The Proteasome Inhibitor Ixazomib Inhibits the Formation and Growth of Pulmonary and Abdominal Osteosarcoma Metastases in Mice

Abstract

Osteosarcoma is the most common form of primary bone cancer. Over 20% of osteosarcoma patients present with pulmonary metastases at diagnosis, and nearly 70% of these patients fail to respond to treatment. Previous work revealed that human and canine osteosarcoma cell lines are extremely sensitive to the therapeutic proteasome inhibitor bortezomib in vitro. However, bortezomib has proven disappointingly ineffective against solid tumors including sarcomas in animal experiments and clinical trials. Poor tumor penetration has been speculated to account for the inconsistency between in vitro and in vivo responses of solid tumors to bortezomib. Here we show that the second-generation proteasome inhibitor ixazomib, which reportedly has enhanced solid tumor penetration compared to bortezomib, is toxic to human and canine osteosarcoma cells in vitro. We used experimental osteosarcoma metastasis models to compare the efficacies of ixazomib and bortezomib against primary tumors and metastases derived from luciferase-expressing KRIB or 143B human osteosarcoma cell lines in athymic mice. Neither proteasome inhibitor reduced the growth of primary intramuscular KRIB tumors, however both drugs inhibited the growth of established pulmonary metastases created via intravenous inoculation with KRIB cells, which were significantly better vascularized than the primary tumors. Only ixazomib slowed metastases from KRIB primary tumors and inhibited the growth of 143B pulmonary and abdominal metastases, significantly enhancing the survival of mice intravenously injected with 143B cells. Taken together, these results suggest ixazomib exerts better single agent activity against osteosarcoma metastases than bortezomib. These data provide hope that incorporation of ixazomib, or other proteasome inhibitors that penetrate efficiently into solid tumors, into current regimens may improve outcomes for patients diagnosed with metastatic osteosarcoma.

Expression and clinical implications of leucine‐rich repeat containing 15 (LRRC15) in osteosarcoma

“…Of note, there was a relatively higher expression of LRRC15 in the osteosarcoma cell line 143B, which is known to be highly metastatic to the lungs of mice following subcutaneous and intramuscular xenotransplantation. [33][34][35] The 143B osteosarcoma cell line is a derivative of the K-Ras oncogene transformed from osteosarcoma cell line HOS-Te85. 34 When comparing in vitro characteristics of these osteosarcoma cell lines, the 143B cell line has the highest rate of proliferation and cell migration.…”

“…In our work, we found a differential expression of LRRC15 in osteosarcoma cell lines by western blots and immunofluorescence assays. Of note, there was a relatively higher expression of LRRC15 in the osteosarcoma cell line 143B, which is known to be highly metastatic to the lungs of mice following subcutaneous and intramuscular xenotransplantation 33–35 . The 143B osteosarcoma cell line is a derivative of the K‐Ras oncogene transformed from osteosarcoma cell line HOS‐Te85 34 .…”

Resistance of osteosarcoma cells to the proapoptotic effects of carfilzomib involves activation of mitogen activated protein kinase pathways

“…It is known that the inhibition of proteasome function leads to the accumulation of proteins targeted for degradation and subsequent cellular apoptosis (Khan & Stewart, 2011). Previous studies have shown that proteasome inhibitors can induce cell apoptosis in osteosarcoma (Bonvini et al, 2007;Harris et al, 2020;Lu et al, 2008;Patatsos et al, 2018), thereby suggesting that targeting proteasomes may represent a novel therapeutic option for the treatment of osteosarcoma.…”

Rare Childhood Malignancy

“…This small collection of six original research papers and two review articles in the Special Issue “Rare Childhood Malignancy” highlights the diversity and importance of empirical research into childhood malignancy, a theme that underpins the significant advances that have been made in treating the diseases that constitute cancers in children. These articles cover significant themes in childhood cancer research and include biological studies on the role of MYCN in poor prognosis Wilms’ tumor [ 1 ] and the mTOR complexes in rhabdomyosarcoma [ 2 ]; studies exploring biologically based treatments in ependymoma [ 3 ] and osteosarcoma [ 4 ]; a comprehensive description of a novel orthotopic model for radiation-induced glioma which will be invaluable for preclinical testing [ 5 ]; and two comprehensive review articles on leukemias. One review describes recently identified rearrangements of DUX4 with IGH in childhood B-cell acute lymphoblastic leukemia (ALL) and the diagnostic challenges associated with identifying the rearrangement [ 6 ], and the second proposes that infant acute myeloid leukemia (AML) is a biologically and clinically distinct entity from AML in older children [ 7 ].…”

“…Validation of this study may lead to better directed therapy for rhabdomyosarcoma. Harris et al [ 4 ] report the exciting finding in preclinical models that the second-generation proteasome inhibitor ixazomib is effective in inhibiting osteosarcoma metastases in athymic mice. When metastatic disease is present in osteosarcoma, the prognosis is poor, with only 20–30% survival.…”