1.Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo.
Manton CA1,2, Johnson B1,2, Singh M1, Bailey CP1,2, Bouchier-Hayes L3, Chandra J1,2. Sci Rep. 2016 Jan 25;6:18953. doi: 10.1038/srep18953.
New therapies for glioblastoma (GBM) are needed, as five-year survival is <10%. The proteasome inhibitor marizomib (MRZ) has inhibitory and death-inducing properties unique from previous inhibitors such as bortezomib (BTZ), and has not been well examined in GBM. We evaluated the mechanism of death and in vivo properties of MRZ in GBM. The activation kinetics of initiator caspases 2, 8, and 9 were assessed using chemical and knockdown strategies to determine their contribution to cell death. Blood brain barrier permeance and proteasome inhibition by MRZ and BTZ were examined in an orthotopic GBM model. Blockade of caspase 9, relative to other caspases, was most protective against both MRZ and BTZ. Only MRZ increased the proteasome substrate p27 in orthotopic brain tumors after a single injection, while both MRZ and BTZ increased p21 levels after multiple treatments. Cleavage of caspase substrate lamin A was increased in orthotopic brain tumors from mice treated with MRZ or BTZ and the histone deacetylase inhibitor vorinostat.
2.Efficacy of panobinostat and marizomib in acute myeloid leukemia and bortezomib-resistant models.
Corrales-Medina FF1, Manton CA2, Orlowski RZ3, Chandra J4. Leuk Res. 2015 Mar;39(3):371-9. doi: 10.1016/j.leukres.2014.12.014. Epub 2015 Jan 3.
Current relapse rates in acute myeloid leukemia (AML) highlight the need for new therapeutic strategies. Panobinostat, a novel pan-histone deacetylase inhibitor, and marizomib, a second-generation proteasome inhibitor, are emerging as valuable therapeutic options for hematological malignancies. Here we evaluated apoptotic effects of this combinatorial therapy in AML models and report earlier and higher reactive oxygen species induction and caspase-3 activation and greater caspase-8 dependence than with other combinations. In a bortezomib refractory setting, panobinostat induced high levels of DNA fragmentation, and its action was significantly augmented when combined with marizomib. These data support further study of this combination in hematological malignancies.
3.Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD(®) immunomodulatory drug pomalidomide.
Das DS1, Ray A1, Song Y1, Richardson P1, Trikha M2, Chauhan D1, Anderson KC1. Br J Haematol. 2015 Dec;171(5):798-812. doi: 10.1111/bjh.13780. Epub 2015 Oct 12.
The proteasome inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that the novel proteasome inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action and effects on proteasomal activities, and that it can overcome bortezomib resistance. Pomalidomide, like lenalidomide, has potent immunomodulatory activity and has been approved by the US Food and Drug Administration for the treatment of RRMM. Here, we demonstrate that combining low concentrations of marizomib with pomalidomide induces synergistic anti-MM activity. Marizomib plus pomalidomide-induced apoptosis is associated with: (i) activation of caspase-8, caspase-9, caspase-3 and PARP cleavage, (ii) downregulation of cereblon (CRBN), IRF4, MYC and MCL1, and (iii) suppression of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities.
4.Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma; NPI 0052 101 Part 1.
Richardson PG1, Zimmerman TM2, Hofmeister CC3, Talpaz M4, Chanan-Khan AA5, Kaufman JL6, Laubach JP7, Chauhan D7, Jakubowiak AJ2, Reich S8, Trikha M8, Anderson KC7. Blood. 2016 Mar 23. pii: blood-2015-12-686378. [Epub ahead of print]
Marizomib (MRZ) is a novel, irreversible proteasome inhibitor in clinical development for the treatment of relapsed or relapsed and refractory multiple myeloma (RRMM). MRZ inhibits the 3 proteolytic activities of the 20S proteasome with specificity distinct from bortezomib and carfilzomib. Study NPI-0052-101 Part 1 enrolled relapsed or RRMM patients into an open-label, dose escalation design to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of MRZ administered intravenously on two different schedules, Schedule A (0.025-0.7 mg/m2once-weekly on Days 1, 8, 15 of 4-week cycles) and Schedule B (0.15-0.6 mg/m2twice weekly on Days 1, 4, 8, 11 of 3-week cycles; concomitant dexamethasone was allowed with Schedule B). Patients had received an average of 4.9 and 7.3 prior treatment regimens (Schedules A and B, respectively). MRZ Schedule A was administered to 32 patients and the RP2D was established as 0.7 mg/m2infused over 10 minutes.