Abstract
Abstract Dual loss of SMARCA4/SMARCA2 ATPases of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex has been reported in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and other tumors. Loss of SMARCA4 is the result of inactivating mutations, and the loss of SMARCA2 results from the absence of mRNA expression. Restoration of either SMARCA4 or SMARCA2 can inhibit the growth of these cancers. We have evaluated the activity of a novel, structurally rigid, and potent, Class I/IIb HDAC inhibitor, GB-3103, against human SCCOHT and other cells lines deficient in SWI/SNF complex. GB-3103 shows potent anti-proliferative activities with low nM IC50 values against human SCCOHT lines BIN67 (51nM), COV434 (35nM) and SCCOHT-1 (293nM), and SWI/SNF-deficient rhabdoid and lung tumor lines A204 (95nM), A427 (174nM), G401 (138 nM), G402 (71nM), H522 (102nM). Treatment of human BIN67 SCCOHT cell line for 72h with GB-3103 revealed potent concentration- and time-dependent induction of SMARCA2 expression at both mRNA and protein levels. Treatment of mice bearing G401 human malignant rhabdoid tumor xenografts with GB-3103 at 5 mg/kg, QD resulted in 70% tumor growth inhibition (TGI) compared to vehicle control (P<0.05). Treatment of mice bearing BIN67 human tumor xenografts with GB-3103 at 5 mg/kg and 10 mg/kg, QD resulted in mean tumor regression of 26% and 33%, respectively, at two weeks post-treatment initiation. RNA-Seq analyses of BIN67 cells treated with GB-3103 revealed that GB-3103 affects DNA replication and mRNA stability as well as inducing the expression of MHC Class II proteins. Given the importance of MHC Class II expression and response to checkpoint inhibitor therapies, we tested the activity of GB-3103 alone and in combination with anti-mPD-1 and anti-mPD-L1 antibodies in a syngeneic CT-26 mouse colon cancer model. GB-3103 induced a 93% TGI as a single agent and caused regression of established CT-26 tumors when combined with either anti-mPD-1 or anti-mPD-L1 demonstrating the potent immunomodulatory activity of GB-3103 in addition to direct anticancer activities. GB-3103 is a novel epigenetic immunomodulator with potent anticancer activity against SWI/SNF-deficient cancers. Clinical development of GB-3103 in these genetically defined rare cancers for which no treatments currently exist provides unique clinical and regulatory opportunity for breakthrough therapy designation where approval could be based on smaller single arm clinical studies. Citation Format: Tong Wang, Paul Gonzales, Kari Kotlarczyk, Myung-Ja Lee, Erin Bossert, Courtney Devore, Haiyong Han, Jessica Lang, William Hendricks, Jeffrey Trent, Stephen Gately. GB-3103, an epigenetic immunomodulator, shows potent antitumor activity against tumors harboring dual loss of SMARCA4/SMARCA2 ATPases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-058.
Published Version
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