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[Rinsho Ketsueki] the Japanese Journal... 2018Recent advances in drug treatment for higher-risk myelodysplastic syndromes (MDS) have focused on DNA hypomethylating agents (HMAs). Azacitidine (AZA), a representative... (Review)
Review
Recent advances in drug treatment for higher-risk myelodysplastic syndromes (MDS) have focused on DNA hypomethylating agents (HMAs). Azacitidine (AZA), a representative HMA available in Japan, has demonstrated a survival benefit over conventional treatment. However, unsatisfactory treatment profiles of AZA exemplified by a low response rate of <20% complete remission (CR), a short duration of response (usually <1 year), and dismal outcomes after the failure to fulfil unmet needs in AZA treatments have highlighted the urgent need for the development of novel therapeutic modalities. In this manuscript, an array of novel agents under clinical investigation for higher-risk MDS is introduced. The drugs in the most advanced phase of development include SGI-110, a next-generation DNA hypomethylating agent that is designed to prolong cellular exposure time, and the multi-kinase inhibitor rigosertib, which is specifically active against patients with higher-risk MDS who fail to respond to conventional HMAs. Other lines of agents under investigation include a combination of histone deacetylase inhibitors and hypomethylating agents, immune checkpoint inhibitors, spliceosome inhibitors, BCL2 inhibitors, and IDH1/2 inhibitors, all of which have been developed by exploiting the recent understanding of the molecular pathogenesis of MDS, including the tumorigenic role of common mutations and disturbance of tumor immunity.
Topics: Azacitidine; DNA Methylation; Glycine; Histone Deacetylase Inhibitors; Humans; Japan; Myelodysplastic Syndromes; Remission Induction; Sulfones
PubMed: 30305509
DOI: 10.11406/rinketsu.59.2058 -
Scientific Reports Dec 2014Rigosertib has demonstrated therapeutic activity for patients with high-risk myelodysplastic syndrome (MDS) in clinical trials. However, the role of rigosertib in MDS...
Rigosertib has demonstrated therapeutic activity for patients with high-risk myelodysplastic syndrome (MDS) in clinical trials. However, the role of rigosertib in MDS has not been thoroughly characterized. In this study, we found out that rigosertib induced apoptosis, blocked the cell cycle at the G2/M phase and subsequently inhibited the proliferation of CD34+ cells from MDS, while it minimally affected the normal CD34+ cells. Further studies showed that rigosertib acted via the activation of the P53 signaling pathway. Bioinformatics analysis based on gene expression profile and flow cytometry analysis revealed the abnormal activation of the Akt-PI3K, Jak-STAT and Wnt pathways in high-grade MDS, while the p38 MAPK, SAPK/JNK and P53 pathways were abnormally activated in low-grade MDS. Rigosertib could markedly inhibit the activation of the Akt-PI3K and Wnt pathways, whereas it activated the SAPK/JNK and P53 pathways in high-grade MDS. A receptor tyrosine kinase phosphorylation array demonstrated that rigosertib could increase the activation of RET and PDGFR-β while reducing the activation of Tie2 and VEGFR2 in MDS cells. Taken together, these data indicate that rigosertib is a selective and promising anti-tumor agent that could ameliorate multiple dysregulated signaling transduction pathways in high-grade MDS.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Cell Line; Female; G2 Phase Cell Cycle Checkpoints; Glycine; Humans; Janus Kinases; Male; Middle Aged; Myelodysplastic Syndromes; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; STAT Transcription Factors; Signal Transduction; Sulfones; Transcriptome; Tumor Suppressor Protein p53; p38 Mitogen-Activated Protein Kinases
PubMed: 25472472
DOI: 10.1038/srep07310 -
Oncotarget Aug 2015The potency of Abelson (ABL) tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML) has been demonstrated. However, ABL TKI resistance can develop. In...
Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with Abelson tyrosine kinase inhibitors, against break point cluster region-c-Abelson-positive leukemia cells.
The potency of Abelson (ABL) tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML) has been demonstrated. However, ABL TKI resistance can develop. In this study, we investigated the efficacy of a combination therapy including rigosertib (ON 01910.Na), a polo-like kinase (PLK) and phosphoinositide 3-kinase (PI3K) inhibitor, and ABL TKIs. A 72-h rigosertib treatment was found to inhibit cell growth, induce apoptosis, reduce phosphorylation of the breakpoint cluster region-c (BCR)-ABL and its substrate Crk-L, and increase the activities of caspase 3 and poly (ADP-ribose) polymerase (PARP). This combination therapy also exerted a synergistic inhibitory effect on Philadelphia chromosome (Ph)-positive cell proliferation and reduced the phosphorylation of BCR-ABL and Crk-L while increasing that of cleaved PARP and the H2A.X histone. Rigosertib also potently inhibited the growth of ABL TKI-resistant cells, and cotreatment with ABL TKIs and rigosertib induced higher cytotoxicity. These results indicate that rigosertib treatment may be a powerful strategy against ABL TKI-resistant cells and could enhance the cytotoxic effects of ABL TKIs.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Glycine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Sulfones; Transfection
PubMed: 26008977
DOI: 10.18632/oncotarget.4047 -
Frontiers in Endocrinology 2024ASCVD is the primary cause of mortality in individuals with T2DM. A potential link between ASCVD and T2DM has been suggested, prompting further investigation.
