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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 -
The Journal of Experimental Medicine Jul 2018RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses...
RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.
Topics: Animals; Apoptosis; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; F-Box-WD Repeat-Containing Protein 7; Gene Deletion; Glycine; HEK293 Cells; Humans; MAP Kinase Signaling System; Melanoma; Mice; Prognosis; Protein Stability; Proteolysis; Proto-Oncogene Proteins B-raf; Sulfones; Ubiquitin Thiolesterase; Vemurafenib
PubMed: 29880484
DOI: 10.1084/jem.20171960 -
Oncotarget Jan 2018Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi-kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for...
Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi-kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for advanced hepatocellular carcinoma (HCC). This underlines the importance of RAS-RAF-ERK-signaling in HCC. Most RAS isoforms were not yet described to play crucial roles in HCC. However, several studies indicate that the HRAS isoform can function as potent oncogene in HCC, but pharmacologic RAS inhibition has not yet been investigated. Moreover, the cell cycle promoting polo-like kinase 1 (PLK1) is an increasingly recognized therapeutic target in HCC that can be activated by RAS-RAF-signaling. A recently developed small molecule inhibitor, ON-01910 ("rigosertib", RGS), was shown to interfere with both RAS- and PLK1-signaling. The aim of this study was to analyze the effects of RGS in HCC and to assess PLK1 and HRAS expression in HCC. RGS treatment reduced cell proliferation and induced cell cycle arrest in human HCC cell lines . Moreover, RGS strongly inhibited both ERK- and AKT-activation in HCC cells, indicating disruption of RAS-signaling. Analysis of HCC patient data showed that PLK1 and HRAS expression levels are upregulated during HCC development and in advanced HCC, respectively. High expression levels of PLK1 significantly correlated with poor patient survival. Moreover, high expression of both PLK1 and HRAS revealed combined effects on patient outcome. This underscores the importance of these genes and associated pathways in HCC. We newly demonstrate the therapeutic potential of RGS in HCC by inhibition of both PLK1 activation and major RAS-pathways, revealing a novel therapeutic "dual-hit" approach for HCC.
PubMed: 29423069
DOI: 10.18632/oncotarget.23188 -
Blood Cancer Journal Dec 2017
Randomized Controlled Trial
Validation of a post-hypomethylating agent failure prognostic model in myelodysplastic syndromes patients treated in a randomized controlled phase III trial of rigosertib vs. best supportive care.
Topics: Antineoplastic Agents; Azacitidine; Decitabine; Drug Resistance, Neoplasm; Glycine; Humans; Kaplan-Meier Estimate; Myelodysplastic Syndromes; Prognosis; Sulfones; Treatment Outcome
PubMed: 29238044
DOI: 10.1038/s41408-017-0018-7 -
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 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Oct 2017To investigate the effects of rigosertib on the apoptosis, proliferation and cell cycle of HEL and K562 cells.
OBJECTIVE
To investigate the effects of rigosertib on the apoptosis, proliferation and cell cycle of HEL and K562 cells.
METHODS
The HEL and K562 cells were treated with different concentration of rigosertib at different time points, the cell apoptosis, proliferation and cycle were determined by using flow cytometry with Annexin V/PI double staining, WST-1 method and 7-AAD assay, respectively. Intracellular signaling proteins were detected by flow cytometry (FCM).
RESULTS
Rigosertib induced obvious apoptosis in HEL and K562 cells, and the apoptotic effect was both time-dependent and dose-dependent manner (P<0.05). The low dose of rigosertib inhibited obviously the proliferation of HEL and K562 cells after treatment from 6 to 54 h, Rigosertib arrested HEL and K562 cells into G/M phase. In addition, Rigosertib obviously increased the expression of apoptosis-related proteins such as cleaved caspase 3 and PARP, and reduced the proliferation-related proteins such as BCL-2 and Cyclin D1. Rigosetib inhibited the activation of AKT-GSK signaling through decreasing the expression of AKT, pAKT(Ser473) and GSK-3α/β (S21/9).
CONCLUSION
Rigosertib inhibites proliferation, induces apoptosis and cell cycle arrest in G/M phase of HEL and K562 cells. This agent may have potential application prospect in leukemia therapy.
Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Glycine; Humans; K562 Cells; Leukemia, Erythroblastic, Acute; Sulfones
PubMed: 29070108
DOI: 10.7534/j.issn.1009-2137.2017.05.014 -
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 -
Scientific Reports Aug 2017In recent years genome-wide RNAi screens have revealed hundreds of cellular factors required for influenza virus infections in human cells. The long-term goal is to...
In recent years genome-wide RNAi screens have revealed hundreds of cellular factors required for influenza virus infections in human cells. The long-term goal is to establish some of them as drug targets for the development of the next generation of antivirals against influenza. We found that several members of the polo-like kinases (PLK), a family of serine/threonine kinases with well-known roles in cell cycle regulation, were identified as hits in four different RNAi screens and we therefore studied their potential as drug target for influenza. We show that knockdown of PLK1, PLK3, and PLK4, as well as inhibition of PLK kinase activity by four different compounds, leads to reduced influenza virus replication, and we map the requirement of PLK activity to early stages of the viral replication cycle. We also tested the impact of the PLK inhibitor BI2536 on influenza virus replication in a human lung tissue culture model and observed strong inhibition of virus replication with no measurable toxicity. This study establishes the PLKs as potential drug targets for influenza and contributes to a more detailed understanding of the intricate interactions between influenza viruses and their host cells.
Topics: A549 Cells; Animals; Antimitotic Agents; Cell Cycle Proteins; Dogs; Glycine; HEK293 Cells; Humans; Influenza A virus; Influenza, Human; Madin Darby Canine Kidney Cells; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; RNA Interference; Sulfones; Tumor Suppressor Proteins; Virus Replication; Polo-Like Kinase 1
PubMed: 28819179
DOI: 10.1038/s41598-017-08942-7 -
AAPS PharmSciTech Jan 2018Rigosertib is a novel anticancer drug in clinical development by Onconova therapeutics, Inc. Currently, it is in pivotal phase III clinical trials for myelodysplastic...
Rigosertib is a novel anticancer drug in clinical development by Onconova therapeutics, Inc. Currently, it is in pivotal phase III clinical trials for myelodysplastic syndrome (MDS) patients. Chemically, it is a sodium salt of weak acid with low solubility in lower pH solutions. In the preliminary studies, it was found that rigosertib is unstable in acidic conditions and forms multiple degradation products. In this research, drug degradation kinetics of rigosertib were studied in acidic conditions. Rigosertib follows pseudo-first-order general acid catalysis reaction. Cholestyramine, which is a strong anion exchange resin, was used to form complex with drug to improve stability and dissolution in acidic conditions. Drug complex with cholestyramine showed better dissolution profile compared to drug alone. Effect of polyethylene glycol was investigated on the release of drug from the drug resin complex. Polyethylene glycol further improved dissolution profile by improving drug solubility in acidic medium.
Topics: Anion Exchange Resins; Antineoplastic Agents; Cholestyramine Resin; Drug Liberation; Glycine; Hydrogen-Ion Concentration; Kinetics; Solubility; Sulfones
PubMed: 28600665
DOI: 10.1208/s12249-017-0820-3 -
Cell Cycle (Georgetown, Tex.) Jun 2017For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator...
For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator of the cell division cycle that controls numerous substrates. It is a promising target for cancer drug development. Inhibitors of the kinase domain of Plk1 had some success in clinical trials. However, they are not perfectly selective. In principle, Plk1 can also be inhibited by interfering with its protein interaction domain, the Polo-Box Domain (PBD). Selective chemical inhibitors of the PBD would constitute tools to probe for PBD-dependent functions of Plk1 and could be advantageous in cancer therapy. The discovery of Poloxin and thymoquinone as PBD inhibitors indicated that small, cell-permeable chemical inhibitors could be identified. Other efforts followed, including ours, reporting additional molecules capable of blocking the PBD. It is now clear that, unfortunately, most of these compounds are non-specific protein alkylators (defined here as groups covalently added via a carbon) that have little or no potential for the development of real Plk1 PBD-specific drugs. This situation should be minded by biologists potentially interested in using these compounds to study Plk1. Further efforts are needed to develop selective, cell-permeable PBD inhibitors.
Topics: Alkylation; Antineoplastic Agents; Benzoates; Benzoquinones; Cell Cycle Proteins; Glycine; Humans; Mitosis; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Quinones; Sulfones; Polo-Like Kinase 1
PubMed: 28521657
DOI: 10.1080/15384101.2017.1325043