Abstract
Osteosarcoma (OS) is the most common bone tumor in pediatric patients, whose effective therapies are of great unmet medical needs, particularly for those of high-risk features. c-Myc, a well-known oncogene, is commonly amplified/overexpressed in OS patients, contributes to dismal prognosis and associates with lower 5-year overall survival rate, which is also confirmed by our retrospective analysis for the correlation between c-Myc gene amplification/overexpression and patient prognosis in our patient cohort. TT-00420, a clinical-stage small molecule targeting Aurora A/B, VEGFRs, FGFRs, JAKs and CSF1R, has demonstrated down-regulation on c-Myc expression in TNBC studies. Moreover, as reported, Aurora kinases and c-Myc regulate each other back and forth, triggering maintenance of the malignant state. In this study, we examined the efficacy of TT-00420 in c-Myc-amplified/overexpressed OS. In pre-clinical clonogenic assay, TT-00420 significantly inhibited the colony formation in c-Myc-overexpressed OS cell lines in a dose-dependent manner. In MNNG/HOS cell line, we demonstrated that TT-00420 dramatically suppressed Aurora kinase pathway and blunted c-Myc protein expression level, indicating TT-00420 might down-regulate c-Myc by Aurora kinases inhibition. In pre-clinical in-vivo efficacy studies, 143B cells were injected into the medullary cavity of the tibia to make the orthotopic OS xenograft model. With 15 mg/kg/day treatment of TT-00420, tumor growth was obviously inhibited as compared to vehicle group. Immunohistochemistry (IHC) analyses in tumors revealed that TT-00420-treated tumors exhibited increased apoptosis with upregulated expression of cleaved caspase 3 (CC3) and H2AX, and significantly decreased proliferations with raised expression of Ki67. Moreover, in a c-Myc-overexpressed OS patient-derived xenograft (PDX) model from a male pediatric patient, 15 mg/kg/day TT-00420 dramatically blunted the tumor growth with a TGI of 87.6%. In China, an investigator-initiated trial is currently ongoing to evaluate the safety and tolerability of TT-00420 in OS patients with c-Myc overexpression (ChiCTR2000036618). Taken together, TT-00420 depicted robust anti-tumor activity in c-Myc overexpressed OS both in vitro and in vivo with downregulation of c-Myc expression, indicating its potential as a novel monotherapy for OS patients with c-Myc overexpression. Future clinical trial result is of great expectation.
Citation Format: Yingqi Hua, Xiaoyan Qiang, Kai Tian, Yafei Jiang, Frank Wu, Peng Peng. TT-00420, a novel kinase inhibitor potentially benefiting c-Myc amplified/overexpressed osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A037.