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.

Different IMiDs are currently used in clinical practice in combination with PI, such as Lenalidomide (LEN) and Pomalidomide (POM), having both cereblon as the main target...Aims: This project's focus was to evaluate the molecular mechanism of resistance to IMiDs resistance, namely LEN and POM, in MM cells and assess the cross-resistance to Bortezomib (BTZ)... The resistant models developed show different degrees of resistance according to IMiD and cell line. In LEN- resistant models, H929-RL and U-266RL cells presented an IC 25 6.5x and over 1000x higher compared to parental cells, respectively. The U-266RP cells showed an IC 25 500x higher than U-266 cells.

Per HOVON-87/NMSG-18 trial protocol, these patients were treated with thalidomide or lenalidomide combined with melphalan and prednisone followed by thalidomide/lenalidomide maintenance (i.e. MPT-T or MPR-R). In conclusion, higher expression of nuclear CRBN was associated with a superior PFS and OS upon MPT or MPR treatment. Levels of nuclear CRBN protein, possibly in combination with IRF-4, may represent a biomarker for predicting treatment outcome in patients treated with IMiDs.

Our findings show convincingly that carbohydrate metabolism regulated by 6PGD is linked to prostate cancer metastasis via CRBN. Based on these data, we propose that the 6PGD-CRBN axis may be a suitable target for further research into new therapeutics for mitigating prostate cancer metastasis.

Moreover, treatment with SIAIS361034 results in no impairment on the bone growth of young mice, accompanying no alteration of the expression of Bcl-x and Gli1 proteins. Our findings demonstrate that selectively targeting Bcl-x by PROTAC is a promising strategy for combating resistance to Smo inhibitors without causing on-target drug toxicities of bone growth.

Lenalidomide and fenofibrate showed opposite effects on acylcarnitines and amino acids. Co-administration of immunomodulatory drugs and PPAR agonists was associated with inferior treatment responses and poor survival. Our study provides the first evidence that PPAR agonists reduce CRBN expression through various mechanisms including inducing methylation of CRBN promoter CpG island, enhancing CRBN protein degradation, and affecting metabolomics of MM cells.

All 5 patients were exposed in previous lines to lenalidomide and pomalidomide. All patients were treated with CC-92480 in combination with dexamethasone...Streptavidin pulldown and immunoprecipitation assays showed decreased binding of thalidomide, DDB1 and CUL4A to R309H-CRBN mutant compared to WT-CRBN... We here defined in primary patient plasma cells the mechanisms of resistance to the novel CELMoD CC-92480 to be driven by biallelic CRBN copy number loss or alteration of its structure, resulting from CRBN mutations or splicing (exon 10) coupled with monoallelic 3p loss. COP9 signalosome subunits gene expression decreased in resistant patients and may also play a critical role in CELMoD sensitivity.

The development of immunomodulatory drugs (IMiDs) such as lenalidomide has profound immunostimulatory effects and direct anti-MM activity; however, acquired resistance to IMiDs commonly underlies relapse, rendering MM largely incurable...The potential role of ADAR1 in modulating immunotherapeutic responses may help unravel potential resistance mechanisms and identify novel therapeutic strategies. Current studies involve elucidating the association of ADAR1 with CRBN pathway.

In this study, the survival time of the patients who received treatment regimens containing protease inhibitors and IMiD was longer, independent of the presence of strong nuclear CRBN expression. The survival rate was significantly higher in those who used IMiD and protease inhibitors in combination. Since the survival rate was found to be increased in IgG positive cases and we thought that evaluation of immunoglobulin tissue expression in MM cases can provide prognostic prediction.

High PPAR expression was correlated with poor clinical outcomes. Our study provides the first evidence that PPARs transcriptionally regulate CRBN and that drug-drug interactions between PPAR agonists and IMiDs may impact myeloma treatment outcomes.

Multicolor flow cytometry, or next-generation flow, and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10. Sustained MRD negativity is related to prolonged survival, and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.

Phthalimide derivatives, such as thalidomide, were tethered to the 3’ end of the decoy molecule without or with aliphatic linkers of different length...To our knowledge, this is the first demonstration that the PROTAC strategy can be employed to decoy DNA-based targeting of undruggable TFs. Our initial results underscore the potential of using this strategy for cell-selective targeting of oncogenic and immunosuppressive STAT3 with potential application to cancer immunotherapy.

CD56 signaling promotes MM growth and adhesion, by activating CREB1 target genes, MCL1 and BCL2. Inhibition of CREB1 alone or in combination with lenalidomide is an unexplored synthetic lethal approach in CD56-expressing MM patients.

Immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide, are used in the routine treatment for multiple myeloma (MM) patients...Interestingly, we found that an EZH2 sensitivity gene expression signature also correlated with high BATF or venetoclax sensitivity scores in these tumors. Together, these data provide a rationale for investigating EZH2 inhibitors or venetoclax in combination with the next generation CRBN-targeting agents, such as CELMoDs, for patients overexpressing the CRBN exon-10 splice variant.

There are multiple gene mutations and overexpression in NDMM. However, there is no dominated single mutation or overexpression of genes. The most common gene mutations are those in the RAS/MAPK pathway and the genes of cyclin family CCND are overexpression.

Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2 (CK2) mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.

JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Further, JQAD1 activity is critically determined by cereblon (CRBN) expression across neuroblastoma cells.

ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.

In conclusion, our study defines an effective threshold for therapeutic intervention in CD56-expressing MM patients. Moreover, our data pioneer the use of CREB1/RSK2 inhibition in CD56-expressing MM cells, either as single agents or in combination with lenalidomide, suggesting that CD56 can be a prognostic and predictive factor of response in MM.

Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition.

Based on these results, we constructed a new nomogram model to predict high CRBN expression and the effectiveness of IMiD therapy in multiple myeloma. This nomogram could improve the prognostic evaluation of myeloma patients exhibiting high CRBN expression treated with IMiD therapy and might help provide personalized treatment strategies to clinicians.