Abstract 3086: SINE compounds demonstrated potent anti-cancer activity in PDX mouse models of chordoma

Abstract

Abstract Introduction: Chordoma is an ultra-rare cancer found in the base of the skull and the mobile spine that originates from embryonic remnants of the notochord. It is often resistant to standard chemotherapy and most systemic anti-cancer treatment, and surgical removal followed by radiation therapy remains the mainstay of current treatment. However, due to the difficult location of chordoma, complete surgical removal is not always possible. In addition, chordoma has a high rate of metastasis and recurrence. Therefore, novel and effective treatment options for chordoma are needed. Selective inhibitor of nuclear export (SINE) compounds selinexor and eltanexor are a class of novel oral drugs that target XPO1 (exportin-1/ CRM1) and exhibit anti-cancer activity across a wide range of solid and hematological malignancies. In July 2019, selinexor was approved by the US FDA to treat patients with multiple myeloma. To investigate the preclinical efficacy and tolerability of SINE compounds in chordoma, two PDX (patient derived xenograft) mouse models of chordoma were tested. Methods: Two SINE drugs, selinexor at 5 mg/kg x 4 times a week and eltanexor at 10 mg/kg x 5 times a week, alone or in combination with bortezomib were used to treat chordoma CF466 and SF8894 PDX mouse models. CF466 PDX was derived from a patient with metastatic sacral chordoma whereas SF8894 PDX was derived from a patient with recurrent clival chordoma. Tumor volume and mouse body weight were monitored during the study. Tumors were collected at the end of 6 weeks of the study for histological, and immunohistochemistry (IHC)-based biomarker analyses. Results: Both selinexor and eltanexor demonstrated potent anti-cancer activity compared to controls. Tumor growth inhibition (TGI) of selinexor was 58% and 78% in the CF466 and SF8894 models, respectively, and TGI of eltanexor was 55% in the SF8894 model. No significant difference in body weight was observed among different treatment groups. Bortezomib did not exhibit anti-tumor activity in these models nor did it have additive/synergistic effects when combined with selinexor or eltanexor. CF466 tumors from mice treated with selinexor showed increased apoptosis, decreased cell proliferation and lowered cell density when compared with the controls. In addition, IHC analysis showed that selinexor treatment increased nuclear retention of eIF4E and tumor suppressor proteins APC, SMAD4 and FOXO3A, and decreased the expression of proteins that may play a role in chordoma tumor biology, such as SHH, GLI1 and SOX9. Conclusions: SINE compounds effectively inhibit tumor growth in PDX mouse models of chordoma. The anti-cancer effects are likely achieved through regulation of multiple signaling pathways. Further investigation of SINE compounds as treatment options for chordoma is warranted. Citation Format: Hua Chang, Leah Henegar, Trinayan Kashyap, Thaddeus J. Unger, Sharon Shacham, Josh Sommer, Patty Cogswell, Stacy Fechner, Michael J. Wick, Joan Levy, Yosef Landesman. SINE compounds demonstrated potent anti-cancer activity in PDX mouse models of chordoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3086.