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Nature Communications Mar 2023Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be...
Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients.
Topics: Humans; Bortezomib; Multiple Myeloma; Proteasome Inhibitors; Drug Resistance, Neoplasm; Cell Line, Tumor; Transcription Factors; Antineoplastic Agents; Proteasome Endopeptidase Complex
PubMed: 36894562
DOI: 10.1038/s41467-023-37013-x -
British Journal of Haematology Jul 2019While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with... (Clinical Trial)
Clinical Trial
While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18-36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0-3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58-65% vs. MRDpos 10-19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.
Topics: Adolescent; Adult; Bortezomib; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Male; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Survival Rate; Time Factors
PubMed: 30957229
DOI: 10.1111/bjh.15919 -
Biomolecules Dec 2021Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby... (Review)
Review
Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.
Topics: Adult; Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Drug Delivery Systems; Humans; Multiple Myeloma; Proteasome Inhibitors
PubMed: 35053199
DOI: 10.3390/biom12010051 -
Blood Cancer Journal Dec 2016Acute myeloid leukemia (AML) is deadly hematologic malignancy. Despite a well-characterized genetic and molecular landscape, targeted therapies for AML have failed to... (Review)
Review
Acute myeloid leukemia (AML) is deadly hematologic malignancy. Despite a well-characterized genetic and molecular landscape, targeted therapies for AML have failed to significantly improve clinical outcomes. Over the past decade, proteasome inhibition has been demonstrated to be an effective therapeutic strategy in several hematologic malignancies. Proteasome inhibitors, such as bortezomib and carfilzomib, have become mainstays of treatment for multiple myeloma and mantle cell lymphoma. In light of this success, there has been a surge of literature exploring both the role of the proteasome and the effects of proteasome inhibition in AML. Pre-clinical studies have demonstrated that proteasome inhibition disrupts proliferative cell signaling pathways, exhibits cytotoxic synergism with other chemotherapeutics and induces autophagy of cancer-related proteins. Meanwhile, clinical trials incorporating bortezomib into combination chemotherapy regimens have reported a range of responses in AML patients, with complete remission rates >80% in some cases. Taken together, this preclinical and clinical evidence suggests that inhibition of the proteasome may be efficacious in this disease. In an effort to focus further investigation into this area, these recent studies and their findings are reviewed here.
Topics: Autophagy; Bortezomib; Cell Proliferation; Humans; Leukemia, Myeloid, Acute; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Signal Transduction
PubMed: 27911437
DOI: 10.1038/bcj.2016.112 -
Cell Metabolism Jan 2024The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In...
The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.
Topics: Humans; Bortezomib; Multiple Myeloma; Gastrointestinal Microbiome; Cell Line, Tumor; Membrane Proteins; NIMA-Related Kinases; Solute Carrier Family 12, Member 2
PubMed: 38113887
DOI: 10.1016/j.cmet.2023.11.019 -
Expert Opinion on Investigational Drugs Oct 2020Glioblastoma is a primary brain tumor with a poor prognosis despite multimodal therapy including surgery, radiotherapy and alkylating chemotherapy. Novel therapeutic... (Review)
Review
INTRODUCTION
Glioblastoma is a primary brain tumor with a poor prognosis despite multimodal therapy including surgery, radiotherapy and alkylating chemotherapy. Novel therapeutic options are therefore urgently needed; however, there have been various drug failures in late-stage clinical development. The proteasome represents a key target for anti-cancer therapy as successfully shown in multiple myeloma and other hematologic malignancies.
AREAS COVERED
This review article summarizes the preclinical and clinical development of proteasome inhibitors in the context of glioblastoma.
EXPERT OPINION
Early clinical trials with bortezomib ended with disappointing results, possibly because this agent does not cross the blood-brain barrier. In contrast to bortezomib and other proteasome inhibitors, marizomib is a novel drug that displays strong inhibitory properties on all enzymatic subunits of the proteasome and, most importantly, crosses the blood-brain barrier, making it a potentially very active novel agent against intrinsic brain tumors. While preclinical studies have demonstrated significant anti-glioma activity, its clinical benefit has yet to be proven. Exploiting the biological effects of proteasome inhibitors in combination with other therapeutic strategies may represent a key next step in their clinical development.
Topics: Animals; Antineoplastic Agents; Bortezomib; Brain Neoplasms; Drug Development; Glioblastoma; Humans; Lactones; Proteasome Inhibitors; Pyrroles
PubMed: 32746640
DOI: 10.1080/13543784.2020.1803827 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2024Daratumumab, lenalidomide and dexamethasone (DRd) and bortezomib, lenalidomide and dexamethasone (VRd) are preferred regimens for transplant ineligible (TIE) patients...
Progression-Free Survival of Daratumumab Versus Bortezomib Triplet Combination With Lenalidomide and Dexamethasone in Transplant Ineligible Patients With Newly Diagnosed Multiple Myeloma: TAURUS Chart Review Study.
