CRBN expression

P1, N=10, Completed, Mayo Clinic | Active, not recruiting --> Completed | Phase classification: P1/2 --> P1 | Trial completion date: Dec 2024 --> Dec 2023

Conclusions These data illustrate that late-line RRMM subjects have appreciable immunosuppression compared to NDMM subjects, with particular dysfunction in the CD4+ helper T-cell compartment, suggesting that the efficacy of immunotherapies in late line myeloma may benefit from combinations with agents that improve CD4+ T-cell function. These data also show enrichment of molecular high-risk segments and CRBN-related genomic aberrations in RRMM subjects in the CC-220-MM-001 study.

Following concentration/duration optimisation, cell lines were treated with EZH2i (Tazemetostat) 0.25-1µM or DMSO control for 5 days alone, and then in combination with IMiD (Lenalidomide, Len, 0-20 µM, Pomalidomide, Pom, 0-8 µM) or CELMoD (Iberdomide, CC-220, 0-2 µM and Mezigdomide, CC-92480, 0-0.1uM) for a further 5 days. Conclusions Our results suggest that combining EZH2i with IMiDs/CELMoDs can overcome resistance to these agents in MM cell line models, with synergy that is CRBN-dependent. By examining the key components of the CRBN pathway we identified that EZH2i reduced H3K27me3 and increased Ikaros and Aiolos association at the IRF4 promoter, suggesting a possible re-coupling of Ikaros/Aiolos to IRF4 expression, which may be responsible for reinstating IMiD/CELMoD activity, driving the synergistic effect seen.

In sight of this, in the present study, we evaluated the CRBN expression, both full-length and spliced isoforms, by using real-time assay data from 87 patients and RNA sequencing data from 50 patients (n = 137 newly diagnosed MM patients), aiming at defining CRBN's role as a predictive biomarker for response to IMiDs-based induction therapy. We found that the expression level of the spliced isoform tends to be higher in not-responding patients, confirming that the presence of a more CRBN spliced transcript predicts for lack of IMiDs response.

Introduction: Although immunomodulatory imide drugs (IMiDs), also called CRBN E3 ligase modulatory drugs (CELMoDs), e.g., lenalidamide (LEN), pomalidomide (POM) and proteasome inhibitor [bortezomib (BTZ)] improved the survival rate of multiple myeloma (MM), all MM patients are relapsed due to drug resistance...Disulfiram (DS), an anti-alcoholism drug used in clinic for over 60 years, demonstrates excellent specific anticancer activity with no/low toxicity to normal tissues... ZnDDC demonstrates CELMoD like property with synergistic effect when used in combination with clinically available IMiDs and BTZ; The effect of ZnDDC is potentially CRL4CRBN-IKZF1/3-IRF4 pathway dependent; Further study is ongoing which could translate this work into MM clinic in a fast track.

We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.

P1, N=27, Not yet recruiting, Abdullah Khan

Through a senolytic-drug screen, CRBN-based PROTAC ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells...Mechanistically, USP2 directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells.ConclusionOur study demonstrates the striking synergy of inducing senescence in liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy and suggest a potential therapeutic strategy for liver cancer treatment.