Abstract 2949: Characterization of TIC10, a novel small molecule inducer of TRAIL, in combination with chemotherapy for lymphoma in vitro. (2013)

Abstract TNF-related apoptosis inducing ligand (TRAIL; Apo2L) is an endogenously-expressed protein that selectively induces apoptosis in a range of human cancer cell lines. Several strategies to therapeutically exploit the desired anti-tumor effects of TRAIL are under investigation. Our laboratory has recently identified TIC10, a small molecule inducer of TRAIL. TIC10 has been shown to cause p53-independent induction of the TRAIL gene, and to induce TRAIL-mediated apoptosis. TIC10 exhibits a favorable therapeutic index, and induces TRAIL in tumor, stromal, and normal cells. TIC10 has further been shown to effectively potentiate anti-tumor effects against several glioblastoma multiforme cell lines. TRAIL-activating therapies have shown promising anti-tumor activity against lymphoma in the preclinical setting. These results have served as the basis for clinical trials using TRAIL-based therapies. TIC10 has been shown to prolong survival of lymphoma-bearing Eu-Myc transgenic mice, and we have previously demonstrated that c-Myc is a major determinant of TRAIL sensitivity. Utilizing SubG1 analysis, we have generated preliminary data demonstrating that TIC10 induces apoptosis of human lymphoma cells in vitro. Granta cells (mantle cell lymphoma) treated with TIC10 (10μM) demonstrated an approximate three-fold increase in SubG1 content compared with untreated cells at 72 hours (12.8% in the untreated group and 38.7% in the TIC10-treated group). Likewise, Daudi cells (Burkitt's lymphoma) treated with TIC10 (10μM) exhibited significantly increased SubG1 content at 72 hours (32.3%) compared to control (19.2%). We are assaying for cleaved PARP as a marker of apoptosis by Western blot in Daudi and Granta cells treated with a dose range of TIC10. Based upon TIC10’s ability to prolong survival in lymphoma-bearing mice, and its ability to induce apoptosis in human lymphoma cell lines in vitro, we are currently evaluating its synergistic potential in combination with chemotherapy for lymphoma in vitro. We hypothesize that chemotherapeutic agents will sensitize tumor cells to TRAIL-sensitive oncogenic drivers of lymphomagenesis. Specifically, we are assessing TIC10 in combination with cyclophosphamide, doxorubicin, vincristine, etoposide, bleomycin, and rituximab against the Granta and Daudi lymphoma cell lines. Inhibition curves for both Daudi and Granta cell lines treated with the above agents as monotherapy have been generated using a luminescent cell viability assay, and IC50 values are being calculated from these experiments. We are planning further studies to characterize mechanisms of cell death in synergistic treatment combinations. Data gathered from these ongoing studies of TIC10 in combination with chemotherapy will be directly applicable to the translation of TIC10 to the clinical setting. Citation Format: Gavin H. Imperato, Joshua E. Allen, Wafik S. El-Deiry. Characterization of TIC10, a novel small molecule inducer of TRAIL, in combination with chemotherapy for lymphoma in vitro. [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 2949. doi:10.1158/1538-7445.AM2013-2949 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.