Abstract B125: A novel BBB-permeable chemotherapeutic agent for the treatment of CNS tumors

Abstract

Abstract Standard of care for glioblastoma multiforme (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide. Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme MGMT and are temozolomide-insensitive, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) remains an obstacle to adequate delivery of chemotherapeutic agents to brain tumors. Lipophilic drugs such as temozolomide and lomustine are able to cross the BBB based on passive diffusion; however, their tissue distribution also causes toxicity to critical systemic organs, such as the bone marrow, leading to dose-limiting toxicity. Therefore, BBB-permeable chemotherapeutic agents that are efficacious in temozolomide-insensitive and refractory patients are needed. The large amino acid transporter 1 (LAT1) is highly expressed on the BBB and in GBM and other malignant brain tumors such as diffuse intrinsic pontine glioma (DIPG), where it is associated with poor prognosis, but is undetectable in normal brain tissue. Targeting LAT1 transport, while avoiding interaction with other closely related transporters expressed on normal tissue such as LAT2, will target brain tumors and avoid uptake into healthy tissue. We report the generation of a novel molecule (QBS10072S) that combines a potent cytotoxic domain with the structural features of a selective LAT1 substrate. QBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays, and demonstrates significant in vitro cytotoxicity to LAT1-expressing GBM cell lines and minimal cytotoxicity to normal human astrocytes (LAT1-negative). Unlike temozolomide, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic glioblastoma xenografts, QBS10072S causes significant delay in tumor growth and increase in mouse survival compared to vehicle. QBS10072S is well tolerated, with no toxicity seen in normal brain or the BBB. In summary, QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat temozolomide-insensitive and recurrent GBM. Citation Format: Theodore P. Nicolaides, Tomoko Ozawa, Tsun Wen Yao, Michael Prados, Wolf-Nicolas Fischer, Bernd Jandeleit, Kerry Koller. A novel BBB-permeable chemotherapeutic agent for the treatment of CNS tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B125.