Abstract PO-003: Mitotic enrichment as an efficient radiosensitization strategy

Radiotherapy remains one of the most effective modalities for anticancer treatment. Boosting the efficacy of radiotherapy is therefore a logical avenue to improve patient survival. We have developed a radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends to a large extent on the phase of the cell cycle and that especially mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied fractionated radiotherapy regimens. We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. Most importantly, this tubulin inhibitor efficiently radiosensitizes a range of preclinical glioblastoma models in vitro and in vivo and significantly improves survival, but only in a mitotic enrichment setup when given several hours prior to radiotherapy to allow accumulation in mitosis. We have initiated development of mitotic enrichment for GBM, the most common primary malignant brain tumor. Their location and highly aggressive nature renders GBM among the most deadly and devastating of human malignancies. Despite extensive treatment involving surgery and adjuvant chemo-radiotherapy, prognosis is still dismal and novel treatment strategies are urgently needed. Of all available adjuvant therapies, radiotherapy contributes most to extending overall survival. Increasing the efficacy of existing radiotherapeutic regimens therefore offers a logical rationale to improve the survival of GBM patients. We are currently also expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other mitotic targets and different cancers for which radiotherapy is a mainstay treatment and have thus far achieved promising results in vitro. In parallel, we are preparing a phase 0 trial to demonstrate induction of mitotic enrichment in human GBM. Citation Format: Mark C. de Gooijer, Paul L.G. Slangen, Hilal Colakoglu, Ceren H. Citirikkaya, Amal El Ouazani, Ronak Shah, Gerben R. Borst, Olaf van Tellingen. Mitotic enrichment as an efficient radiosensitization strategy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-003.