ABSTRACT
Proteasome inhibitors (PIs), such as bortezomib and calfizomib, were backbone agents in the treatment of multiple myeloma (MM). In this study, we investigated bortezomib interactors in MM cells and identified dihydrolipoamide dehydrogenase (DLD) as a molecular target of bortezomib. DLD catalyzes the oxidation of dihydrolipoamide to form lipoamide, a reaction that also generates NADH. Our data showed that bortezomib bound to DLD and inhibited DLD's enzymatic function in MM cells. DLD knocked down MM cells (DLD-KD) had decreased levels of NADH. Reduced NADH suppressed assembly of proteasome complex in cells. As a result, DLD-KD MM cells had decreased basal-level proteasome activity and were more sensitive to bortezomib. Since PIs were used in many anti-MM regimens in clinics, we found that high expression of DLD correlated with inferior prognosis of MM. Considering the regulatory role of DLD in proteasome assembly, we evaluated DLD targeting therapy in MM cells. DLD inhibitor CPI-613 showed a synergistic anti-MM effect with bortezomib in vitro and in vivo. Overall, our findings elucidated DLD as an alternative molecular target of bortezomib in MM. DLD-targeting might increase MM sensitivity to PIs.
Subject(s)
Bortezomib , Dihydrolipoamide Dehydrogenase , Multiple Myeloma , Bortezomib/pharmacology , Humans , Dihydrolipoamide Dehydrogenase/metabolism , Dihydrolipoamide Dehydrogenase/genetics , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Multiple Myeloma/metabolism , Multiple Myeloma/enzymology , Animals , Cell Line, Tumor , Proteasome Endopeptidase Complex/metabolism , Antineoplastic Agents/pharmacology , Mice , Proteasome Inhibitors/pharmacology , Xenograft Model Antitumor Assays , NAD/metabolism , Female , Male , Molecular Targeted TherapyABSTRACT
Computational pharmacogenomics can potentially identify new indications for already approved drugs and pinpoint compounds with similar mechanism-of-action. Here, we used an integrated drug repositioning approach based on transcriptomics data and structure-based virtual screening to identify compounds with gene signatures similar to three known proteasome inhibitors (PIs; bortezomib, MG-132, and MLN-2238). In vitro validation of candidate compounds was then performed to assess proteasomal proteolytic activity, accumulation of ubiquitinated proteins, cell viability, and drug-induced expression in A375 melanoma and MCF7 breast cancer cells. Using this approach, we identified six compounds with PI properties ((-)-kinetin-riboside, manumycin-A, puromycin dihydrochloride, resistomycin, tegaserod maleate, and thapsigargin). Although the docking scores pinpointed their ability to bind to the ß5 subunit, our in vitro study revealed that these compounds inhibited the ß1, ß2, and ß5 catalytic sites to some extent. As shown with bortezomib, only manumycin-A, puromycin dihydrochloride, and tegaserod maleate resulted in excessive accumulation of ubiquitinated proteins and elevated HMOX1 expression. Taken together, our integrated drug repositioning approach and subsequent in vitro validation studies identified six compounds demonstrating properties similar to proteasome inhibitors.
Subject(s)
Bortezomib , Drug Repositioning , Proteasome Inhibitors , Humans , Proteasome Inhibitors/pharmacology , Proteasome Inhibitors/chemistry , Drug Repositioning/methods , Bortezomib/pharmacology , Transcriptome , Proteasome Endopeptidase Complex/metabolism , Cell Line, Tumor , MCF-7 Cells , Molecular Docking Simulation , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Puromycin/pharmacology , Gene Expression Profiling , Cell Survival/drug effectsABSTRACT
Repurposing of FDA-approved drugs is a quick and cost-effective alternative to de novo drug development. Here, we identify genes involved in bortezomib sensitivity, predict cancer types that may benefit from treatment with bortezomib, and evaluate the mechanism-of-action of bortezomib in breast cancer (BT-474 and ZR-75-30), melanoma (A-375), and glioblastoma (A-172) cells in vitro. Cancer cell lines derived from cancers of the blood, kidney, nervous system, and skin were found to be significantly more sensitive to bortezomib than other organ systems. The in vitro studies confirmed that although bortezomib effectively inhibited the ß5 catalytic site in all four cell lines, cell cycle arrest was only induced in G2/M phase and apoptosis in A-375 and A-172 after 24h. The genomic and transcriptomic analyses identified 33 genes (e.g. ALDH18A1, ATAD2) associated with bortezomib resistance. Taken together, we identified biomarkers predictive of bortezomib sensitivity and cancer types that might benefit from treatment with bortezomib.
