Abstract
Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors.
Highlights
The primary bone cancer osteosarcoma typically arises in teenagers, with an incidence of 8 per million per year in adolescents and young adults
None of the IAP antagonists were toxic to osteosarcoma cells as sole agents or in conjunction with TNF-related apoptosis inducing ligand (TRAIL)
IAP antagonists cooperated with low doses of TNFα to kill cells from most primary and metastatic murine osteosarcomas, suggesting that members of this class of drugs may be therapeutically useful anti-osteosarcoma agents
Summary
The primary bone cancer osteosarcoma typically arises in teenagers, with an incidence of 8 per million per year in adolescents and young adults. Osteosarcoma is rare in people aged 25-60, but its incidence increases in older individuals including those with Paget’s disease [1]. The introduction of high dose multi-agent chemotherapy in the 1970s, doxorubicin and cisplatin, led to substantial increases in survival rates for osteosarcoma patients [2]. Most osteosarcoma patients are treated with high dose methotrexate, doxorubicin and cisplatin, before and after surgery [4]. These chemotherapeutic agents can cause severe and sometimes fatal adverse effects including cardiac and kidney damage, neurotoxicity and/or therapy-related second cancers [5], which preclude administration of higher, more effective, doses of these drugs. To improve outcomes for osteosarcoma patients, drugs are needed that can either (1) eliminate osteosarcoma cells as sole agents, without causing severe sequelae, or (2) cooperate with lower doses of currently used chemotherapies to destroy tumor cells more safely
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
