carfilzomib

Screening identified elimusertib (ATR inhibitor), proteasome inhibitors (ixazomib, carfilzomib), and dinaciclib (Cdk1/2/5/9 inhibitor) as synergistic agents with olaparib. These results demonstrate that elimusertib is a very potent ATR inhibitor for combination with olaparib and provide mechanistic insight into this synergy through replication fork interference. Because this synergy spanned both HRD and HRP organoids, these findings support further preclinical optimization and well-designed clinical evaluation of the olaparib-elimusertib combination in HGSC, with attention to dose-finding, hematologic safety, and patient selection.

Incorporating early NT-proBNP monitoring, carfilzomib exposure, and refined age categorization may improve risk prediction and support more personalized cardiovascular surveillance strategies in cardio-oncology. However, this refined dynamic model should be regarded as exploratory and requires validation in larger independent cohorts before it can be considered for clinical application.

To address this, we performed proteome and phosphoproteome profiling of 12 MM cell line models, comprising four parental lines (AMO-1, ARH77, L363, and RPMI8226) paired with lines that acquired resistance to bortezomib (BTZ) or carfilzomib (CFZ). Beyond known adaptations such as the overexpression of the PI target PSMB5 and the drug efflux transporter ABCB1, we identified the oxidoreductases NQO1 and NQO2 as significantly upregulated proteins under chronic proteotoxic stress across several models. Pharmacological follow up in PI resistant AMO-1 cells showed that NQO2 inhibition by imatinib fully restored CFZ sensitivity, validating NQO2 as a contributor to resistance formation in this model system.

P=N/A, N=17, Completed, University Hospital, Limoges | Recruiting --> Completed

P=N/A, N=120, Recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

P3, N=386, Completed, Celgene | Active, not recruiting --> Completed | Trial completion date: Apr 2027 --> Apr 2026 | Trial primary completion date: Apr 2027 --> Apr 2026

P2, N=20, Recruiting, Shanghai Changzheng Hospital

Anti-glioma effects with the lowest drug concentrations were achieved for proteasome inhibitors (carfilzomib, bortezomib, ixazomib), and HDAC inhibitors (panobinostat, romidepsin). The impact of their drug targets PSMB5 and HDAC1/2 on the growth of GBM cells was successfully validated by RNAi experiments. We established an aHTS platform for GBM TOs, and identified proteasome and HDAC inhibitors as promising drugs for the treatment of GBMs.

Mezigdomide-carfilzomib-dexamethasone provided a significant PFS benefit compared with carfilzomib-dexamethasone alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. These findings support mezigdomide-carfilzomib-dexamethasone as a clinically meaningful treatment option as early as first relapse in predominantly triple-class-exposed, anti-CD38 antibody-refractory and lenalidomide-refractory patients, a growing population with substantial unmet need.

Moreover, insulin and IGF-II attenuated apoptosis and the inhibition of cell migration induced by the proteasome inhibitors (PIs) bortezomib and carfilzomib, and these effects were reversed by IFITM1 knockdown. The ability of insulin to reduce bortezomib-induced apoptosis and G2/M phase cell cycle arrest was likewise dependent on IFITM1 expression. Collectively, these findings suggest that insulin-induced IFITM1 plays a pivotal role in MM progression and resistance to bortezomib, highlighting IFITM1 as a potential prognostic biomarker and therapeutic target.

P1/2, N=140, Recruiting, Australasian Myeloma Research Consortium | Active, not recruiting --> Recruiting | N=68 --> 140

This indicates that although proteasomal inhibition is not inflammatory, TNF present in the microvascular environment synergizes with the drugs to compromise endothelial function. Our observations provide an explanation for how microvascular damage potentially underlies tissue injury driven by Bortezomib or Carfilzomib.