Proteasome inhibition as a therapeutic approach in atypical teratoid/rhabdoid tumors

Abstract

Background Atypical teratoid/thabdoid tumor (AT/RT) remains a difficult-to-treat tumor with a 5-year overall survival rate of 15%–45%. Proteasome inhibition has recently been opened as an avenue for cancer treatment with the FDA approval of bortezomib (BTZ) in 2003 and carfilzomib (CFZ) in 2012. The aim of this study was to identify and characterize a pre-approved targeted therapy with potential for clinical trials in AT/RT. Methods We performed a drug screen using a panel of 134 FDA-approved drugs in 3 AT/RT cell lines. Follow-on in vitro studies used 6 cell lines and patient-derived short-term cultures to characterize selected drug interactions with AT/RT. In vivo efficacy was evaluated using patient derived xenografts in an intracranial murine model. Results BTZ and CFZ are highly effective in vitro, producing some of the strongest growth-inhibition responses of the evaluated 134-drug panel. Marizomib (MRZ), a proteasome inhibitor known to pass the blood–brain barrier (BBB), also strongly inhibits AT/RT proteasomes and generates rapid cell death at clinically achievable doses in established cell lines and freshly patient-derived tumor lines. MRZ also significantly extends survival in an intracranial mouse model of AT/RT. Conclusions MRZ is a newer proteasome inhibitor that has been shown to cross the BBB and is already in phase II clinical trials for adult high-grade glioma (NCT NCT02330562 and NCT02903069). MRZ strongly inhibits AT/RT cell growth both in vitro and in vivo via a moderately well-characterized mechanism and has direct translational potential for patients with AT/RT.

Recent progress and novel approaches to treating atypical teratoid rhabdoid tumor

“…An unbiased drug screen of AT/RT identified proteasome inhibitors as being highly effective in vitro. The brain-penetrant proteasome inhibitor marizomib demonstrated activity against BT16 and MAF-737A AT/RT orthotopic xenografts [65] . Clinical development of marizomib is currently halted, however, the orally bioavailable and brain-penetrant proteasome inhibitor ixazomib also demonstrated activity against malignant rhabdoid tumor (MRT) in vitro and in vivo and killed AT/RT cells [63] .…”

Atypical Teratoid/Rhabdoid Tumor in Taiwan: A Nationwide, Population-Based Study

“…Kai et al studied high-dose chemotherapy with SCT and found that it may contribute to a better outcome [27]. Proteasome inhibitors (Marizomib, carfilzomib, and bortezomib) were recently studied as potential targeted therapy for patients with AT/RT, and tumor models have shown promising results [40,41].…”

“…Although cisplatin-or carboplatin-based chemotherapy regimens have been used in many centers [4], we did not yet have a standardized chemotherapy protocol for AT/RT in Taiwan during the study period. The recent discovery of the preclinical activity of proteasome inhibitors in AT/RT [40,41], however, has encouraged us to initiate a multi-center phase II trial using a proteasome inhibitor as an add-on therapy to standard chemotherapy for newly diagnosed AT/RT. Thirdly, since AT/RT is a rare cancer and the number of cases is limited, the analysis of the relationship between tumor site, treatment type, and age group required that small groups (of less than five patients) be combined as a single unit.…”

SMARCB1-Deficient Cancers: Novel Molecular Insights and Therapeutic Vulnerabilities

“…Another group had similar findings, showing that proteasomal inhibition paired with genetic suppression of autophagy led to durable responses in a faithful rhabdoid tumor mouse model [ 157 ]. These effects of proteasomal inhibition were similarly validated within the context of rhabdoid tumors, yet the synergistic effects when paired with autophagy inhibition were not observed in the context of ATRT [ 158 ]. Further studies are still needed to elucidate the clinical benefits of proteasomal inhibition in SMARCB1-deficient cancers.…”