A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas

Abstract

One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor.

The functional genomic circuitry of human glioblastoma stem cells

“…This finding is in line with new studies describing unique molecular mechanisms employed by stem cells or their malignant counterparts to maintain their unique functional properties (Dolma et al, 2016;van Galen et al, 2014;Tang and Rando, 2014). Our findings therefore provide a molecular basis for triggering proteotoxic crisis (Urra et al, 2017), either by inhibiting stress response pathways or by increasing ER stress over homeostatic levels, such as by inhibition of proteasome activity (Raizer et al, 2016), as a consideration for GBM treatment.…”

Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study

“…This is consistent with previous trials using concurrent schedules 22 with intensive and prolonged treatment, as well as with various drug combinations. [33][34][35][36][37][38][39] Our patients scored relatively high on the quality of life EQ-5D-5L questionnaire that was previously validated for the Norwegian population. 40 The ability to perform usual daily activity, ataxia, and changes in strength were the strongest predictors of KPS and this finding is corroborated by a previous study of Norwegian patients after surgery.…”

High content screening of patient-derived cell lines highlights the potential of non-standard chemotherapeutic agents for the treatment of glioblastoma

“…However, the promise of bortezomib in vitro has yet to be reflected in clinical trials, with two phase II trials combining bortezomib with tamoxifen[ 43 ] and verinostat[ 44 ] proving ineffectual. A recent phase II study has also demonstrated that combination bortezomib and TMZ was ineffective in rGBM despite promising pre-clinical data[ 45 ]. Measurable concentrations of bortezomib were however found in the tumor tissue post-treatment, strengthening our view that ABC-transporter substrates can penetrate the BBB in GBM.…”