BACKGROUND
ASCVD is the primary cause of mortality in individuals with T2DM. A potential link between ASCVD and T2DM has been suggested, prompting further investigation.
METHODS
We utilized linear and multivariate logistic regression, Wilcoxon test, and Spearman's correlation toanalyzethe interrelation between ASCVD and T2DM in NHANES data from 2001-2018.The Gene Expression Omnibus (GEO) database and Weighted Gene Co-expression Network Analysis (WGCNA) wereconducted to identify co-expression networks between ASCVD and T2DM. Hub genes were identified using LASSO regression analysis and further validated in two additional cohorts. Bioinformatics methods were employed for gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, along with the prediction of candidate small molecules.
RESULTS
Our analysis of the NHANES dataset indicated a significant impact of blood glucose on lipid levels within diabetic cohort, suggesting that abnormal lipid metabolism is a critical factor in ASCVD development. Cross-phenotyping analysis revealed two pivotal genes, ABCC5 and WDR7, associated with both T2DM and ASCVD. Enrichment analyses demonstrated the intertwining of lipid metabolism in both conditions, encompassing adipocytokine signaling pathway, fatty acid degradation and metabolism, and the regulation of adipocyte lipolysis. Immune infiltration analysis underscored the involvement of immune processes in both diseases. Notably, RITA, ON-01910, doxercalciferol, and topiramate emerged as potential therapeutic agents for both T2DM and ASCVD, indicating their possible clinical significance.
CONCLUSION
Our findings pinpoint ABCC5 and WDR7 as new target genes between T2DM and ASCVD, with RITA, ON-01910, doxercalciferol, and topiramate highlighted as promising therapeutic agents.
Topics: Female; Humans; Male; Middle Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gene Expression; Heart Disease Risk Factors; Lipid Metabolism
PubMed: 38715799
DOI: 10.3389/fendo.2024.1383772 -
Leukemia Research Jan 2018This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13)...
This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650-1700mg/m/day in 14-day cycles. Initial dose escalation followed a Fibonacci scheme, followed by recommended phase 2 dose confirmation in an expanded cohort. Rigosertib was well tolerated for up to 23 cycles, with no treatment-related deaths and 18% of patients with related serious adverse events (AEs). Common AEs were fatigue, diarrhea, pyrexia, dyspnea, insomnia, and anemia. Rigosertib exhibited biologic activity, with reduction or stabilization of bone marrow blasts and improved peripheral blood counts in a subset of patients. Ten of 19 evaluable patients (53%) demonstrated bone marrow/peripheral blood responses (n=4 MDS, n=1 AML) or stable disease (n=3 MDS, n=2 AML). Median survival was 15.7 and 2.0 months for responders and non-responders, respectively. Additional studies of rigosertib are ongoing in higher-risk MDS (NCT00854646).
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Female; Glycine; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Middle Aged; Myelodysplastic Syndromes; Sulfones; Survival Analysis
PubMed: 29144985
DOI: 10.1016/j.leukres.2017.11.006 -
Clinical Cancer Research : An Official... Jun 2019Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic...
PURPOSE
Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC and .
RESULTS
ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib.
CONCLUSIONS
These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle Proteins; Epidermolysis Bullosa Dystrophica; Gene Knockdown Techniques; Genes, Recessive; Glycine; Humans; Keratinocytes; Molecular Targeted Therapy; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Messenger; RNA, Small Interfering; Skin Neoplasms; Sulfones; Polo-Like Kinase 1
PubMed: 30846478
DOI: 10.1158/1078-0432.CCR-18-2661 -
Cellular Signalling Sep 2021The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms...
BACKGROUND
The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action.
METHODS
The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC).
RESULTS
The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9.
CONCLUSION
Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Glycine; Humans; Signal Transduction; Sulfones; Xenograft Model Antitumor Assays
PubMed: 34214591
DOI: 10.1016/j.cellsig.2021.110069 -
Hematological Oncology Jun 2015Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells,... (Meta-Analysis)
Meta-Analysis
Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System. Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts. One patient with a complete bone marrow response also achieved a complete cytogenetic response. A second patient with stable bone marrow blasts achieved a partial cytogenetic response. Two of the responding patients and three patients with stable disease had hematological improvements. Rigosertib-induced bone marrow blast decreases and stability appeared to be predictive of prolonged survival. IV rigosertib had a favorable safety profile without significant myelosuppression. Most common drug-related toxicities included fatigue, diarrhea, nausea, dysuria, and hematuria. In summary, IV rigosertib is well tolerated and has clinical activity in patients with higher risk MDS following DNMT inhibitor treatment. A multinational pivotal phase 3 randomized clinical trial of rigosertib versus best supportive care for patients with MDS with excess blasts following prior treatment with DNMT inhibitors (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE) has recently completed enrollment.
