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Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid
Nancy Levin1, Andrew Spencer2, Simon J Harrison3
1Triphase Accelerator, San Diego, CA, USA.
Abstract:
Proteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin-like (CT-L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase-like (C-L) and trypsin-like (T-L) subunits, in response to CT-L blockade. Marizomib (MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan-proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with advanced solid tumours and haematological malignancies. Functional inhibition of all proteasome subunits was achieved with once- or twice-weekly MRZ dosing; 100% inhibition of CT-L was frequently achieved within one cycle at therapeutic doses. Concomitantly, C-L and T-L activities were either unaffected or increased, suggesting compensatory hyperactivation of these subunits. Importantly, this response was overcome by continued administration of MRZ, with robust inhibition of T-L and C-L (up to 80% and 50%, respectively) by the end of Cycle 2 and maintained thereafter. This enhanced proteasome inhibition was independent of tumour type and may underlie the clinical activity of MRZ in patients resistant to other PIs.
Insights
Marizomib, a novel proteasome inhibitor, effectively targets all proteasome subunits, overcoming resistance mechanisms seen with other drugs. Continued marizomib treatment ensures sustained inhibition, potentially improving outcomes for patients with multiple myeloma and other cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Proteasome inhibitors (PIs) are crucial in multiple myeloma (MM) treatment, but resistance is a significant clinical challenge.
- Resistance to existing PIs may involve compensatory hyperactivation of caspase-like (C-L) and trypsin-like (T-L) proteasome subunits when chymotrypsin-like (CT-L) activity is blocked.
- Marizomib (MRZ) is an irreversible pan-proteasome inhibitor with a distinct inhibitory profile, under development for MM and malignant glioma.
Purpose of the Study:
- To evaluate the pan-proteasome pharmacodynamic activity of marizomib (MRZ) in patients with advanced solid tumors and hematological malignancies.
- To assess MRZ's ability to inhibit all three 20S proteasome subunits, including overcoming potential resistance mechanisms.
Main Methods:
- Pharmacodynamic activity of MRZ was measured in packed whole blood and peripheral blood mononuclear cells from patients in two clinical studies.
- Patients received once- or twice-weekly dosing of MRZ.
- Proteasome subunit activities (CT-L, C-L, T-L) were assessed at various time points.
Main Results:
- Once- or twice-weekly MRZ dosing achieved functional inhibition of all proteasome subunits.
- 100% CT-L inhibition was frequently observed within the first cycle at therapeutic doses.
- Initially, C-L and T-L activities were unaffected or increased, indicating compensatory hyperactivation.
- Continued MRZ administration overcame this compensatory effect, achieving robust inhibition of T-L (up to 80%) and C-L (up to 50%) by Cycle 2, which was maintained thereafter.
- This enhanced inhibition was independent of tumor type.
Conclusions:
- Marizomib demonstrates potent pan-proteasome inhibition, effectively overcoming compensatory subunit activation observed with other PIs.
- Sustained MRZ administration leads to robust and durable inhibition of all proteasome subunits.
- These findings suggest a potential mechanism for MRZ's clinical activity in patients resistant to other PIs.
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