Abstract LOR-253 is a potent and selective growth inhibitor of several cancer types, including non-small cell lung cancer (NSCLC), colon cancer and leukemia. LOR-253 stimulates Krüppel Like Factor-4 (KLF-4), a tumor suppressor factor which is characteristically deficient in a variety of cancers, and so represents a new approach to cancer therapy. The current Phase I dose-escalation study is being conducted at Memorial Sloan-Kettering Cancer Center in New York and MD Anderson Cancer Center in Houston. In the present preclinical study, the changes in KLF-4 expression levels were evaluated in vivo to examine the utility of KLF-4 as a pharmacodynamic biomarker, aiming at linking the antitumor effects of LOR-253 to the induction of KLF-4. In the human H226 NSCLC xenograft mouse model, LOR-253 demonstrated dose-dependent antitumor activity when administered at 1, 5, and 15 mg/kg and mediated significant tumor growth inhibition of about 55% at the highest dose given by intravenous bolus injection (p=0.05). Tumors were harvested 24h after the last dose following the treatments at 1, 5, and 15 mg/kg and KLF-4 mRNA and protein levels were analyzed by real-time RT-PCR and Western blot, respectively. A dose-dependent induction of KLF-4 mRNA and protein levels was observed. Pharmacodynamic studies to characterize the effect of LOR-253 on intratumoral KLF-4 were also conducted in the H226 NSCLC xenograft mouse model to determine the optimal time point for tumor biopsy sampling, following the treatment schedule in the ongoing Phase 1 clinical trial (2 days dosing, 12 day break, 2 days of dosing, 12 day break (1 cycle)). Tumor samples were taken 24h after the second, fourth and eighth dose of LOR-253 and analyzed for KLF-4 expression. It was determined that tumor sampling after the second and eighth doses was optimal at demonstrating increased intratumoral KLF-4 levels. Furthermore, antitumor efficacy of LOR-253 was also evaluated in nude rats bearing established human H226 NSCLC tumors when LOR-253 was infused intravenously following the current Phase I clinical dosing schedule. A significant efficacy was observed at the end of the first cycle of treatment, demonstrating 44% decrease in mean tumor volume when compared with the control treatment (p=0.025). Inhibition of tumor growth was paralleled by the induction of KLF-4 in isolated tumors when analyzed by real-time RT-PCR and Western blot. Taken together, the in vivo data obtained in both mouse and rat models provide strong preclinical support for utilizing KLF-4 as a potential pharmacodynamic biomarker for LOR-253 treatment in clinic. Citation Format: Howard Cukier, Robert Peralta, Hongnan Jin, Yu Cheng, Venkata Nedunuri, Salah Salehi, Yoon S. Lee, Aiping Young. Utilization of KLF-4 as a pharmacodynamic biomarker for in vivo anticancer activity of a novel small molecule drug LOR-253. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4649. doi:10.1158/1538-7445.AM2013-4649
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