Topics: Aged; Aged, 80 and over; Anemia, Refractory, with Excess of Blasts; Bone Marrow; Cell Cycle Proteins; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Female; Glycine; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Risk; Signal Transduction; Sulfones; Polo-Like Kinase 1
PubMed: 24777753
DOI: 10.1002/hon.2137 -
Translational Research : the Journal of... Sep 2016Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, shows either no response or development of resistance to further treatment in 30% of the patients that...
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, shows either no response or development of resistance to further treatment in 30% of the patients that warrants the development of novel drugs. We have reported that ON 01910.Na (rigosertib), a multikinase inhibitor, is selectively cytotoxic for DLBCL and induces more hyperphosphorylation and sumoylation of Ran GTPase-activating protein 1 (RanGAP1) in DLBCL cells than in non-neoplastic lymphoblastoid cell line. However, the exact mechanism of rigosertib-induced cell death in DLBCL remains to be clarified. Here, we analyzed the efficacy of rigosertib against DLBCL cells in vitro and in vivo and its molecular effects on tumor biology. We found for the first time that rigosertib attenuated expression of unmodified and sumoylated tumor necrosis factor receptor-associated factor 6 (TRAF6) and c-Myb and inhibited nuclear entry of sumoylated RanGAP1, TRAF6, and c-Myb that was confirmed by immunofluorescence. Moreover, co-immunoprecipitation showed that rigosertib induced sequestration of c-Myb and TRAF6 in the cytoplasm by stimulating their sumoylation through the RanGAP1*SUMO1/Ubc9 pathway. Specific knockdown of c-Myb and TRAF6 induced tumor cell apoptosis and cell cycle arrest at G1 phase. Xenograft mice bearing lymphoma cells also exhibited effective tumor regression on rigosertib treatment along with cytoplasmic expression of c-Myb and TRAF6. Nuclear expression of c-Myb in clinical cases of DLBCL correlated with a poor prognosis. Thus, suppression of c-Myb and TRAF6 activity may have therapeutic implication in DLBCL. These data support the clinical development of rigosertib in DLBCL.
Topics: Animals; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cytoplasm; Fluorescent Antibody Technique; GTPase-Activating Proteins; Gene Knockdown Techniques; Glycine; Humans; Lymphoma, Large B-Cell, Diffuse; Mice, Inbred NOD; Mice, SCID; Models, Biological; Phosphorylation; Prognosis; Proto-Oncogene Proteins c-myb; Sulfones; Sumoylation; TNF Receptor-Associated Factor 6; Ubiquitin-Conjugating Enzymes
PubMed: 27150054
DOI: 10.1016/j.trsl.2016.04.001 -
Molecular Cell Oct 2017Chemical libraries paired with phenotypic screens can now readily identify compounds with therapeutic potential. A central limitation to exploiting these compounds,...
Chemical libraries paired with phenotypic screens can now readily identify compounds with therapeutic potential. A central limitation to exploiting these compounds, however, has been in identifying their relevant cellular targets. Here, we present a two-tiered CRISPR-mediated chemical-genetic strategy for target identification: combined genome-wide knockdown and overexpression screening as well as focused, comparative chemical-genetic profiling. Application of these strategies to rigosertib, a drug in phase 3 clinical trials for high-risk myelodysplastic syndrome whose molecular target had remained controversial, pointed singularly to microtubules as rigosertib's target. We showed that rigosertib indeed directly binds to and destabilizes microtubules using cell biological, in vitro, and structural approaches. Finally, expression of tubulin with a structure-guided mutation in the rigosertib-binding pocket conferred resistance to rigosertib, establishing that rigosertib kills cancer cells by destabilizing microtubules. These results demonstrate the power of our chemical-genetic screening strategies for pinpointing the physiologically relevant targets of chemical agents.
Topics: Antineoplastic Agents; CRISPR-Cas Systems; Colchicine; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genetic Testing; Genetic Vectors; Glycine; HeLa Cells; Humans; K562 Cells; Kinesins; Lentivirus; Microtubules; Mutation; Myelodysplastic Syndromes; RNA, Guide, CRISPR-Cas Systems; Recombinant Fusion Proteins; Small Molecule Libraries; Sulfones; Tubulin; Tubulin Modulators; Vinblastine
PubMed: 28985505
DOI: 10.1016/j.molcel.2017.09.012