In Vitro and In Vivo Therapeutic Efficacy of Carfilzomib in Mantle Cell Lymphoma: Targeting the Immunoproteasome

Abstract

Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse after treatment with current existing therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the therapeutic effect and mechanism of carfilzomib, a novel long-acting second-generation proteasome inhibitor, in MCL cells. We found that carfilzomib induced growth inhibition and apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition, carfilzomib inhibited the growth and survival signaling pathways NF-kB and STAT3. Interestingly, we discovered that expression of immunoproteasome (i-proteasome) subunits is required for the anti-MCL activity of carfilzomib in MCL cells. In MCL-bearing SCID mice/primary MCL-bearing SCID-hu mice, intravenous administration of 5 mg/kg carfilzomib on days 1 and 2 for 5 weeks slowed/abrogated tumor growth and significantly prolonged survival. Our preclinical data show that carfilzomib is a promising, potentially less toxic treatment for MCL. Furthermore, an intact i-proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-proteasome could serve as a biomarker for identifying patients who will benefit from carfilzomib. Mol Cancer Ther; 12(11); 2494-504. Ó2013 AACR.

Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis

“…We compared the PD activity of CB-5083, bortezomib, carfilzomib and ixazomib in female nude mice bearing HCT116 or A549 tumors. All agents were dosed at their optimal dosing route and published active dose in hematological models (Kupperman et al, 2010; Teicher et al, 1999; Zhang et al, 2013) and were generally well tolerated after repeat dosing (Figures S6). After a single administration of CB-5083, a strong and sustained induction of polyubiquitin was observed in tumor tissue suggesting inhibition of the protein homeostasis pathway (Figures 6A).…”

Spasmogenic Effects of the Proteasome Inhibitor Carfilzomib on Coronary Resistance, Vascular Tone and Reactivity

“…CFZ was administered in the perfusion buffer or infused at three different concentrations (10 − 9 , 10 − 8 and 10 − 7  M) by bolus injection of 1 cc over 5 min, using a collateral arm of the perfusion cannula. The above concentrations were chosen based on prior in vitro work showing that carfilzomib doses ranging from 5 to 80 nmol/L resulted in a significant growth inhibition of mantle cell lymphoma (MCL) cells, harvested from peripheral blood samples or bone marrow aspirates obtained from patients with MCL (Zhang et al, 2013). …”

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

“…Carfilzomib, which is currently being evaluated in a phase 2 study for relapse/refractory MCL, induced apoptosis with the activation of JNK, Bcl-2, and mitochondria-related pathways. Its activity was dependent on the immunoproteasome subunit LMP2, which can function as a biomarker to monitor the therapeutic effect of carfilzomib [180]. While many proteasome inhibitors inhibit the catalytic activity of both constitutive proteasome and immunoproteasome, agents that can selectively inhibit the immunoproteasome have recently received attention.…”