Feasibility of Using Bortezomib With or Without Chemotherapy in Patients With Atypical Teratoid/Rhabdoid Tumors

• Status: ACTIVE_NOT_RECRUITING
• Trial end date: 2025-12-01

Summary

Atypical teratoid/rhabdoid tumors (AT/RTs) account for 1%-2% of all central nervous system (CNS) tumors in children aged 0-14 years, yet are among the most common malignant CNS tumors in infants less than 1 year old. AT/RTs are defined by the loss of INI1 or, rarely, BRG1, encoded by the SMARCB1 and SMARCA4 genes, respectively. Patients with AT/RTs have dismal outcomes due to their highly malignant nature and young age at diagnosis. There remains no standard therapy for AT/RTs. Multimodal treatment strategies include a selective combination of conventional chemotherapy, high dose chemotherapy and stem cell rescue, intrathecal chemotherapy, and radiotherapy after tumor resection. The survival rate, even with aggressive treatment, is still low (2-year survival rate is 32.6%-44.6%). Moreover, currently used cytotoxic therapies incur some neurocognitive side effects, particularly in infants, highlighting the urgent need for novel targeted therapies.

Bortezomib (Velcade) is the first generation proteasome inhibitor developed by Millennium Pharmaceuticals, Inc. as an anti-cancer medication. Bortezomib was approved by FDA for the treatment of adult patients with multiple myeloma and mantle cell lymphoma (newly diagnosed or relapse/recurrent disease). In children, the safety of BTZ has been proved in phase I clinical trial of patients with acute lymphoblastic leukemia, refractory or recurrent solid tumors, relapsed/refractory high-risk neuroblastoma. Recently, we found the proteasome-encoding genes were highly expressed in AT/RTs compared with that in normal brain tissues, correlated with the malignant phenotype of tumor cells, and were essential for tumor cell survival. Bortezomib targets proteostasis, inhibiting tumor growth and inducing apoptosis through p53 accumulation in three Myc-AT/RT cell lines and in mice with orthotopic xenografts of AT/RT. Our findings suggest that BTZ is a promising targeted therapy for Myc-AT/RTs (manuscript under review). To determine whether the other subgroups of ATRTs (i.e., SHH and TYR subgroups) are sensitive to BTZ, we conducted the in vivo drug test in 2 SHH-AT/RT cell lines (CHLA-02 and CHLA-04). Although CHLA-02 and CHLA-04 cell line were less sensitive to BTZ (IC50 of 15.1 (14.3-15.9) nM and 15.8 (14.5-17.3) nM, respectively) than Myc-AT/RT cell line (IC50 of 5.84 to 8.7 nM), these inhibitory concentrations are still clinically achievable (Cmax, 231.6-312.3 nM). Furthermore, the dependence on ubiquitin proteasome system for survival and high sensitivity to proteasome inhibitors have been reported in SMARCB1-deficient cancer cells. Additionally, we also observed the subgroup shifting in one infant with AT/RTs, from SHH subgroup of primary tumor to Tyr subgroup of the first recurrent tumor and Myc subgroup of the second recurrent tumor. Therefore, we hypothesize that BTZ treatment is potentially effective to all subgroups of CNS AT/RT and propose a clinical trial utilizing BTZ as an add-on therapy to standard and high-dose chemotherapy

• Phase: PHASE2

Details

• Lead Sponsor: Taipei Medical University
• Treatments: Bortezomib