Subject(s)
Antineoplastic Agents , Bortezomib , Drug Repositioning , Hematologic Neoplasms , Humans , Bortezomib/pharmacology , Bortezomib/therapeutic use , Drug Repositioning/methods , Cell Line, Tumor , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/genetics , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Apoptosis/drug effects , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Female , MultiomicsABSTRACT
Objective: To explore the efficacy and safety of domestic bortezomib in combination with lenalidomide and dexamethasone in the treatment of newly diagnosed multiple myeloma (NDMM) . Methods: This multicenter, prospective, single-arm clinical study included 126 patients with NDMM admitted to seven hospitals between December 2019 and January 2022. All patients received domestic bortezomib in combination with lenalidomide and dexamethasone (BLD regimen), and the efficacy, prognostic factors, and safety were analyzed. Results: Among the 126 patients with NDMM, 118 completed four cycles of treatment, with an overall response rate (ORR) of 93.22% (110/118) and a ≥very good partial response (VGPR) rate of 68.64% (81/118). Ultimately, 114 patients completed at least eight cycles of treatment, with an ORR of 92.98% (106/114) and a ≥VGPR rate of 77.19% (88/114). Eighteen patients underwent autologous hematopoietic stem cell transplantation after completing 6-8 cycles of the BLD regimen, with an ORR of 100% (18/18) and a ≥VGPR rate of 88.9% (16/18). The proportion of patients achieving ≥VGPR increased with the treatment duration, and factors such as staging and age did not significantly affect efficacy. Single-factor analysis showed that R2-ISS stage â ¢/â £, blood calcium >2.27 mmol/L, and failure to achieve VGPR after six cycles were adverse prognostic factors for progression-free survival (PFS) (P<0.05), whereas failure to achieve VGPR after six cycles was an adverse prognostic factor for overall survival (OS) (P<0.001). Multifactor analysis demonstrated that failure to achieve VGPR after six cycles is an independent adverse prognostic factor for PFS (P=0.002). The incidence of hematologic adverse reactions was 16.7% (19/114), and nonhematologic adverse reactions were mainly mild to moderate, with no significant cardiac or renal adverse reactions observed. Conclusion: The BLD regimen is effective in treating NDMM, in which patients with high-risk genetic features are still achieving a high ≥VGPR rate, and the overall safety is good.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bortezomib , Dexamethasone , Lenalidomide , Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/diagnosis , Dexamethasone/administration & dosage , Lenalidomide/administration & dosage , Bortezomib/administration & dosage , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prognosis , Hematopoietic Stem Cell Transplantation , Treatment Outcome , Male , Female , Middle AgedABSTRACT
Although the significant strides in novel therapeutic approaches have prolonged the survival of multiple myeloma (MM) patients, the unfavorable prognosis of cytogenetically high-risk newly diagnosed MM (NDMM) remains intractable with the lack of consensus regarding the choice of maintenance regimens. Therefore, this study was initiated with the aim of examining the effectiveness of various maintenance treatments for this group of patients in jeopardy. Overall, 17 studies with 1937 high-risk NDMM patients were included in the network meta-analysis. Combination therapies involving novel drugs presented encouraging prospects in the maintenance phase, while the patients and circumstances for the application of different regimens still needed to be further distinguished and clarified. To investigate the current status of maintenance therapy of high-risk NDMM patients in clinical practice, a real-world cohort of high-risk NDMM was retrospectively incorporated 80 patients with lenalidomide maintenance and 53 patients with bortezomib maintenance, presenting the median PFS of 31.7 months and 30.4 months, respectively (p = 0.874, HR = 0.966, 95% CI: 0.628-1.486). Collectively, this study illuminated the present constraints of conventional approaches during the maintenance phase for high-risk NDMM patients while highlighting the future potential associated with enhanced regimens integrating novel medications.
