A Novel Blood-Brain Barrier-Permeable Chemotherapeutic Agent for the Treatment of Glioblastoma

Tomoko Ozawa; Mirna Rodriguez; Guisheng Zhao; Tsun Wen Yao; Wolf-Nicolas Fischer; Bernd Jandeleit; Kerry Koller; Theodore Nicolaides

doi:10.7759/cureus.17595

A Novel Blood-Brain Barrier-Permeable Chemotherapeutic Agent for the Treatment of Glioblastoma

Cureus. 2021 Aug 31;13(8):e17595. doi: 10.7759/cureus.17595. eCollection 2021 Aug.

Authors

Tomoko Ozawa¹, Mirna Rodriguez², Guisheng Zhao³, Tsun Wen Yao⁴, Wolf-Nicolas Fischer², Bernd Jandeleit², Kerry Koller², Theodore Nicolaides³

Affiliations

¹ Neurological Surgery, University of California San Francisco, San Francisco, USA.
² Science, Quadriga BioSciences, Los Altos, USA.
³ Pediatric Hematology-Oncology, New York University (NYU), New York, USA.
⁴ Science, Bristol Myers Squibb, San Diego, USA.

Abstract

Introduction The standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) and are TMZ-resistant, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) is an obstacle to the delivery of chemotherapeutic agents to GBM, and BBB-permeable agents that are efficacious in TMZ-resistant and refractory patients are needed. The large amino acid transporter 1 (LAT1) is expressed on the BBB and in GBM and is detected at much lower levels in normal brain tissue. A LAT1-selective therapeutic would potentially target brain tumors while avoiding uptake by healthy tissue. Methods We report a novel chemical entity (QBS10072S) that combines a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate and tested it against GBM models in vitro and in vivo. For in vitro studies, DNA damage was assessed with a gamma H2A.X antibody and cell viability was assessed by WST-1 assay and/or CellTiter-Glo assay. For in vivo studies, QBS10072S (with or without radiation) was tested in orthotopic glioblastoma xenograft models, using overall survival and tumor size (as measured by bioluminescence), as endpoints. Results QBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays and demonstrates significant growth suppression in vitro of LAT1-expressing GBM cell lines. Unlike TMZ, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic GBM xenografts, QBS10072S treatment significantly delayed tumorigenesis and prolonged animal survival compared to the vehicle without adverse effects. Conclusion QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat TMZ-resistant and recurrent GBM as monotherapy or in combination with radiation treatment.

Keywords: blood brain barrier; glioblastoma; lat1; qbs10072s; temozolomide.

Abstract

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