Abstract C070: CLR 180099, a lipid raft targeted phospholipid-drug conjugate, shows potent improved safety and efficacy against colorectal tumors

Abstract

Lipid rafts (LR) are specialized regions or microdomains within the cell membrane that are highly enriched with cholesterol and sphingolipids. The presence of LR in tumor cell membranes is as much as 10 fold higher than in normal tissue. Our phospholipid ether (PLE) molecules [18-(p-iodophenyl)octadecyl phosphocholine] have a high affinity for binding and being transported into cells via LRs(1). In this study, we report the development of CLR 180099, a LR targeting phospholipid-drug conjugate (PDC), consisting of a PLE with a cleavable peptide linker (non-cathepsin cleavage) bound to a flavagline (FLV) analogue, a highly potent inhibitor of cell proliferation and simulator of apoptosis. We first study the presence of LR on a large panel of cancer cell lines. Then, we evaluated the uptake of multiple PLE conjugates in a similar panel of cancer cell lines. Then CLR 180099 was assessed for uptake and the release of the FLV in in vitro tumor cell lines. Finally, we present a series in vitro anti-proliferation assays in multiple cell lines and in vivo tolerability as compared to free FLV and efficacy of CLR 180099 in HCT 116 colorectal cancer xenograft. Presence of LR was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the PDC. Importantly, CLR 180099 demonstrated significant improvement in tolerability of FLV versus free FLV. These results suggest that PLEs could be used to make PDCs that improve tolerability and efficacy of the warhead molecule. The ability to specifically deliver a variety of warheads/payloads to a broad range of tumor cells offers a unique advantage of PDCs. These findings support the continued development of CLR 180099 PDC as a novel targeted therapy. The PDC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this PDC will be available commercially.

Citation Format: Jarrod Longcor, Anatoly Pinchuk, Randall Hoover, John Friend. CLR 180099, a lipid raft targeted phospholipid-drug conjugate, shows potent improved safety and efficacy against colorectal tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C070. doi:10.1158/1535-7163.TARG-19-C070