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Bone sarcomas are rare heterogeneous tumors that affect patients of all ages including children, adolescent young adults, and older adults. They include many aggressive subtypes and patient groups with poor outcomes, poor access to clinical trials, and lack of defined standard therapeutic strategies. Conventional chondrosarcoma remains a surgical disease, with no defined role for cytotoxic therapy and no approved targeted systemic therapies. Here, we discuss promising novel targets and strategies undergoing evaluation in clinical trials. Multiagent chemotherapy has greatly improved outcomes for patients with Ewing sarcoma (ES) and osteosarcoma, but management of those with high-risk or recurrent disease remains challenging and controversial. We describe the impact of international collaborative trials, such as the rEECur study, that aim to define optimal treatment strategies for those with recurrent, refractory ES, and evidence for high-dose chemotherapy with stem-cell support. We also discuss current and emerging strategies for other small round cell sarcomas, such as CIC-rearranged, BCOR-rearranged tumors, and the evaluation of emerging novel therapeutics and trial designs that may offer a new paradigm to improve survival in these aggressive tumors with notoriously bad (to the bone) outcomes.

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Background: Osteosarcoma is an aggressive bone cancer in which therapeutic advancements have been limited over the last 30 years, in part due to genomic heterogeneity. The combination of high-throughput drug screening platforms that efficiently pinpoint drug sensitivities with patient-derived cross-species models is an innovative approach to address the critical need to identify novel treatment strategies for osteosarcoma patients. Methods: We performed high-throughput drug screens on patient-derived osteosarcoma cell lines D418 (canine) and 17-3x (human), followed by validation of the top compounds, to identify drug sensitivities and novel therapeutic combinations. Results: High-throughput drug screens using 2100 bioactive compounds show that osteosarcoma cell lines D418 and 17-3x exhibited sensitivity to standard-of-care chemotherapy drugs, inhibitors of XPO1 nuclear export, and proteasome inhibitors. The XPO1 inhibitor, verdinexor (VER), and the proteasome inhibitor, bortezomib (BORT), induced dose-dependent cytotoxicity in multiple osteosarcoma cell lines (D418, IC50VER: 3187 nM, IC50BORT: 2.8 nM; 17-3x IC50VER: 679 nM, IC50BORT: 10.9 nM). In addition, dual XPO1 and proteasome inhibition synergistically reduced cell proliferation in D418 (synergy score=12.89) and 17-3x (synergy score=17.87) cell lines (p <0.05). Selinexor (SEL), an FDA approved XPO1 inhibitor used in combination with bortezomib to treat multiple myeloma, also demonstrated dose-dependent single-agent activity in patient-derived osteosarcoma cell lines (D418, IC50SEL: 370 nM; 17-3x IC50SEL: 101 nM). With drug screening of 119 oncology compounds in combination with selinexor in 17-3x cells, XPO1 inhibition again shows synergistic activity with proteasome inhibition in osteosarcoma. Conclusions: Inhibition of XPO1-mediated nuclear export is a promising therapeutic strategy in osteosarcoma. These effects may be further potentiated when used in combination with other agents, such as proteasome inhibitors. Additional drug screening and validation assays are underway to identify novel synergistic agents for use in combination with XPO1 inhibitors in osteosarcoma. Citation Format: Laurie Graves, Gabrielle Rupprecht, Erdem Altunel, Etienne M. Flamant, Sneha Rao, Dharshan Sivara, Alexander L. Lazarides, Sarah M. Hoskinson, Maya U. Sheth, Serene Cheng, So Young Kim, Kathryn E. Ware, Anika Agarwal, Mark M. Cullen, Casey Syal, Laura E. Selmic, Jeffrey I. Everitt, Shannon J. McCall, Cindy Eward, Trinayan Kashyap, Marie Maloof, Christopher J. Walker, Yosef Landesman, Lars Wagner, William C. Eward, David S. Hsu, Jason A. Somarelli. Exportin 1 (XPO1) inhibition alone or in combination as a novel therapeutic strategy in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1061.