Subject(s)
Lenalidomide , Maintenance Chemotherapy , Multiple Myeloma , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Humans , Lenalidomide/therapeutic use , Bortezomib/therapeutic use , Male , Female , Middle Aged , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Retrospective Studies , Antineoplastic Agents/therapeutic use , Treatment OutcomeABSTRACT
Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy.
Subject(s)
Gene Expression Regulation, Neoplastic , Multiple Myeloma , Protein Phosphatase 1 , Proteostasis , Super Enhancers , Transcription Factor CHOP , Animals , Humans , Activating Transcription Factor 4/metabolism , Activating Transcription Factor 4/genetics , Bortezomib/pharmacology , Cell Line, Tumor , Eukaryotic Initiation Factor-2/metabolism , Eukaryotic Initiation Factor-2/genetics , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Protein Phosphatase 1/metabolism , Protein Phosphatase 1/genetics , Super Enhancers/genetics , Transcription Factor CHOP/metabolism , Transcription Factor CHOP/geneticsABSTRACT
RATIONALE: TAFRO syndrome is a systemic inflammatory disorder, manifesting as thrombocytopenia (t), anasarca (a), fever (f), reticulin myelofibrosis/renal insufficiency (r), and organomegaly (o), and considered as a unique clinical subtype of idiopathic multicentric Castleman disease (iMCD). Such syndrome gave rise to a clinical picture similar to that of either a connective tissue disease or an autoimmune disease. PATIENT CONCERNS: A Chinese young female initially presenting with arthralgia, Raynaud phenomenon, generalized edema, and a positive anti-small nuclear ribonucleoprotein particle antibody was diagnosed as mixed connective tissue disease. The kidney biopsy showed thrombotic microangiopathy. Bone marrow smear showed bone marrow hyperplasia and biopsy revealed suspected light chain restricted expression, megakaryocyte proliferation, and moderate to severe bone marrow fibrosis. A lymph node biopsy was conducted and the histopathological findings were consistent with the subtype of mixed Castleman disease. The clinical symptoms were relieved after regular chemotherapy. DIAGNOSES: After above examination results and clinical manifestations, the final diagnoses was TAFRO syndrome. INTERVENTION: The she was started on chemotherapy with bortezomib, cyclophosphamide, and dexamethasone. OUTCOME: After chemotherapy, symptoms such as thrombocytopenia, hematuria and proteinuria disappeared, lymphadenopathy and VEGF level decreased, and bone marrow fibrosis relieved. LESSONS: Our case illustrated the first cases of shared characteristics of mixed connective tissue disease and iMCD-TAFRO syndrome. Cytokines may play a role in the shared pathogenicity of the iMCD-TAFRO syndrome and systemic autoimmune diseases. Therapy directly against inflammatory factors such as corticosteroids or chemotherapy have an important therapeutic implication.
Subject(s)
Castleman Disease , Delayed Diagnosis , Thrombocytopenia , Humans , Female , Castleman Disease/diagnosis , Castleman Disease/drug therapy , Castleman Disease/pathology , Thrombocytopenia/diagnosis , Syndrome , Cyclophosphamide/therapeutic use , Fever/etiology , Edema/diagnosis , Edema/etiology , Bortezomib/therapeutic use , Adult , Dexamethasone/therapeutic useABSTRACT
PURPOSE: Given the high heterogeneity in survival for patients with multiple myeloma, it would be clinically useful to quantitatively predict the individual survival instead of attributing patients to two to four risk groups as in current models, for example, revised International Staging System (R-ISS), R2-ISS, or Mayo-2022-score. PATIENTS AND METHODS: Our aim was to develop a quantitative prediction tool for individual patient's 3-/5-year overall survival (OS) probability. We integrated established clinical and molecular risk factors into a comprehensive prognostic model and evaluated and validated its risk discrimination capabilities versus R-ISS, R2-ISS, and Mayo-2022-score. RESULTS: A nomogram for estimating OS probabilities was built on the basis of a Cox regression model. It allows one to translate the individual risk profile of a patient into 3-/5-year OS probabilities by attributing points to each prognostic factor and summing up all points. The nomogram was externally validated regarding discrimination and calibration. There was no obvious bias or overfitting of the prognostic index on the validation cohort. Resampling-based and external evaluation showed good calibration. The c-index of the model was similar on the training (0.76) and validation cohort (0.75) and significantly higher than for the R-ISS (P < .001) or R2-ISS (P < .01). CONCLUSION: In summary, we developed and validated individual quantitative nomogram-based OS prediction. Continuous risk assessment integrating molecular prognostic factors is superior to R-ISS, R2-ISS, or Mayo-2022-score alone.
