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Indian Journal of Cancer 2014Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed...
CONTEXT
Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies.
AIMS
To determine the safety, dose-limiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD).
SETTINGS AND DESIGN
Phase 1, open-label, dose-escalation study in men and women ≥18 years of age.
MATERIALS AND METHODS
An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD).
STATISTICAL ANALYSIS USED
All data summaries were descriptive. PK parameters were estimated using compartmental analysis.
RESULTS
25 patients (16 male, 9 female, 26-66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days.
CONCLUSIONS
2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.
Topics: Adult; Aged; Antineoplastic Agents; Cohort Studies; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glycine; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Prognosis; Sulfones; Time Factors; Tissue Distribution
PubMed: 24947095
DOI: 10.4103/0019-509X.134617 -
Experimental Hematology Apr 2016Mammalian erythroblasts undergo enucleation through a process thought to be similar to cytokinesis. Microtubule-organizing centers (MTOCs) mediate organization of the...
Mammalian erythroblasts undergo enucleation through a process thought to be similar to cytokinesis. Microtubule-organizing centers (MTOCs) mediate organization of the mitotic spindle apparatus that separates the chromosomes during mitosis and are known to be crucial for proper cytokinesis. However, the role of MTOCs in erythroblast enucleation remains unknown. We therefore investigated the effect of various MTOC inhibitors on cytokinesis and enucleation using human colony-forming units-erythroid (CFU-Es) and mature erythroblasts generated from purified CD34(+) cells. We found that erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA), a dynein inhibitor, and monastrol, a kinesin Eg5 inhibitor, as well as various inhibitors of MTOC regulators, including ON-01910 (Plk-1), MLN8237 (aurora A), hesperadin (aurora B), and LY294002 (PI3K), all inhibited CFU-E cytokinesis. Among these inhibitors, however, only EHNA blocked enucleation. Moreover, terminally differentiated erythroblasts expressed only dynein; little or none of the other tested proteins was detected. Over the course of the terminal differentiation of human erythroblasts, the fraction of cells with nuclei at the cell center declined, whereas the fraction of polarized cells, with nuclei shifted to a position near the plasma membrane, increased. Dynein inhibition impaired nuclear polarization, thereby blocking enucleation. These data indicate that dynein plays an essential role not only in cytokinesis but also in enucleation. We therefore conclude that human erythroblast enucleation is a process largely independent of MTOCs, but dependent on dynein.
Topics: Cell Differentiation; Cell Division; Cell Proliferation; Cells, Cultured; Dyneins; Erythroblasts; Erythroid Precursor Cells; Erythropoiesis; Gene Expression; Glycine; Humans; Microtubule-Organizing Center; Molecular Motor Proteins; Sulfones; Tubulin
PubMed: 26724640
DOI: 10.1016/j.exphem.2015.12.003 -
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: Humans; Diabetes Mellitus, Type 2; Female; Cardiovascular Diseases; Male; Middle Aged; Heart Disease Risk Factors; Lipid Metabolism; Gene Expression
PubMed: 38715799
DOI: 10.3389/fendo.2024.1383772 -
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 -
Oncology Research Sep 2021Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1)....
Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Profiling; Glycine; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Retinal Neoplasms; Retinoblastoma; Sulfones; Xenograft Model Antitumor Assays; p38 Mitogen-Activated Protein Kinases; Polo-Like Kinase 1
PubMed: 33573708
DOI: 10.3727/096504021X16130322409507 -
Molecular Cancer Jun 2021While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side...
BACKGROUND
While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.
METHODS
Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAF and BRAF melanoma and analyzed in reference to patient data.
RESULTS
RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8 cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40SOX10 melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.
CONCLUSIONS
Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.
TRIAL REGISTRATION
NCT01205815 (Sept 17, 2010).
Topics: Animals; Antineoplastic Agents; CD40 Antigens; Female; Glycine; Humans; Immune Checkpoint Inhibitors; Male; Melanoma; Mice; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Signal Transduction; Sulfones; Xenograft Model Antitumor Assays; raf Kinases; ras Proteins
PubMed: 34092233
DOI: 10.1186/s12943-021-01366-y -
Frontiers in Oncology 2023To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor...
OBJECTIVE
To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor treatments, and assess the methodological quality and the strength of evidence of the included meta-analysis.
METHODS
The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies.
RESULTS
A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, 0.0%, <0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, 77.6%, =0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state.
CONCLUSIONS
Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.
PubMed: 36845678
DOI: 10.3389/fonc.2023.1062885 -
IUBMB Life Oct 2005Prostate cancer (PCa) is the most commonly occurring cancer in American men, next to skin cancer. Existing treatment options and surgical intervention are unable to... (Review)
Review
Prostate cancer (PCa) is the most commonly occurring cancer in American men, next to skin cancer. Existing treatment options and surgical intervention are unable to effectively manage this cancer. Therefore, continuing efforts are ongoing to establish novel mechanism-based targets and strategies for its management. The serine/threonine kinases Polo-like kinase (Plk) 1 plays a key role in mitotic entry of proliferating cells and regulates many aspects of mitosis which are necessary for successful cytokinesis. Plk1 is over-expressed in many tumor types with aberrant elevation frequently constituting a prognostic indicator of poor disease outcome. This review discusses the studies which indicate that Plk1 could be an excellent target for the treatment as well as chemoprevention of prostate cancer.
Topics: Animals; Antibodies; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Transformation, Neoplastic; Chemoprevention; Female; Glycine; Humans; Male; Mice; Mitosis; NIH 3T3 Cells; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Sulfones; Polo-Like Kinase 1
PubMed: 16223707
DOI: 10.1080/15216540500305910 -
Cells Dec 2020In cancer pharmacology, a drug candidate's therapeutic potential is typically expressed as its ability to suppress cell growth. Different methods in assessing the cell...
In cancer pharmacology, a drug candidate's therapeutic potential is typically expressed as its ability to suppress cell growth. Different methods in assessing the cell phenotype and calculating the drug effect have been established. However, inconsistencies in drug response outcomes have been reported, and it is still unclear whether and to what extent the choice of data post-processing methods is responsible for that. Studies that systematically examine these questions are rare. Here, we compare three established calculation methods on a collection of nine in vitro models of glioblastoma, exposed to a library of 231 clinical drugs. The therapeutic potential of the drugs is determined on the growth curves, using growth inhibition 50% (GI50) and point-of-departure (PoD) as the criteria. An effect is detected on 36% of the drugs when relying on GI50 and on 27% when using PoD. For the area under the curve (AUC), a threshold of 9.5 or 10 could be set to discriminate between the drugs with and without an effect. GI50, PoD, and AUC are highly correlated. The ranking of substances by different criteria varies somewhat, but the group of the top 20 substances according to one criterion typically includes 17-19 top candidates according to another. In addition to generating preclinical values with high clinical potential, we present off-target appreciation of top substance predictions by interrogating the drug response data of non-cancer cells in our calculation technology.
Topics: Antineoplastic Agents; Area Under Curve; Bortezomib; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Glycine; Humans; Sulfones
PubMed: 33333810
DOI: 10.3390/cells9122689 -
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