Abstract LB-383: Translational studies of the novel prodrug PI3K/mTOR/PIM1 inhibitor SF1126 in DLBCL
Authors: Joseph Garlich, Wenqing Qi, Michael Becker, Amy Stejskal, Daruka Mahadevan
Journal: Cancer Research (2011)

Abstract Background: While selective inhibition of the δ PI3K isoform has demonstrated clinical efficacy in some B-cell malignancies (except diffuse large B-cell lymphoma, DLBCL) recent studies suggest that inhibition of all Class IA isoforms (α, β, δ) will be essential to produce maximal inhibition of cell proliferation and induce apoptosis. mTOR inhibitors have demonstrated promising clinical activity in DLBCL. Additionally, PIM1 has become a target of interest in various malignancies including DLBCL. Recent preclinical studies indicate synergy between pan-PI3K and PIM1 inhibitors suggesting enhanced efficacy might be found in a molecule that inhibited mTOR/PI3K as well as PIM1. Objectives: SF1126 is designed to overcome potential toxicity due to simultaneous inhibition of mTOR and all PI3K isoforms by accumulating preferentially in tumor tissue. SF1126 is a peptidic prodrug that converts to LY294002, a pan-PI3K inhibitor that also significantly inhibits mTOR kinase along with PIM1 and is thought to generate oxidative stress in cancer cells in a PI3K independent manner. SF1126 has completed a phase I study in refractory solid tumors, now expanded to include patients with B-cell malignancies and recent results in CLL look encouraging (ASH 2010). Because of the potential for enhanced efficacy of an mTOR/PI3K/PIM1 inhibitor in DLBCL an increased focus on this disease is warranted. The objectives of the current study are: 1) to determine if SF1126 can generate oxidative stress in cancer cells; 2) to characterize the in vitro effect of the multi-kinase inhibitor SF1126 on DLBCL cell lines (as a single agent and in combination with rituximab) and compare to results obtained with a δ PI3K isoform selective inhibitor (CAL-101). These translational studies are designed to guide the clinical evaluation of SF1126 as a single agent and in combination with rituximab in DLBCL patients. Methods: Cell viability assays (MTS) and apoptosis by flow cytometry and PARP-cleavage were employed to evaluate the effect of SF1126 and CAL-101 on DLBCL cell lines TMD8 and SUDHL4 alone and in combination with rituximab. Western blotting for dose- and time-dependent de-phosphorylation of Akt and PIM1 with SF1126 or CAL-101 alone or with rituximab are performed. The Oxidative Stress Kit (BioMol; Cat. AK150–0001) was used in accordance with the manufacturer's instructions. Results: Using a method that quantitates peroxidation of lipids it was determined that over a 24-hour period of exposure SF1126 generated more than a 12-fold increase in oxidative stress in the prototype cancer cell line LnCAP. Results anticipated are that in DLBCL cell lines SF1126 shows: 1) apoptosis increases and proliferation inhibition as a single agent and amplification in combination with rituximab; 2) superiority to CAL-101. These effects may be due to the combined inhibition of pan-PI3K/ mTOR and PIM1 found uniquely in SF1126. [Funded in part by Lymphoma SPORE 1 P50 CA 130805 01A1] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-383. doi:10.1158/1538-7445.AM2011-LB-383