| Popis: |
Background: Alterations in tumor cell metabolism are one of the central processes guiding cancer progression. The increased glucose dependence of cancer cells, also known as the Warburg effect, opens the possibility to therapeutically target the glycolytic pathway and challenge the metabolic needs of tumor cells. We generated 24 monoclonal antibodies targeting the main glucose transporter on cancer cells - SLC2A1 (GLUT1). We evaluated the ability of the antibodies to affect cancer cell fitness alone and in combination with OXPHOS inhibitors to find clinically applicable therapeutics targeting tumor metabolism. virus like particle (VLP)-based immunization strategy (Kivi, et al., BMC Biotechnology, 2016). Antibodies were functionally characterized by 2-deoxyglucose uptake interference assay and sensitivity to antibody single and combination treatments were evaluated in various tumor cell lines. Metabolomics and oxygen consumption rates were examined as mechanistic endpoints for tumor cell lines and primary tumor samples. Results: The anti-SLC2A1 antibodies specifically bind to SLC2A1 with low nanomolar EC50 values and not to other glucose transporters. Antibody clones with functional properties inhibit glucose uptake leading to reduced metabolic activity and growth inhibition in a subset of cancer cell lines. A drastic cell proliferation inhibition is moreover observed in combination of anti-SLC2A1 antibodies and OXPHOS inhibitors metformin, phenformin or IACS-010759 in 2D cultures of colon, breast and pancreatic cancer cell lines. The inhibition of metabolic activity was further confirmed in an ex vivo primary patient tissue samples highlighting the putative translational applicability of our antibodies. Conclusions: This is the first study to provide highly specific antibodies bocking the function of SLC2A1 transporter and demonstrate the proof of principle for inhibiting complex muti-pass membrane transporters with antibody therapeutics. While the developed anti-SLC2A1 antibodies could be efficacious in some indications as single agents, appreciable clinical activity could be obtained by the combined use with OXPHOS inhibitors. Citation Format: Siret Tahk, Kai Virumäe, Paule Hermet, Korneelia Anton, Maiken Abel, Denis Belitškin, Luciano Galdieri, Steven Garner, Jillian Krings, Kaleb Collver, Emily Hoehn, Brendan Lahm, Kaitlyne Powers, Tuuli Käämbre, Alastair J. King, Francisca Neethling, Anu Planken, Mart Ustav, Andres Männik, Mart Ustav. Functional antibodies against multi span transmembrane proteins - revisiting the Warburg effect in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6036. |
