The effectiveness of current approaches to cancer therapy is often limited by off-target toxicity or, if relatively selective, by lack of drug target expression in tumors. To address these shortcomings, structure-activity relationship studies were undertaken and identified a series of iodophenyl-containing phospholipid ether (PLE) analogs that selectively accumulate in cancer cells/cancer stem cells compared to normal cells/stem cells, in vitro and in vivo. Isosteric iodine substitution in CLR1404 affords either a diagnostic/imaging agent (e.g. using 124I for cancer-selective PET imaging) or a molecular radiotherapeutic agent (e.g. using 131I for cancer-selective cytotoxicity), both of which are in clinical development. We suggest the term “diapeutic” to describe such drugs which can be used in one form to identify and characterize patients who will benefit from a specific therapy and, in another form, to effect that therapy. Here we describe the broad-spectrum efficacy of the 131I-labeled homolog of one such diapeutic compound (CLR1404) in human tumor xenograft models in mice including Caki-2 (renal; clear cell carcinoma), HCT-116 (colorectal carcinoma), Ovcar-3 (ovarian adenocarcinoma), MDA-MB-231 (triple negative mammary gland adenocarcinoma, MES-SA/Dx5 (uterine sarcoma), U87 (glioma), Mia Paca-2 (pancreatic carcinoma) and PC-3 (prostate carcinoma). In these models, a single i.v. injection of 131I-CLR1404 (100 αCi, 3.8 μg/mouse) resulted in significant tumor growth suppression and extension of survival. A separate radiotoxicology study in normal rats followed for six months or until death after a single dose of 131I-CLR1404 did not find significant radiation toxicity below 5 mCi suggesting that 131I-CLR1404 may display an acceptable therapeutic index in man. At 100-fold higher mass dose (380 μg/mouse, i.v.) CLR1404, the non-radioactive, 127I-containing homolog, was also highly efficacious in human tumor mouse xenograft models including MDA-MB-231 (triple negative breast cancer) and A549 (non-small cell lung cancer). CLR1404 inhibited proliferation of multiple human cancer cell lines in vitro with an IC50 of ∼5 μM compared to ∼50 μM for growth suppression of normal fibroblasts. Similar concentrations inhibited the PI3K/Akt cell signaling pathway and stimulated pro-apoptotic caspases in human cancer cell lines but not in normal fibroblasts. Thus, 131I-CLR1404 and CLR1404 each combine wide-ranging, cancer cell-selective targeting with cytotoxicity mechanisms known be broadly effective (intracellular radiation or PI3K/Akt inhibition, respectively). As such, both agents have the potential to provide effective, well-tolerated therapy across numerous cancer types.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3831. doi:1538-7445.AM2012-3831