Despite significant progress in 5-year survival rates for Non-Hodgkin's Lymphoma (NHL) using conventional treatment standards, there is still a need for improved therapies especially for children and adolescents with advanced-stage disease and for those who relapse after conventional therapy. TRAIL (TNF-related apoptosis-inducing ligand) is an endogenous protein that induces apoptosis selectively in cancer cells by binding to death receptors DR4 or DR5. Our laboratory identified a small molecule, TIC10, that induces TRAIL gene transcription and TRAIL-dependent cell death and overcomes the most critical efficacy-limiting drug properties of available TRAIL-based therapies. Selective advantages of TIC10 include longer half-life, stimulation of TRAIL and death receptor expression, stability, lower production cost, and ability to cross the intact blood-brain barrier. Our lab has reported that TIC10 is orally active and has potent anti-tumor effects in several preclinical models, including prolonging survival of lymphoma-bearing Eu-myc transgenic mice. We hypothesize that TIC10 induces apoptosis in human lymphoma cell lines. We selected a diverse sub-type panel of lymphoma cell lines [BJAB, Daudi, Ramos and Raji (Burkitt's lymphoma); Karpas299 (T-cell NHL), and UPN2 (Mantle Cell lymphoma)] to assess lymphoma sensitivity to TIC10. Cell viability assays demonstrated sharp dose-response curves in all of the above cell lines at 72 hours post-treatment. Quantitative analysis of these relationships yielded TIC10 IC50 values in the range of 1.3 to 2.9 uM, which is comparable to the reported activity of TIC10 in other tumor types. Using low micromolar dose ranges, Daudi and Ramos cell lines were treated with TIC10 and sub-G1 analysis by flow cytometry revealed that TIC10 induced significant levels of apoptosis of both the treated cell lines at 72 hours post-treatment in a dose-dependent manner [Daudi cells: untreated cells: 9.4%; increase in sub-G1 content to 39% (4.3 fold); Ramos cells: untreated cells: 41.4%; increase in sub-G1 content to 72.1% (1.74 fold)]. These preliminary findings suggest that TIC10 induces apoptosis in human lymphoma cell lines at low micromolar concentrations. Our lab has previously established that TIC10 synergizes with several approved antitumor agents such as taxanes and sorafenib in other tumor types. We further hypothesize that TIC10 will have synergistic cytotoxic effects in lymphoma in combination with standard chemotherapeutic agents used to treat lymphoma. We have established monoagent dose-response relationships for gemcitabine, etoposide, doxorubicin and vincristine in the above mentioned lymphoma panel of cell lines. In conclusion, TIC10 is a first-in-class therapy that has apoptotic activity in human lymphoma cells that is promising as a monoagent and may be enhanced by combination with approved therapies to improve the standard of care in this setting.
Citation Format: Mala K. Talekar, Joshua E. Allen, Wafik S. El-Deiry. TRAIL-inducing agent -TIC10 and combinatorial therapeutics in pediatric lymphoma: a targeted approach. [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 LB-307. doi:10.1158/1538-7445.AM2013-LB-307
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