (p>0.05) to published literature. We applied this method to brain-tumors and observed brain metastases of breast cancer to have a ∼2.5-fold reduction (p>0.05) in vessels/mm(2) compared to normal cortical regions. In contrast, vascular density in a glioma model was significantly higher (sections/mm(2) 736±84; p<0.05).

Conclusions: In summary, we present a vascular density counting method that is rapid, sensitive, and uses fluorescence microscopy without antibodies.
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http://dx.doi.org/10.1016/j.jneumeth.2016.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981522PMC
September 2016

Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer.

Clin Exp Metastasis 2016 Apr 5;33(4):373-83. Epub 2016 Mar 5.

Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA.

The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.
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http://dx.doi.org/10.1007/s10585-016-9784-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804888PMC
April 2016

NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer.

BMC Cancer 2015 Oct 13;15:685. Epub 2015 Oct 13.

Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, WV, 26506-905, USA.

Background: Brain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity.

Methods: Female nude mice were intracranially or intracardially implanted with human brain seeking breast cancer cells (MDA-MB-231Br) and dosed with irinotecan or NKTR-102 to determine plasma and tumor pharmacokinetics of irinotecan and SN38. Tumor burden and survival were evaluated in mice treated with vehicle, irinotecan (50 mg/kg), or NKTR-102 low and high doses (10 mg/kg, 50 mg/kg respectively).

Results: NKTR-102 penetrates the blood-tumor barrier and distributes to brain metastases. NKTR-102 increased and prolonged SN38 exposure (>20 ng/g for 168 h) versus conventional irinotecan (>1 ng/g for 4 h). Treatment with NKTR-102 extended survival time (from 35 days to 74 days) and increased overall survival for NKTR-102 low dose (30 % mice) and NKTR-102 high dose (50 % mice). Tumor burden decreased (37 % with 10 mg/kg NKTR-102 and 96 % with 50 mg/kg) and lesion sizes decreased (33 % with 10 mg/kg NKTR-102 and 83 % with 50 mg/kg NKTR-102) compared to conventional irinotecan treated animals.

Conclusions: Elevated and prolonged tumor SN38 exposure after NKTR-102 administration appears responsible for increased survival in this model of breast cancer brain metastasis. Further, SN38 concentrations observed in this study are clinically achieved with 145 mg/m(2) NKTR-102, such as those used in the BEACON trial, underlining translational relevance of these results.
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http://dx.doi.org/10.1186/s12885-015-1672-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604629PMC
October 2015

Molecular determinants of blood-brain barrier permeation.

Ther Deliv 2015 25;6(8):961-71. Epub 2015 Aug 25.

Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26505, USA.

The blood-brain barrier (BBB) is a microvascular unit which selectively regulates the permeability of drugs to the brain. With the rise in CNS drug targets and diseases, there is a need to be able to accurately predict a priori which compounds in a company database should be pursued for favorable properties. In this review, we will explore the different computational tools available today, as well as underpin these to the experimental methods used to determine BBB permeability. These include in vitro models and the in vivo models that yield the dataset we use to generate predictive models. Understanding of how these models were experimentally derived determines our accurate and predicted use for determining a balance between activity and BBB distribution.
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http://dx.doi.org/10.4155/tde.15.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675962PMC
July 2016

A novel preclinical method to quantitatively evaluate early-stage metastatic events at the murine blood-brain barrier.

Cancer Prev Res (Phila) 2015 Jan 27;8(1):68-76. Epub 2014 Oct 27.

Department of Basic Pharmaceutical Sciences, Health Sciences Center, School of Pharmacy, West Virginia University, Morgantown, West Virginia. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas.

