P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Mar 2025 | Trial primary completion date: Dec 2024 --> Mar 2025

After 96 h from inhibitor removal, the G361 line presented signs of senescence (increased level of SA-β-galactosidase, IL-8, P-P53, G2/M and S phases of cell cycle, decreased lamin B1 and cleaved lamin B1), while the A375 line demonstrated more signs of apoptosis (increased subG1 phase, P-P53, cleaved lamin B1). The gathered findings suggest that MZB resulted in the induction of cellular senescence (line G361) or enhanced apoptosis (line A375) in the melanoma cell lines tested here and could be a promising therapeutic factor in malignant melanoma treatment.

P2, N=3, Active, not recruiting, M.D. Anderson Cancer Center | N=24 --> 3 | Trial completion date: Jun 2024 --> Dec 2025

P2, N=61, Active, not recruiting, Omar Nadeem, MD | Recruiting --> Active, not recruiting | Trial completion date: Mar 2029 --> Dec 2030 | Trial primary completion date: Mar 2026 --> Dec 2026

All mAB-treated patients with malignancies developed polyfunctional immunity humoral and T-cell immunity to SARS-CoV-2 even in the setting of B-cell deficiency. The evolution of this immunity, including new variant-specific antibodies, without secondary illnesses suggests that patients were protected from symptomatic re-infection, and mAB therapy did not blunt the development of host immunity. Future studies are warranted to better characterize immunologic memory over time with exposures to new viral variants, evaluate prolonged viral shedding and the continued use of appropriate mAB for infection in high-risk patients.

P=N/A, N=26, Completed, University of Turin, Italy | Recruiting --> Completed | N=100 --> 26 | Trial completion date: Sep 2022 --> Dec 2024

Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib...In the case of drug intervention, SP-A attenuates the binding of SSRP1 and USP10 by inhibiting protein interactions between TRIB3 and SSRP1 and promoted SSRP1 protein degradation, leading to significant inhibition of MM development. Visual abstract created with Biorender.

We further showed that FAK-I reduced DNMT3A expression in breast cancer cells and that treatment with the proteasome inhibitor MG132 prevented loss of DNTM3A protein stability...Immunostaining of 4T1 tumors showed FAK-I decreased DNMT3A, DNA methylation (5-methylcytosine, 5-mC), and increased DAB2 expression. Taken together, these data suggest that nuclear FAK-mediated regulation of DNMT3A can alter the epigenetic landscape and induce tumor suppressor gene expression.

We corroborated these findings in human MM datasets, and in ex vivo patient MM cells. These preclinical studies suggest that ASAH1 may be a potential therapeutic target for the treatment of relapsed/refractory MM (RRMM).

The observation that CAV1 inhibition modulated by 6-mercaptopurine, daidzin, and statins enhances the efficacy of bortezomib in vitro and in vivo highlights the translational significance of these FDA-approved drugs in improving MM outcomes. These data demonstrate that CAV1 serves as a potent therapeutic target for enhancing chemotherapy and immunotherapy for MM.

Doxorubicin enhances bortezomib-induced cell death in MM by inhibiting aggresome formation and amplifying ER/Golgi stress and apoptosis. This study highlights the potential therapeutic benefits of combining bortezomib with doxorubicin for MM treatment.

Important advances include the development of compounds with novel MOA, including apratoxin and coibamide A analogues, modulating cotranslational translocation at the level of Sec61 in the endoplasmic reticulum, largazole and santacruzamate A targeting class I histone deacetylases, and proteasome inhibitors based on carmaphycins, resembling the approved drug carfilzomib...The review covers the state of current knowledge of marine cyanobacteria as anticancer agents with a focus on the mechanism, target identification and potential for drug development. We highlight the importance of solving the supply problem through chemical synthesis as well as illuminating the biological activity and in-depth mechanistic studies to increase the value of cyanobacterial natural products to catalyze their development.

Finally, we demonstrated that the NF-κB inhibitor Bortezomib further enhances DNMT2 deletion-induced apoptosis in hepatocellular carcinoma cells. This study reveals DNMT2's role in liver cancer and presents a new therapeutic target for future treatments.

We revealed a new regulatory effect of OA in CRC tumorigenesis via PPARγ-mediated Nur77 ubiquitin degradation.

P1/2, N=68, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Sep 2024 --> Dec 2024

Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3ITDTet2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.

These findings suggest that MG132 exerts potent anti-leukemic effects through modulation of the Akt/FOXO3a/Bim axis, offering a promising therapeutic avenue for treating ALL.

These data suggest that combination therapy involving bortezomib and the DA regimen may represent a promising strategy for HL-AML.

P1, N=72, Recruiting, Queen Mary University of London | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Aug 2024 --> Jun 2025

P1/2, N=0, Withdrawn, Kathleen Dorritie | N=34 --> 0 | Recruiting --> Withdrawn

P1/2, N=101, Active, not recruiting, University of Chicago | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P2, N=54, Completed, Amgen | Active, not recruiting --> Completed

Drug sensitivity analysis revealed altered IC50 values for drugs like 5-fluorouracil and bortezomib. CNN3 and LGR4 were identified as modulators of cAML progression, making them potential therapeutic targets. Future studies with larger cohorts are essential to validate these findings and further explore CRGs-targeted therapies.

P2, N=18, Completed, Institute of Hematology & Blood Diseases Hospital, China | Terminated --> Completed | Trial completion date: Feb 2024 --> Sep 2024 | Trial primary completion date: Jan 2024 --> Jul 2024

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. Conclusions : 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