Additionally, this degradation was inhibited by the proteasome inhibitor MG132. As a part of the ongoing effort to develop HIF-1 inhibitors, targeting the degradation of HIF-1α may offer an effective treatment strategy against solid tumors.

Moreover, Pin1 inhibition combined with Pyk2 inhibition decreases myeloma burden both in vitro and in vivo. Altogether, our findings reveal the tumor-promoting role of Pin1 in MM and provide evidence that targeting Pin1 could be a therapeutic strategy for MM.

In PC cells, the inhibition of Rac1 leads to a time-dependent decline in YAP protein, which could be blocked by proteosome inhibitor MG132... These results reveal Rac1 as an oncogenic KRAS effector that contributes to YAP stabilization in PC cells. They also show that this regulation of YAP by Rac1 requires the SCFβTrCP ligase but occurs independently of the LATS1/2 kinases.

Additionally, molecule A7 reversed growth factor IL-6 induced MM cell proliferation, improved the antiproliferative activity of Ixazomib and increased the apoptotic rate of MM cells treated with Ixazomib. Collectively, potent SIRT3 inhibitors with MM cell differentiation potency were developed for the cancer therapy used alone or in combination.

DSF alone overcomes CFZ resistance through lipid peroxidation elevation and acts synergistically with CFZ in CFZ-resistant MM cell lines. Our results suggest that DSF is a promising anti-myeloma agent for overcoming CFZ resistance in MM through ferroptosisinduction.

Polyubiquitinated bands of SOX17 were observed in MG132 treated OVTOKO, but not in OVISE or RMG-V OCCC cells...These findings indicate that SOX17 is not uniformly and heterogeneously expressed in OCCCs, independent of ARID1A deficiency. Impaired ubiquitin-mediated proteasome degradation may stabilize SOX17 in some OCCC cells.

P3, N=847, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

P=N/A, N=50, Recruiting, The First Affiliated Hospital of Soochow University

The regulatory effect of FMRP on DDX5 protein expression was assessed using the protein synthesis inhibitor cycloheximide (CHX) and proteasome inhibitor MG132...On the other hand, the expression of these proteins was reversed by combined FMRP overexpression (P<0.05). FMRP targets DDX5 and promotes BC cell migration and EMT via the activation of the Wnt/β-catenin signaling pathway.

Thrombocytopenia was associated with the activity of NDMM and predicted prognosis in NDMM. When combined with high CRP levels, thrombocytopenia serves as a new indicator of poor prognosis in these patients.

In our study, as in previous similar studies, we could not see the increased survival trend in pPCL which is observed in MM. New studies are needed for pPCL patients, which is likely to increase with the new diagnostic criteria, based on current agents and information in MM.

We recently reported that increased expression of ST3GAL1 was associated with inferior PFS in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed MM patients treated with bortezomib, thalidomide, and dexamethasone (VTd) +/- Dara as induction and consolidation within the CASSIOPEIA study. Within part 2 of CASSIOPEIA, increased expression of ST3GAL1 is significantly associated with inferior PFS and predicts lack of sustained MRD and disease progression in patients MRD negative (10-5) prior to the onset of maintenance therapy or observation. Our preliminary data suggest that desialylation strategies, currently in clinical development, could help achieve deep and durable remissions in MM patients receiving current Dara based quadruplet treatment approaches.

The prediction model based on bone marrow MVD and vasogenesis factors (VEGF, HGF, bFGF) in MM patients has higher clinical evaluation performance and predictive value.

Ixazomib combined with thalidomide and dexamethasone is effective in the treatment of MM, with good short-term efficacy, survival and safety. However, its long-term efficacy needs further observation.

Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM.

ESCC cell lines (KYSE150 and TE10) were treated with the proteasome inhibitor MG-132, followed by siRNA screening of deubiquitinases (DUBs) to identify regulators of WISP1...Furthermore, knockdown of USP13 or WISP1 impaired the activation of the Wnt/CTNNB1 signaling pathway and reduced immune checkpoint marker expression, indicating a mechanism by which USP13 promotes immune evasion in ESCC. USP13 stabilizes WISP1 through deubiquitination, enhancing ESCC progression by activating the Wnt/CTNNB1 pathway and promoting immune evasion, making USP13 a potential therapeutic target in ESCC.

P1, N=80, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2024 --> Sep 2026 | Trial primary completion date: Sep 2024 --> Sep 2026

P2, N=221, Completed, GlaxoSmithKline | Active, not recruiting --> Completed

HT exhibits anticancer activity against CRC probably by inhibiting Wnt/β-catenin signaling, with YAP playing an indispensible role during the process, highlighting HT as a potential novel candidate drug for CRC therapy.

Identifying the key gene MDK and its associated signaling pathways extends our understanding of the molecular processes that underlie resistance to BTZ in MCL. This discovery establishes a theoretical framework for future investigations of targeted therapy in clinical settings.