Subject(s)
Bortezomib , Multiple Myeloma , Nomograms , Transplantation, Autologous , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Multiple Myeloma/drug therapy , Humans , Bortezomib/therapeutic use , Male , Female , Middle Aged , Aged , Prognosis , Hematopoietic Stem Cell Transplantation , Antineoplastic Agents/therapeutic use , Induction Chemotherapy , Adult , Survival RateABSTRACT
The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.
Subject(s)
Antibodies, Monoclonal , Antineoplastic Combined Chemotherapy Protocols , Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Multiple Myeloma/diagnosis , Aged , Female , Male , Middle Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Adult , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Bortezomib/therapeutic use , Bortezomib/administration & dosage , Lenalidomide/therapeutic use , Lenalidomide/administration & dosageABSTRACT
RATIONALE: Multiple myeloma (MM) with secondary amyloidosis (AL) is a rare clonal plasma cell proliferation disease, which causes dysfunction of multiple organs and tissues. We report a case of dysphagia as the first symptom in a patient with MM and secondary AL. PATIENT CONCERNS: The patient was a 73-year-old female, was admitted to our hospital, because of progressive dysphagia for 4 months and limb weakness for 1 month. DIAGNOSES: The bone marrow smear and pathology diagnosis revealed the presence of MM, while the biceps myopathy diagnosis indicated AL. INTERVENTIONS: The VCD regimen consisted of bortezomib at a dosage of 1.9 mg on days 1, 8, 15, and 22, cyclophosphamide 0.4 g on days 1, 8, and 15, and dexamethasone at a dosage of 40 mg on days 1, 8, 15, and 22. The patient simultaneously received comprehensive treatment including anti-infective therapy, enhanced cardiac function, and nutritional support. OUTCOMES: The M protein in the blood and urine protein were negative, indicating a reduction in bone marrow plasma cells to 2%. Flow cytometric analysis revealed a minimal percentage 0.04%. As a result, complete remission was achieved. LESSONS: The clinical manifestations of MM exhibit a wide range, with the symptoms of secondary injury causing significant disturbing, while the atypical symptoms of extramedullary manifestations pose challenges in diagnosing the disease.
Subject(s)
Amyloidosis , Deglutition Disorders , Multiple Myeloma , Humans , Multiple Myeloma/complications , Multiple Myeloma/diagnosis , Female , Aged , Deglutition Disorders/etiology , Amyloidosis/complications , Amyloidosis/diagnosis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/therapeutic use , Bortezomib/administration & dosageABSTRACT
Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.
