Summary: CXR1002 is an ammonium salt of perfluorooctanoic acid. It has a unique pharmacokinetic, pharmacologic and toxicity profile and induces cell death in a wide range of human tumor cells in vitro and in vivo. CXR1002 causes an ER stress response, acts as a fatty acid mimetic, and binds to PPARs in both an agonistic and antagonistic manner. The aim of this study was to explore further its mechanism of action in vitro, and to determine its cytotoxicity both in vitro and in vivo. Methods: In vitro cytotoxicity of CXR1002 was determined using an ATP depletion assay, alone and and in combination with 12 other drugs in a panel of tumor cell lines. The mode of action was examined using microarray analysis (followed by analysis using the Ingenuity system), transactivation assays and western blots. Four CXR1002 xenograft studies (25 mg/kg p.o. 3x per week) were performed in nu/nu mice. Results: CXR1002 was cytotoxic to a wide range of human tumor cells, including pancreatic and ovarian carcinoma and sarcoma. The IC50 value was lower after 7 days vs 2 days exposure (range 229 - 625 μM vs 300 - >1000 μM), suggesting potency was linked to duration of exposure. IC50 values were comparable to the plasma concentrations achieved with a non-toxic dose in an on-going Phase I trial. Drug combination studies with 12 anti-cancer drugs in 11 human cancer cell lines indicated that CXR1002 was synergistic with other anti-tumor drugs, particularly doxorubicin, gemcitabine, geldanamycin, MAPK inhibitors and AKT/PI3K inhibitors, but it was antagonistic when combined with rapamycin. In transactivation assays CXR1002 was an agonist of PPARα, and to a lesser extent PPARγ, but it demonstrated antagonist activity against PPARδ, in the presence of bezafibrate. Microarray studies in the pancreatic cell line PANC-1 treated with an IC15 dose of CXR1002 showed 4996 gene changes. Representation analysis of the 4996 signature list identified a number of pathways that were over-represented, in particular, genes in the ER stress pathway, including the ATF family of transcription factors. Western blot analysis of PANC-1 cells using PCNA and cleaved PARP antibodies showed that PCNA was reduced and cleaved PARP increased 24 hr after treatment with 450 μM CXR1002, suggesting a pro-apoptotic/anti-proliferative outcome. CXR1002 was active in all 4 human xenograft (i.e. pancreatic, liver, prostate and colon) models examined with best absolute tumor volume as a % of control of 50.13%, 77.05%, 19.14% and 49.22% respectively. Conclusions: CXR1002 is a unique potential anti-cancer therapy that exhibits unique pharmacokinetics and a wide spectrum of biological activities. CXR1002 appears to act in part by its ability to induce ER stress. A Phase I human trial is on-going.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3566.