A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance.

A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence.

A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

Purpose: High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs.

Potentiation of temozolomide activity against glioblastoma cells by aromatase inhibitor letrozole.

Purpose: The DNA alkylating agent temozolomide (TMZ), is the first-line therapeutic for the treatment of glioblastoma (GBM). However, its use is confounded by the occurrence of drug resistance and debilitating adverse effects. Previously, we observed that letrozole (LTZ), an aromatase inhibitor, has potent activity against GBM in pre-clinical models.

Letrozole targets the human ether-a-go-go-related gene potassium current in glioblastoma.

Aberrant expression of human ether-a-go-go-related gene (hERG) potassium channels has been implicated in the pathophysiology of glioblastoma (GBM). Letrozole has demonstrated efficacy in pre-clinical GBM models. The objective of this research was to assess the potential for hERG inhibition by letrozole to mediate efficacy in GBM.

CYP2B6 Genotype-Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers.

We investigated the effect of efavirenz on the activities of cytochrome P450 (CYP)1A2, CYP2A6, xanthine oxidase (XO), and N-acetyltransferase 2 (NAT2), using caffeine as a probe. A single 150 mg oral dose of caffeine was administered to healthy volunteers (n = 58) on two separate occasions; with a single 600 mg oral dose of efavirenz and after treatment with 600 mg/day efavirenz for 17 days. Caffeine and its metabolites in plasma and urine were quantified using liquid chromatography/tandem-mass spectrometry.

Model-Informed Dosing of Venetoclax in Healthy Subjects: An Exposure-Response Analysis.

Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B-lymphocyte counts as an on-target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B-lymphocyte levels to inform dosing of venetoclax in healthy subjects.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.

Introduction: Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics.

Accelerating Drug Development in Pediatric Oncology With the Clinical Pharmacology Storehouse.

Pediatric drug development is a challenging process due to the rarity of the population, the need to meet regulatory requirements across the globe, the associated uncertainty in extrapolating data from adults, the paucity of validated biomarkers, and the lack of systematic testing of drugs in pediatric patients. In oncology, pediatric drug development has additional challenges that have historically delayed availability of safe and effective medicines for children. In particular, the traditional approach to pediatric oncology drug development involves conducting phase 1 studies in children once the drug has been characterized and in some cases approved for use in adults.

Model-based meta-analysis of progression-free survival in non-Hodgkin lymphoma patients.

Background: Non-Hodgkin lymphoma (NHL) is a group of lymphoproliferative malignancies with varying treatment responses and progression-free survival (PFS) times. The objective of this study was to quantify the effect of treatment and patient-population characteristics on PFS in patients with NHL.

Methods: A database was developed from 513 NHL clinical trials reported from 1993 to 2015.

Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas.

We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor-positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells served as controls.

The pharmacokinetics of letrozole in brain and brain tumor in rats with orthotopically implanted C6 glioma, assessed using intracerebral microdialysis.

Purpose: Emerging evidence suggests that primary and metastatic brain tumors may be sensitive to hormonal manipulations. However, the pharmacokinetics of compounds against such targets in the brain and, more importantly, in the brain tumor are not well characterized. Here, we investigated the pharmacokinetics of letrozole, a third-generation aromatase inhibitor, in the normal brain and in orthotopically implanted C6 glioma in Sprague-Dawley rats.

Solubilization of flurbiprofen into aptamer-modified PEG-PLA micelles for targeted delivery to brain-derived endothelial cells in vitro.

Novel aptamer-functionalized polyethylene glycol-polylactic acid (PEG-PLA) (APP) micelles were developed with the objective to target the transferrin receptor on brain endothelial cells. Flurbiprofen, a potential drug for therapeutic management of Alzheimer's disease (AD), was loaded into the APP micelles using the co-solvent evaporation method. Results indicated that 9.

The pharmacokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects.

Background: Ghrelin stimulates GH secretion and regulates energy and glucose metabolism. The two circulating isoforms, acyl (AG) and des-acyl (DAG) ghrelin, have distinct metabolic effects and are under active investigation for their therapeutic potentials. However, there is only limited data on the pharmacokinetics of AG and DAG.