Program: Oral and Poster Abstracts
Session: 802. Chemical Biology and Experimental Therapeutics: Poster III
The OncoPanelTM high content screening platform was used to evaluate the cytotoxicity of SL-801 against 205 solid tumor and 35 liquid tumor cell lines. SL-801 demonstrated potent activity, with 50% growth inhibitory (GI50) values ≤ 10 nM in 51/240 (21.3%) cell lines and GI50 values ≤ 100 nM in 230/240 (95.8%) cell lines. SL-801 sensitivity was independent of cell proliferation rate or XPO1 expression levels. While SL-801 was broadly cytotoxic, cell lines of hematopoietic origin exhibited greater sensitivity. GI50s in hematologic cancers ranged from 3-93 nM in leukemias, 1-103 nM in lymphomas, and 3-11 nM in multiple myelomas. SL-801 also inhibited solid tumor growth, with GI50s ≤ 10 nM in several breast, brain, cervical, ovarian, gastric, kidney, liver, lung, melanoma, prostate, and sarcoma lines. In addition, a 5-fold increase in active caspase-3 staining was observed at SL-801 concentrations ≤ 100 nM in 117/240 (48.8%) cell lines, consistent with induction of apoptosis. To understand tumor sensitivity to SL-801, results of the cell line cytotoxicity screen were analyzed against publicly available genomic datasets. This analysis revealed that SL-801 was cytotoxic towards cell lines regardless of mutation status of key oncogenes (e.g., KRAS) and tumor suppressor genes (e.g., TP53).
The in vitro cytotoxicity of SL-801 against tumor cell lines was further validated in several xenograft models in SCID mice. In the RPMI-8226 multiple myeloma xenograft model, tumor growth was significantly inhibited at oral SL-801 doses of 31.25 mg/kg administered daily for five days for two weeks. In the ARH-77 human multiple myeloma xenograft model, overall survival was significantly prolonged by daily oral administration of 125 mg/kg SL-801 for ten days. This dose and regimen were well tolerated, and 90% of SL-801-treated mice survived > 150 days, whereas median survival was 39.5 days in the vehicle-treated group (p < 0.001). Significant tumor growth inhibition was also observed in the NCI-H226 non-small cell lung cancer and 22RV1 prostate cancer xenograft models.
These data demonstrate that SL-801 is a promising clinical candidate that inhibits a novel, clinically validated target and support its clinical development in a broad range of oncologic indications. The reversible binding of SL-801 to XPO1 may offer the potential to develop dosing schedules to enable recovery in normal tissues, thus broadening the therapeutic index of this class of agents. IND-enabling work is underway to support entry into clinical trials, and a Phase I trial design will be discussed.
Disclosures: Chen: Stemline Therapeutics, Inc.: Employment , Equity Ownership . Brooks: Stemline Therapeutics, Inc.: Employment , Equity Ownership , Patents & Royalties . McDonald: Stemline Therapeutics, Inc.: Employment , Equity Ownership . Schwartz: Stemline Therapeutics, Inc.: Employment , Equity Ownership . Schneider: Stemline Therapeutics, Inc.: Employment . Sakakibara: CanBas Co., Ltd.: Employment , Equity Ownership . Saito: CanBas Co., Ltd.: Employment , Equity Ownership . Sato: CanBas Co., Ltd.: Employment , Equity Ownership , Patents & Royalties . Kawabe: CanBas Co., Ltd.: Employment , Equity Ownership , Patents & Royalties . Rowinsky: Stemline Therapeutics: Employment , Equity Ownership .
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