Abstract PR13: Pivotal role of interleukin 23 in osteosarcoma development and its link with glutamate metabotropic 4: Identification of novel therapeutic targets for osteosarcoma

Abstract

Abstract Objective: The 5-year survival of patients with metastatic or recurrent osteosarcoma is less than 25%. There is an urgent need to identify new treatment options for this cancer. Osteosarcomas represent a promising indication for strategies that target the immune system (1). Here we identify interleukin 23 (IL23), an inflammatory cytokine, as a potential therapeutic target in osteosarcoma. Our interest in IL23 is reinforced by the recent genome-wide association study, where a locus at rs1906953 at 6p21.3 in the glutamate metabotropic receptor 4 (Grm4) gene was identified as having the strongest association with genetic susceptibility to osteosarcoma in humans (2). GRM4 activation has been associated with autoimmune diseases through suppression of inflammatory cytokines, including IL23 (3). Whether GRM4 plays an immune modulatory role in cancer development is unknown. Methods: We screened a panel of mouse genotypes deficient in immune-related genes or cells to identify those genotypes that would predispose or protect from the development of osteosarcoma using a radiation model of cancer. IL23 expression was examined in mouse and human osteosarcomas using in situ hybridization. We investigated targeting IL23 alone and in combination with chemotherapy in a preclinical transplant model of osteosarcoma. The role of Grm4 and its association with IL23 was investigated using Grm4 knockout mice and Grm4 agonists. Results: IL23 knockout mice were strikingly protected from the development of osteosarcomas with 80% of animals disease free at 2 years of age compared to tumors in 100% of wild-type mice (P<0.0001). This suggests that IL23 is oncogenic in cancer development. In both mouse and human osteosarcomas infiltrating dendritic cells were found to express this cytokine, contributing to an inflammatory immune environment. Antagonist blocking IL23 could suppress tumor growth and in preliminary studies combining IL23 antagonists with doxorubicin further synergized to suppress tumor growth. GRM4 knockout mice were found to have significantly enhanced IL23 expression compared to wild-type mice. In vitro agonists to Grm4 were found to down-regulate IL23 and are being explored further in preclinical models of osteosarcoma. Conclusion: We find that blocking IL23 suppresses the growth of primary osteosarcomas. Blocking IL23 may have more profound roles in suppressing metastatic disease and is currently being studied. These findings are important, as Ustekinumab a neutralizing antibody to IL23, is FDA approved for the treatment of plaque psoriasis. This antibody targets IL-12 p40, which blocks both IL12 and IL23, but more specific monoclonal antibodies to human IL23p19 are in development for autoimmune diseases and could be repurposed for the treatment of cancer. In addition, agonists targeting GRM4 are in development and we will further investigate whether these have utility in osteosarcoma. References Kansara M et al. Translational biology of osteosarcoma. Nat Rev Cancer 2014;14:722-35; doi:10.1038/nrc3838. Jiang C et al. GRM4 gene polymorphism is associated with susceptibility and prognosis of osteosarcoma in a Chinese Han population. Med Oncol 2014;31:50. Fallarino F et al. Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation. Nat Med 2010;16:897-902; doi:10.1038/nm.2183. This abstract is also being presented as Poster B30. Citation Format: Maya Kansara, Puiyi Pang, Nina Sulkowski, Michele Teng, Mark Smyth, David Thomas. Pivotal role of interleukin 23 in osteosarcoma development and its link with glutamate metabotropic 4: Identification of novel therapeutic targets for osteosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR13.