Abstract 2072: SNDX-275 synergistically inhibits the growth of sarcoma cells when combined with AKT inhibitors, platinum drugs and Topo II poisons.
Authors: Cubitt Christopher L. , Menth Jillaina , Dawson Jana , Goldberg John M. , Reed Damon , Sullivan Daniel M. 
Published: August 2014

The number of effective drugs available for the treatment of soft tissue and bone sarcomas is limited to a small group of antineoplastic agents. Previously, we have identified synergistic anti-tumor activities when the HDAC inhibitor Vorinostat was used in combination with FDA approved chemotherapies. With newer and more selective HDAC inhibitors entering clinical trials we examined the effectiveness of SNDX-275, an inhibitor of HDAC I, II & III when combined with Akt inhibitors and other FDA approved drugs. CT-Blue cell viability experiments were performed to first obtain IC50s for 72 hour treatments. IC50s for SNDX-275 ranged from 0.84 to 11.4 μM (Table). SNDX-275 alone and in combination with the drugs listed in the Table showed synergistic cooperativity in viability experiments. Using Chou and Talalay's Combination Index (CI) analyses (ED levels of 0.7, 0.9 & 0.95), a synergistic or strongly synergistic reduction in cell viability (CI &lt;0.7) was observed in most combinations tried in the majority of cell lines. Synergy was observed over a wide dose range and remained synergistic when as little as 0.5 μM of SNDX-275 was used in the combination. Ongoing experiments are underway to identify the effects of SNDX-275 combinations on apoptosis and the effect of drug sequencing on growth inihibition. The results of this study indicate that a drug combination including SNDX-275 may be an effective treatment regimen for sarcoma patients. Funded by the Pediatric Cancer Foundation.

Table. IC50s and Chou and Talalay Combination Index (CI) Synergy Analysis. Inhibitory concentration of SNDX-275 required for 50% reduction in viable cells after 72 hour treatment (IC50). CI values represent the level of synergy resulting from concurrent SNDX-275 plus indicated combination treatment. +/- symbols indicate calculated CI synergy level.

SNDX-275 MK-2206 Triciribine Carboplatin Cisplatin Etoposide sarcoma type cell line IC50 (μM) CI Syn CI Syn CI Syn CI Syn CI Syn osteosarcoma MNNG HOS 4.9 0.393 +++ 0.384 +++ 0.214 ++++ 0.037 +++++ 0.252 ++++ U2-OS 1.8 1.025 +/− 0.391 +++ 0.379 +++ rhabdomyosarcoma A-204 2.4 0.305 +++ 0.328 +++ 0.908 +/− 0.815 ++ Ewing type A-673 11.4 0.350 +++ 0.029 +++++ 0.185 ++++ RD-ES 1.5 0.962 +/− SK-ES-1 0.84 0.284 ++++ 0.293 ++++ 0.459 +++ 0.593 +++ 1.278 −− leiomyosarcoma SK-LMS-1 4.3 0.029 +++++ 0.510 +++ SK-UT-1 3.4 0.332 +++ 0.845 ++ 0.099 +++++ 0.082 +++++ 0.985 +/− liposarcoma SW-872 1.6 0.286 ++++ 0.540 +++ 0.511 +++ 0.457 +++ 0.617 +++ fibrosarcoma HT-1080 5.7 0.179 ++++ 0.060 +++++ 0.038 +++++ 0.267 ++++

Citation Format: Christopher L. Cubitt, Jillaina Menth, Jana Dawson, John M. Goldberg, Damon Reed, Daniel M. Sullivan. SNDX-275 synergistically inhibits the growth of sarcoma cells when combined with AKT inhibitors, platinum drugs and Topo II poisons. [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 2072. doi:10.1158/1538-7445.AM2013-2072