BACKGROUND
Daratumumab, lenalidomide and dexamethasone (DRd) and bortezomib, lenalidomide and dexamethasone (VRd) are preferred regimens for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). Both DRd and VRd demonstrated superior efficacy versus Rd in the MAIA and SWOG S0777 trials, respectively, but there is no head-to-head (H2H) clinical trial comparing their efficacy. Differing populations in the MAIA and S0777 trials make an unadjusted comparison of outcomes challenging and biased. The current TAURUS study is the first real-world H2H study comparing progression-free survival (PFS) among TIE NDMM patients treated with DRd or VRd as first-line (1L) in similar clinical settings.
MATERIALS AND METHODS
A multicenter chart review study was conducted at nine sites across the United States. All TIE patients treated with DRd and a randomly selected population of VRd patients were included. TIE NDMM patients aged ≥65 were included if they initiated 1L DRd/VRd between January 2019 and September 2021. PFS was defined as the time from DRd/VRd initiation until disease progression or death. A doubly-robust multivariable Cox regression model combined with inverse probability of treatment weighting (IPTW) methodology was used to compare PFS between cohorts.
RESULTS
Weighted cohorts comprised 91 DRd and 87 VRd patients. Thirteen DRd and 24 VRd patients experienced progression/death. Patients treated with DRd had a lower risk of progression/death versus VRd (adjusted hazard ratio: 0.35, 95% confidence interval: [0.17; 0.73]).
CONCLUSION
DRd is associated with a significantly lower risk of disease progression or death compared to VRd as 1L treatment for TIE NDMM patients.
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease Progression; Lenalidomide; Multiple Myeloma; Progression-Free Survival; Aged; Clinical Trials as Topic
PubMed: 37838502
DOI: 10.1016/j.clml.2023.09.003 -
Hematology/oncology and Stem Cell... Dec 2020
Topics: Anemia, Hemolytic, Autoimmune; Bortezomib; Humans; Purpura, Thrombocytopenic, Idiopathic
PubMed: 31202670
DOI: 10.1016/j.hemonc.2019.05.006 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2023In the phase 3 LEPUS study, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone in Chinese patients with relapsed... (Randomized Controlled Trial)
Randomized Controlled Trial
Daratumumab, Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS.
BACKGROUND
In the phase 3 LEPUS study, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Here, we report updated efficacy and safety results from LEPUS.
PATIENTS AND METHODS
Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to bortezomib (1.3 mg/m) and dexamethasone (20 mg) for eight cycles ± daratumumab (16 mg/kg) until disease progression. The primary endpoint was progression-free survival (PFS).
RESULTS
In total, 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a 25.1-month median follow-up, D-Vd prolonged PFS versus Vd (median, 14.8 vs. 6.3 months; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.51; P < .00001). PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib (HR, 0.36; 95% CI, 0.25-0.53), patients who were refractory to last prior line of therapy (HR, 0.42; 95% CI, 0.27-0.65), and patients with high-risk cytogenetics (HR, 0.41; 95% CI, 0.23-0.71). Overall response rate (84.7% vs.66.7%; P = .00314) and rates of very good partial response or better (71.5% vs. 34.9%; P < .00001) and complete response or better (40.1% vs 14.3%; P = .00016) were higher with D-Vd versus Vd. No new safety concerns were identified.
CONCLUSIONS
In this updated analysis, D-Vd maintained significant efficacy benefits versus Vd alone and demonstrated a consistent safety profile, further supporting the use of D-Vd as a standard of care in Chinese patients with RRMM.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; East Asian People; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 36402700
DOI: 10.1016/j.clml.2022.10.007 -
The Oncologist Jul 2022Patients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment...
BACKGROUND
Patients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options. Recent meta-analyses evaluating the impact of incorporating daratumumab in the backbone regimen on progression-free survival (PFS) have found mixed results in these patients.
MATERIALS AND METHODS
A pooled analysis of patient-level data for ASCT-ineligible patients with HR-NDMM [ie, del(17p), t(4;14), t(14;16)] from the MAIA and ALCYONE trials; stratified by study identifier and adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, myeloma type, and renal impairment; was conducted. Impact of daratumumab on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR) was compared to control.
RESULTS
Among 101 patients in the daratumumab and 89 patients in the control cohort, median follow-up was 43.7 months. Daratumumab reduced the risk of progression or death by 41% (adjusted hazard ratio for PFS [95% confidence interval (CI)] = 0.59 [0.41-0.85]) versus control. At 36 months, the estimated proportion of patients who did not progress and were still alive was 41.3% in the daratumumab and 19.9% in the control cohort. Rates of ≥CR (41.6% vs. 22.5%), MRD-negative CR (24.8% vs. 5.6%), ≥VGPR (75.2% vs. 46.1%), and ORR (92.1% vs. 74.2%) were higher for daratumumab versus control.
CONCLUSION
These findings demonstrate that incorporation of daratumumab in frontline treatment regimens reduced the risk of progression or death and improved response rates among ASCT-ineligible HR-NDMM patients.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Multiple Myeloma; Progression-Free Survival; Treatment Outcome
PubMed: 35462406
DOI: 10.1093/oncolo/oyac067