The observation that approximately 15% of women with disseminated breast cancer will develop symptomatic brain metastases combined with treatment guidelines discouraging single-agent chemotherapeutic strategies facilitates the desire for novel strategies aimed at outright brain metastasis prevention. Effective and robust preclinical methods to evaluate early-stage metastatic processes, brain metastases burden, and overall mean survival are lacking. Here, we develop a novel method to quantitate early metastatic events (arresting and extravasation) in addition to traditional end time-point parameters such as tumor burden and survival in an experimental mouse model of brain metastases of breast cancer. Using this method, a reduced number of viable brain-seeking metastatic cells (from 3,331 ± 263 cells/brain to 1,079 ± 495 cells/brain) were arrested in brain one week postinjection after TGFβ knockdown. Treatment with a TGFβ receptor inhibitor, galunisertib, reduced the number of arrested cells in brain to 808 ± 82 cells/brain. Furthermore, we observed a reduction in the percentage of extravasated cells (from 63% to 30%) compared with cells remaining intralumenal when TGFβ is knocked down or inhibited with galunisertib (40%). The observed reduction of extravasated metastatic cells in brain translated to smaller and fewer brain metastases and resulted in prolonged mean survival (from 36 days to 62 days). This method opens up potentially new avenues of metastases prevention research by providing critical data important to early brain metastasis of breast cancer events.
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http://dx.doi.org/10.1158/1940-6207.CAPR-14-0225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311570PMC
January 2015

Complex issues affecting student pharmacist debt.

Am J Pharm Educ 2014 Sep;78(7):131

Harrison School of Pharmacy, Auburn University, Auburn, Alabama.

It is time for colleges and schools of pharmacy to examine and confront the rising costs of pharmacy education and the increasing student loan debt borne by graduates. These phenomena likely result from a variety of complex factors. The academy should begin addressing these issues before pharmacy education becomes cost-prohibitive for future generations. This paper discusses some of the more salient drivers of cost and student debt load and offers suggestions that may help alleviate some of the financial pressures.
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http://dx.doi.org/10.5688/ajpe787131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174373PMC
September 2014

Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study.

Neuro Oncol 2015 Feb 11;17(2):289-95. Epub 2014 Jul 11.

Memorial Sloan-Kettering Cancer Center, New York, New York (A.M., C.G.M., A.S., V.T., A.D.S.); Cleveland Clinic, Cleveland, Ohio (D.M.P., R.J.W.); Texas Tech University Health Sciences Center, Amarillo, Texas (H.R.T., R.S., R.B., P.R.L., Q.R.S.); Center for Cancer Research National Cancer Institute, Bethesda, Maryland (P.S.S.).

Background: Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood-tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy.

Methods: Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m(2)) 2-3 h before surgery or 2-5 doses of lapatinib (1250 mg) daily, the last dose 2-3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry.

Results: Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19-9.8) was noted for lapatinib BCBM-to-serum ratio.

Conclusions: This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.
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http://dx.doi.org/10.1093/neuonc/nou141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288517PMC
February 2015

Novel treatment strategies for brain tumors and metastases.

Pharm Pat Anal 2014 May;3(3):279-96

Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Egypt.

This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood-brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application.
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http://dx.doi.org/10.4155/ppa.14.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465202PMC
May 2014

Pharmacy student debt and return on investment of a pharmacy education.

Am J Pharm Educ 2014 Feb;78(1)

Harrison School of Pharmacy, Auburn University, Auburn, Alabama.

Objective: To describe the current landscape within the profession of pharmacy regarding student tuition, indebtedness, salaries, and job potential.

Methods: Pharmacy tuition and student debt data were obtained through the American Association of Colleges of Pharmacy Institutional Research website. Tuition was defined as average first-year tuition and fees for accredited schools. Debt was defined as the total average amount borrowed. Median salaries and numbers of jobs were obtained from the United States Department of Labor.

Results: In-state tuition at public schools rose an average of $1,211 ± 31 (r2 = 0.996), whereas out-of-state tuition at public schools rose significantly faster at $1,838 ± 80 per year (r2 = 0.988). The average tuition cost for pharmacy school has increased 54% in the last 8 years. The average pharmacist salary has risen from $75,000 to over $112,000 since 2002. The increase in salary has been nearly linear (r2 = 0.988) rising $4,409 ± $170 dollars per year. However, average salary in 2011 was $3,064 below the predicted value based upon a linear regression of salaries over 10 years. The number of pharmacist jobs in the United States has risen from 215,000 jobs in 2003 to 275,000 in 2010. However, there were 3,000 fewer positions in 2012 than in 2011. In 2011, average indebtedness for pharmacy students ($114,422) was greater than average first-year salary ($112,160).

Conclusion: Rising tuition and student indebtedness is a multifaceted problem requiring attention from a number of parties including students, faculty members, universities, and accreditation and government entities.
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http://dx.doi.org/10.5688/ajpe7815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930253PMC
February 2014