Subject(s)
Bortezomib , Cell Cycle Proteins , Mitosis , Proteasome Endopeptidase Complex , Protein-Tyrosine Kinases , Pyroptosis , Pyroptosis/drug effects , Humans , Mice , Animals , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Mitosis/drug effects , Mitosis/genetics , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/genetics , Bortezomib/pharmacology , Cell Line, Tumor , Cell Cycle Proteins/genetics , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Proteasome Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrazoles/pharmacology , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Xenograft Model Antitumor Assays , Gasdermins , PyrimidinonesSubject(s)
Antineoplastic Combined Chemotherapy Protocols , Bortezomib , Bridged Bicyclo Compounds, Heterocyclic , Dexamethasone , Mutation , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Rituximab , Sulfonamides , Humans , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Bortezomib/administration & dosage , Bortezomib/therapeutic use , Rituximab/administration & dosage , Rituximab/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Tumor Suppressor Protein p53/genetics , Inotuzumab Ozogamicin , Child , Male , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/genetics , FemaleABSTRACT
PURPOSE: Proteasome inhibitors (PIs), which cause cell death via tumor suppressor and pro-apoptotic proteins, are integral to treatment of many hematologic malignancies but are limited by their gastrointestinal adverse effects. Evidence regarding these PI-related adverse effects is scant. In this study, we evaluated gastrointestinal adverse events caused by PIs and compared gastrointestinal toxicities between bortezomib, carfilzomib, and ixazomib. METHODS: We conducted a retrospective study of cancer patients treated with PIs at a tertiary care cancer center to investigate the clinical characteristics of PI-related gastrointestinal adverse events. RESULTS: Our sample comprised 973 patients with PI exposure and stool studies ordered between January 2017 and December 2022. Of these, 193 patients (20%) had PI-related gastrointestinal toxicity based on clinical symptoms and stool study results. The most common symptom was diarrhea, present in 169 (88% of those with gastrointestinal toxicity). Twenty-two (11%) required hospitalization, and 71 (37%) developed recurrence of symptoms. Compared to bortezomib or carfilzomib, ixazomib had a longer interval from PI initiation to the onset of gastrointestinal symptoms (313 days vs 58 days vs 89 days, p = 0.002) and a significantly lower percentage of diarrhea-predominant presentation of gastrointestinal toxicity (71% vs 96% vs 91%, p = 0.048). CONCLUSION: While PI-related gastrointestinal toxicities have various presentations and courses based on different regimens, the vast majority of patients presented with milder disease behavior. Despite a considerably high rate of hospitalization and recurrence after treatment necessitating optimization of clinical management, our cohort demonstrates favorable outcomes without long-term consequences.
Subject(s)
Boron Compounds , Bortezomib , Gastrointestinal Diseases , Glycine , Proteasome Inhibitors , Humans , Proteasome Inhibitors/adverse effects , Male , Female , Retrospective Studies , Middle Aged , Boron Compounds/adverse effects , Boron Compounds/therapeutic use , Aged , Glycine/analogs & derivatives , Glycine/adverse effects , Bortezomib/adverse effects , Bortezomib/administration & dosage , Gastrointestinal Diseases/chemically induced , Oligopeptides/adverse effects , Adult , Aged, 80 and overABSTRACT
It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Dexamethasone , Frailty , Lenalidomide , Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/therapy , Aged , Prospective Studies , Male , Female , Aged, 80 and over , Dexamethasone/therapeutic use , Dexamethasone/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Lenalidomide/therapeutic use , Lenalidomide/administration & dosage , Bortezomib/therapeutic use , Bortezomib/administration & dosage , Precision Medicine/methods , Frail Elderly , Geriatric Assessment/methods , Antibodies, MonoclonalABSTRACT
Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel Escherichia coli (E. coli) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg2+. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.
Subject(s)
Antineoplastic Agents , Ascorbic Acid , Metal-Organic Frameworks , T-Lymphocytes , Animals , Mice , Metal-Organic Frameworks/chemistry , Ascorbic Acid/chemistry , Ascorbic Acid/pharmacology , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Immunotherapy , Bortezomib/chemistry , Bortezomib/pharmacology , Bortezomib/therapeutic use , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Escherichia coli/drug effects , Silicon Dioxide/chemistry , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Magnesium/chemistry , Nanoparticles/chemistry , Humans , Cell Line, Tumor , Tumor Microenvironment/drug effects , Drug LiberationSubject(s)
Proteasome Inhibitors , Pulmonary Arterial Hypertension , Humans , Proteasome Inhibitors/adverse effects , Proteasome Inhibitors/therapeutic use , Pulmonary Arterial Hypertension/chemically induced , Pulmonary Arterial Hypertension/drug therapy , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/drug therapy , Bortezomib/adverse effectsSubject(s)
