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Development of a Blood Brain Barrier Permeability Database for Investigational Anti-Cancer Agents for Use in Glioblastoma Research

Description

Glioblastoma (GBM) is an extremely malignant form of brain cancer characterized by rapid progression and poor patient survival. Even after standard of care treatments, less than ten percent of patients

Glioblastoma (GBM) is an extremely malignant form of brain cancer characterized by rapid progression and poor patient survival. Even after standard of care treatments, less than ten percent of patients with this disease survive five years. More effective therapeutic options are urgently needed to improve outcomes for patients with GBM. Adequate drug delivery is a critical challenge in GBM treatment, as drugs delivered systemically must be able to penetrate the blood brain barrier (BBB) and reach the tumor at therapeutic levels. To address this, we developed a resource to catalog BBB penetration information for investigational agents currently in clinical trials in cancer. Using an in silico prediction model and manual annotation to capture existing knowledge from the published literature, BBB content for ~500 investigational drugs was added to the investigational database tool. In addition to BBB content, the database also includes information on the gene targets of the included therapies. The investigational database tool was used to identify investigational agents that (1) may have increased activity against GBM based on the presence of a specific mutation in the tumor sample and (2) have evidence suggesting the compounds may penetrate the BBB. By prioritizing investigational agents for further study based on evidence for BBB penetration, this resource can help the GBM research community pursue more effective treatments for GBM.

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Date Created
  • 2016-05

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Evaluating Efficacy of Repurposed Drugs in Treatment of Glioblastoma

Description

Glioblastoma (GBM) is the most aggressive adult brain tumor with a devastating median survival time of about fourteen months post-surgery and standard of care therapy with radiation and temozolomide. The

Glioblastoma (GBM) is the most aggressive adult brain tumor with a devastating median survival time of about fourteen months post-surgery and standard of care therapy with radiation and temozolomide. The low incidence of GBM, cost of developing novel therapeutics, and time cost of clinical trials are dis-incentives to develop novel therapies. To overcome that obstacle, we investigated the efficacy of repurposing four FDA approved drugs known to cross the blood brain barrier (BBB), minocycline, propranolol, chlorpromazine, and metformin, to inhibit signaling and metabolism in GBM cells.
Minocycline is a tetracycline class broad spectrum antibiotic commonly used to treat severe acne and other skin infections. Propranolol is a beta blocker type heart medication primarily used to treat high blood pressure and irregular heartbeat. Chlorpromazine is a phenothiazine antipsychotic usually used for schizophrenia. Metformin is the most widely used first-line oral treatment for type-2 diabetes. Based on a literature survey, minocycline is expected to prevent the phosphorylation of STAT3, a transcription factor downstream of EGFR; propranolol is expected to disrupt EGFR trafficking; chlorpromazine is expected to target the PI3K/mTOR/Akt signaling pathway; metformin is believed to exploit vulnerabilities in cancer cell metabolism, as well as upregulate AMPK against the PI3K/mTOR/Akt pathway.
Efficacy of minocycline in inhibiting EGFR-driven STAT3 activation was investigated using western blot analysis. Our results demonstrate that Minocycline effectively inhibits activation of EGFR-driven STAT3 in U373 glioma cells at 100μM. The ability of chlorpromazine to inhibit the PI3K/mTOR/Akt pathway was similarly tested via western blot, which showed inhibition of phosphorylated Akt and S6 at 10μM. Efficacy of propranolol in perturbing EGFR trafficking was evaluated using flow cytometry and immunofluorescence, which failed to depict altered membrane-associated EGFR abundance. Finally, concentration-dependent inhibition of colony formation was tested for all four drugs. Propranolol and minocycline showed potential biphasic stimulatory effects at 10μM, but all drugs inhibited cell growth at 50μM and higher. Efficacy of these drugs in the treatment of GBM is being further evaluated using in vitro neurosphere cultures from patients identified as having the cellular vulnerabilities potentially targeted by these drugs. Successful completion of this project will lead to in vivo efficacy testing of these four drugs in orthotopic GBM PDX models.

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Date Created
  • 2019-05