Abstract 1565: Targeting of KIF11 and AURKA to improve outcomes in Ewing sarcoma

Abstract

Abstract Ewing Sarcoma (EWS) is a rare and aggressive pediatric malignancy of the bone and soft tissues. Despite intensive systemic combination chemotherapy and surgery/radiotherapy for local control, patients with metastatic disease have dismal prognosis (<30% overall survival rate). To identify better therapies for patients with refractory, recurrent and metastatic disease, we previously conducted in silico and drug re-purposing screens (PMID: 27863422; 31025088) that identified proteins essential for mitotic spindle formation and cell cycle progression such as Aurora Kinase A (AURKA), Kinesin Family Member 11 (KIF11), Kinesin Family Member 15 (KIF15) and its binding partner; targeting protein for Xklp2 (TPX2) that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, indicating their potential as therapeutic targets. KIF11 and KIF15 are mitotic motor kinesins essential for bipolar spindle formation, whereas AURKA is a mitotic kinase essential for centrosome maturation and mitotic spindle assembly. Though KIF11 and AURKA inhibitors have been extensively used in clinical trials before but have not been tested together in combination for any type of cancer. We hypothesized that targeting these two key proteins essential for mitotic progression provides a therapeutic vulnerability for Ewing Sarcoma by inducing G2/M arrest and mitotic catastrophe. Specific KIF11 (SB-743921) and AURKA (VIC-1911, VITRAC Therapeutics) inhibitors were used for targeting these proteins. We evaluated the in vitro activity of VIC-1911 and SB-743921 and synergy was measured by percentage inhibition of growth via SynergyFinder, that employs reference models (Bliss) to score synergy (scores >10 is synergistic). EWS showed strong synergistic interaction at physiologically relevant doses compared to control cell lines (e.g., mesenchymal stem cells and non-EWS tumor cells). This drug combination was effective in refractory EWS cells established post-chemotherapy (synergy score >24) and at much lower doses in cells established from pre-treatment tumor tissue (synergy score >27) indicating effectiveness at various clinical stages of EWS disease. Importantly, this therapy appeared preferential to EWS cells with an EWS-ETS fusion as compared to non-EWS cells. We observed zero colony formation in vitro with the combination treatment and increased percentage accumulation of cells in G2/M phase upon cell-cycle analysis indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed sustained tumor regression (NED at 30 days after ending therapy). The combination arm showed significant survival versus control (p≤ 0.001, HR=0.42, 95% CI=0.14-1.25), VIC-1911 (p≤ 0.001, HR=0.48, 95% CI=0.16-1.42) or SB-743921 (p ≤ 0.01, p≤ HR=0.71, 95% CI=0.21-2.34) alone. Efforts are underway to translate these preclinical studies into an early phase clinical trial of patients with histologically proven EWS who have failed standard of care therapy. Citation Format: Soumya M. Turaga, Vikalp Vishwakarma, Stacey Hembruff, Rajni Puri, Priya Sabu, Glenson Samuel, Andrew K. Godwin. Targeting of KIF11 and AURKA to improve outcomes in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1565.