Abstract A111: The alkyl phosphocholine analog CLR1404 delays radiation-induced dsDNA damage repair in pediatric and adult solid tumors

Abstract

Abstract Exposure of normal tissues to radiation is a major limitation in cancer radiotherapy, with significant consequences particularly in the pediatric setting. Increasing the selective anticancer effect of radiation on malignant cells utilizing cancer-targeted drugs could provide an option to lessen adverse radiation effects on healthy tissue. We investigated the radiosensitizing properties of 18-(p-iodophenyl) octadecyl phosphocholine (CLR1404), a clinical-grade phospholipid ether analog with selective sequestration in cancer cells, in pediatric and adult human solid tumor cell lines. Preliminary data in our laboratory using a fluorescently-labeled analog indicated that human cancer cells uptake and retain 6- to 10-fold more CLR1404 when compared with normal primary cells. In vitro, the clonogenic survival of tumor cells after irradiation was significantly decreased when cells were pretreated with CLR1404. This radiosensitizing effect was detected also in vivo, in xenograft-bearing mice treated with CLR1404 during fractionated radiation, resulting in decreased tumor volumes and markedly delayed tumor regrowth in CLR1404-treated mice compared to controls. We investigated mechanisms responsible for the radiosensitizing properties of CLR1404. Western blotting of tumor cell lysates indicated increased accumulation and prolonged persistence of γ-H2AX in irradiated tumor cells pretreated with CLR1404 compared to nontreated controls. Expression of select markers of homologous and non-homologous end-joining dsDNA radiation damage repair pathways were markedly decreased and significantly delayed in CLR1404-treated tumor cells after exposure to irradiation compared to non-CLR1404-treated cells. CLR1404 treatment also markedly decreased the activation of p53 after irradiation in p53-functional rhabdomyosarcoma cells compared to cells treated with radiation alone. In conclusion, our data show that, in both pediatric and adult human solid tumor cell lines, the alkyl phosphocholine analog CLR1404 interferes with sensing of dsDNA damage, delays DNA damage repair, and potentially interferes with other cell survival mechanisms, for example involving p53. These mechanisms might be responsible for the observed in vitro and in vivo radiosensitizing properties of CLR1404. Tumor-targeted radiosensitization with CLR1404 could improve the selective antitumor effect of radiation, and provide a distinct therapeutic benefit to cancer patients. Citation Format: Ankita Shahi, Mohamed Y. Elsaid, Dana C. Baiu, Eric A. Armstrong, Jamey P. Weichert, Paul M. Harari, Mario Otto. The alkyl phosphocholine analog CLR1404 delays radiation-induced dsDNA damage repair in pediatric and adult solid 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 A111.