Therefore, a better understanding of its precise mechanism of action may help mitigate these side effects. In this review, we have discussed the proposed mechanisms of action and off target effects of Bortezomib, along with the prospects of next generation potential proteasome inhibitor drugs in the treatment of cancer.

ADAM8 regulates intracellular STAT3 levels via miR-181a-5p and NEAT1 in pancreatic cancer.

Significantly, KS18 triggered caspase-dependent apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. Furthermore, the study shows the tremendous impact of KS18 in inhibiting colony formation in bortezomib-resistant cells and demonstrates significant tumor shrinkage in KS18-treated NSG mice without notable toxicity signs after 4 weeks of therapy with a single acceptable dose each week, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance.

P1/2, N=37, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed

Our KCMC-PPB-1 is the first genuine, molecularly characterized PPB cell line. The cell line is transplantable to nu/nu mice; therefore, it is suitable for a preclinical model for new drug development. The cytotoxicity assay demonstrated that bortezomib is active in the current PPB model.

Methods Patients diagnosed with myeloma and concomitant dialysis-dependent renal dysfunction were admitted for ASCT after achieving at least partial response with bortezomib-based induction therapy. For both patients, mobilization consisted of granulocyte colony stimulating factor for 5 days and CD34 directed Plerixafor on Day 1...Use of reduced dose melphalan, pre-emptive dialysis after 24 hours and monitoring for acidosis and symptoms of uraemia to identify acidosis at an early stage allows safe administration of high dose chemotherapy. A major proportion of patients can potentially achieve reduction or freedom from dialysis support post-transplant.

P1/2, N=63, Completed, European Myeloma Network B.V. | Active, not recruiting --> Completed

P3, N=761, Recruiting, Pfizer | Active, not recruiting --> Recruiting

P2, N=130, Not yet recruiting, Novartis Pharmaceuticals

Moreover, treatment with AA but not 12-HETE partially abrogated the inhibitory effect of palmitic acid on MΦ-mediated MM cell survival in response to bortezomib or melphalan. Overall, we identified palmitic acid as a factor that inhibits MΦ-mediated resistance to bortezomib and melphalan in MM, which may have clinical significance.

P1, N=9, Not yet recruiting, Emory University | Initiation date: Aug 2024 --> Dec 2024

Remarkably, chemical inactivation of NF-кB synergized MG132-induced cell mortality. All the findings suggest that NF-кB dictates aggresome assembly via upregulating HDAC6, and NF-кB inhibitor may serve as a potential drug potentiating proteasome inhibitor medicine-induced cytotoxicity during the treatment of cancer cells.

The mice were infected with lentivirus and treated with proteasome inhibitor MG132...Overexpression of IRF1 or silencing TREM2 reversed the improvement of TRIM21 overexpression on lung injury in mice. In conclusion, TRIM21 reduced IRF1 expression by ubiquitination to improve TREM2 expression and ameliorate sepsis-induced ALI.

MG132 enhances the therapeutic efficacy of cisplatin in human EC cells by suppressing the ubiquitin- proteasome pathway, reducing cell viability, enhancing apoptosis, and shifting the inflammatory response. These findings highlighted the potential of MG132 as an adjuvant in endometrial cancer chemotherapy. Further research is needed to explore detailed mechanisms and clinical applications of this combination therapy.

P=N/A, N=83, Recruiting, Hospital General de Mexico | Trial completion date: Mar 2024 --> Oct 2024

P2, N=401, Active, not recruiting, Stichting European Myeloma Network | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: May 2024 --> Jun 2025

P2, N=236, Active, not recruiting, Washington University School of Medicine | Trial completion date: Aug 2024 --> Aug 2025

P1, N=61, Completed, Amgen | Phase classification: P1b --> P1

P=N/A, N=160, Recruiting, Takeda | N=320 --> 160 | Trial completion date: Oct 2025 --> Jun 2027 | Trial primary completion date: Oct 2025 --> Jun 2027

Meanwhile, the reduction of PD-L1 protein levels by Z2d/Z3d was counteracted by MG132, which indicated that Z2d/Z3d degraded PD-L1 through the proteasome pathway. Moreover, the molecular modeling results indicated that the HyT group of Z2d or Z3d extended the surface of the protein to mimic the misfold. Importantly, our work also identified a novel HyT, which could be applied to develop the HyTTD for other target proteins.

P1, N=30, Not yet recruiting, Augusta University | Initiation date: Jan 2024 --> Oct 2024

Further, bortezomib-mediated killing of MM cells could be enhanced or inhibited by in vitro manipulation of UPR activities in representative cell lines. In conclusion, MCL1-M based molecular subtypes of MM are characterized by distinct signaling activities from both malignant cells and bone marrow microenvironment, which may drive distinct prognosis and treatment responses.