Antineoplastic Combined Chemotherapy Protocols , Black or African American , Bortezomib , Dexamethasone , Hematopoietic Stem Cell Transplantation , Lenalidomide , Multiple Myeloma , Transplantation, Autologous , Humans , Multiple Myeloma/therapy , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Lenalidomide/therapeutic use , Lenalidomide/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/therapeutic use , Bortezomib/administration & dosage , Prognosis , Treatment Outcome , Male , Female , Middle AgedABSTRACT
BACKGROUND: A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce proteotoxic stress. Phosphatase and tensin homolog (PTEN) have been reported to be involved in proteostasis, and PTEN-associated pathways are commonly altered in CCA. Celastrol, a triterpene from plants, exhibits cytotoxic effects in various types of cancer. However, the underlying mechanisms remain unclear. PURPOSE: We investigated the therapeutic effect of celastrol in CCA and identified the molecular characteristics of tumors that were sensitive to celastrol. The target of celastrol was explored. We then evaluated the candidate combination therapeutic strategy to increase the effectiveness of celastrol in celastrol-insensitive CCA tumors. METHODS: Various CCA cells were categorized as either celastrol-sensitive or celastrol-insensitive based on their response to celastrol. The molecular characteristics of cells from different groups were determined by RNA-seq. PTEN status and its role in proteasome activity in CCA cells were investigated. The CMAP analysis, molecular docking, and functional assay were performed to explore the effect of celastrol on proteasome activities. The correlation between PTEN status and clinical outcomes, as well as proteasomal activity, were measured in CCA patients. The synergistic therapeutic effect of autophagy inhibitors on celastrol-insensitive CCA cells were measured. RESULTS: Diverse responses to celastrol were observed in CCA cells. PTEN expression varied among different CCA cells, and its status could impact cell sensitivity to celastrol: PTENhigh tumor cells were resistant to celastrol, while PTENlow cells were more sensitive. Celastrol induced proteasomal dysregulation in CCA cells by directly targeting PSMB5. Cells with low PTEN status transcriptionally promoted proteasome subunit expression in an AKT-dependent manner, making these cells more reliant on proteasomal activities to maintain proteostasis. This caused the PTENlow CCA cells sensitive to celastrol. A negative correlation was found between PTEN levels and the proteasome signature in CCA patients. Moreover, celastrol treatment could induce autophagy in PTENhigh CCA cells. Disrupting the autophagic pathway in PTENhigh CCA cells enhanced the cytotoxic effect of celastrol. CONCLUSION: PTEN status in CCA cells determines their sensitivity to celastrol, and autophagy inhibitors could enhance the anti-tumor effect in PTENhigh CCA.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , PTEN Phosphohydrolase , Pentacyclic Triterpenes , Triterpenes , Cholangiocarcinoma/drug therapy , Pentacyclic Triterpenes/pharmacology , PTEN Phosphohydrolase/metabolism , Humans , Cell Line, Tumor , Bile Duct Neoplasms/drug therapy , Triterpenes/pharmacology , Molecular Docking Simulation , Tripterygium/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/drug effects , Autophagy/drug effects , Bortezomib/pharmacologyABSTRACT
The prognosis of patients with multiple myeloma (MM) has significantly improved over the past ten years because of several innovative treatments, including the proteasome inhibitor Bortezomib and immunomodulatory drugs (IMiDs) like Thalidomide and Lenalidomide. The present study aimed to determine the effectiveness of Bortezomib-based regimens on survival state of MM patients. This retrospective study included 204 newly diagnosed MM patients who were registered at Nanakali Hospital for Blood Diseases and Cancer, Erbil- Iraq, between April 2008 and April 2022. The patients were split into two primary groups: those receiving treatment with Bortezomib and those not. Clinical and laboratory data, treatment type, responsiveness to induction therapy, and survival results were examined in the enrolled patients' medical records. The mean patient age was 60 years, males constituted 55.8% of the included patients. At the time of diagnosis, 98 individuals (48%) had stage 3 illness. Except for the LDH, which was noticeably higher in the non-Bortezomib group, the patients laboratory results did not substantially change between the Bortezomib and non-Bortezomib groups (p = 0.001). In patients treated with Bortezomib, the complete response (CR) rate following induction was substantially greater (35.2%) than in those treated without Bortezomib (9.1%). Compared to the non-Bortezomib group, the median survival time of the Bortezomib group was considerably greater (p < 0.001). Bortezomib has a significant role in inducing a CR before bone marrow (BM) transplantation, and it has a significant role in the survival outcome in MM.