ABSTRACT
Aim: Objective was to compare adherence and persistence, as well as direct healthcare costs and utilization, of ospemifene to available local estrogen therapies (LETs). Patients & methods: This retrospective database study used integrated medical and pharmacy claims data from the IQVIA Real-World Data Adjudicated Claims - US Database. Results: Ospemifene patients had significantly greater adherence and persistence compared with the other nonring LETs. Ospemifene had the lowest mean outpatient costs of any of the LET cohorts, including the estradiol vaginal ring. Total all-cause healthcare costs were also significantly less for ospemifene patients compared with all other LETs.
Subject(s)
Dyspareunia/drug therapy , Estrogens/economics , Estrogens/therapeutic use , Tamoxifen/analogs & derivatives , Administration, Intravaginal , Age Factors , Aged , Data Management , Estrogens/administration & dosage , Female , Health Care Costs , Health Expenditures , Humans , Medication Adherence , Middle Aged , Postmenopause , Retrospective Studies , Selective Estrogen Receptor Modulators , Tamoxifen/administration & dosage , Tamoxifen/economics , Tamoxifen/therapeutic useABSTRACT
There is a vital need for improved therapeutic strategies that are effective in both primary and metastatic triple-negative breast cancer (TNBC). Current treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in multiple TNBC subtypes. Since coexpression of receptor tyrosine kinases (RTKs) can promote signaling crosstalk and cell survival in the presence of kinase inhibitors, it is likely that multiple RTKs will need to be inhibited to enhance therapeutic benefit and prevent resistance. The MET and EGFR receptors are actionable targets due to their high expression in TNBC; however crosstalk between MET and EGFR has been implicated in therapeutic resistance to single agent use of MET or EGFR inhibitors in several cancer types. Therefore it is likely that dual inhibition of MET and EGFR is required to prevent crosstalk signaling and acquired resistance. In this study, we evaluated the heterogeneity of MET and EGFR expression and activation in primary and metastatic TNBC tumorgrafts and determined the efficacy of MET (MGCD265 or crizotinib) and/or EGFR (erlotinib) inhibition against TNBC progression. Here we demonstrate that combined MET and EGFR inhibition with either MGCD265 and erlotinib treatment or crizotinib and erlotinib treatment were highly effective at abrogating tumor growth and significantly decreased the variability in treatment response compared to monotherapy. These results advance our understanding of the RTK signaling architecture in TNBC and demonstrate that combined MET and EGFR inhibition may be a promising therapeutic strategy for TNBC patients.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Receptor Cross-Talk/drug effects , Signal Transduction/drug effects , Triple Negative Breast Neoplasms/drug therapy , ErbB Receptors/analysis , Erlotinib Hydrochloride/administration & dosage , Female , Humans , Proto-Oncogene Proteins c-met/analysis , Proto-Oncogene Proteins c-met/genetics , Triple Negative Breast Neoplasms/chemistryABSTRACT
The Met receptor tyrosine kinase (RTK) is an attractive oncology therapeutic target. Met and its ligand, HGF, play a central role in signaling pathways that are exploited during the oncogenic process, including regulation of cell proliferation, invasion, angiogenesis, and cancer stem cell regulation. Elevated Met and HGF as well as numerous Met genetic alterations have been reported in human cancers and correlate with poor outcome. Alterations of pathways that regulate Met, such as the ubiquitin ligase c-Cbl are also likely to activate Met in the oncogenic setting. Moreover, interactive crosstalk between Met and other receptors such as EGFR, HER2 and VEGFR, underlies a key role for Met in resistance to other RTK-targeted therapies. A large body of preclinical and clinical data exists that supports the use of either antibodies or small molecule inhibitors that target Met or HGF as oncology therapeutics. The prognostic potential of Met expression has been suggested from studies in numerous cancers including lung, renal, liver, head and neck, stomach, and breast. Clinical trials using Met inhibitors indicate that the level of Met expression is a determinant of trial outcome, a finding that is actively under investigation in multiple clinical scenarios. Research in Met prognostics and predictors of drug response is now shifting toward more sophisticated methodologies suitable for development as validated and effective biomarkers that can be partnered with therapeutics to improve patient survival.
Subject(s)
Carcinogenesis , Drug Resistance, Neoplasm , Proto-Oncogene Proteins c-met/physiology , Animals , Biomarkers, Tumor , Drug Discovery , Gene Amplification , Gene Dosage , Humans , Mutation , Protein Structure, Tertiary , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/chemistry , Proto-Oncogene Proteins c-met/genetics , Signal TransductionABSTRACT
A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.
ABSTRACT
A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamides targeting RON receptor tyrosine kinase was designed and synthesized. SAR study of the series allowed us to identify compounds possessing either inhibitory activity of RON kinase enzyme in the low nanomolar range with low residual activity against the closely related c-Met or potent dual inhibitory activity against RON and c-Met, with no significant activity against VEGFR2 in both cases.
Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Humans , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Rats , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.
Subject(s)
Enzyme Inhibitors/chemistry , Histone Deacetylase Inhibitors , Histone Deacetylases/chemistry , Acetylation , Catalytic Domain , Chemistry, Pharmaceutical/methods , Drug Design , Histone Deacetylase 6 , Histone Deacetylases/metabolism , Histones/chemistry , Humans , Hydroxamic Acids/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Piperazine , Piperazines/chemistry , Protein Isoforms , Tubulin/chemistryABSTRACT
Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that catalyze the deacetylation and acetylation of lysine residues located in the NH(2) terminal tails of histones and non-histone proteins. Perturbation of this balance is often observed in human cancers and inhibition of HDACs has emerged as a novel therapeutic strategy against cancer. To date, more that 30 groups, academic and industrial, are involved in research related to these target enzymes. Over the past year, dozens of research papers and patent applications describing new HDAC inhibitors belonging to different structural classes have been disclosed. The present review highlights the latest developments in design and synthesis of HDAC inhibitors -- potential anti-cancer drugs.
Subject(s)
Antineoplastic Agents , Enzyme Inhibitors , Histone Deacetylase Inhibitors , Neoplasms/drug therapy , Acetyltransferases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Proliferation/drug effects , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Histone Acetyltransferases , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
The hepatocyte growth factor receptor tyrosine kinase Met promotes cell dissociation and the inherent morphogenic program of epithelial cells. In a search for substrates downstream from Met, we have previously identified the Grb2-associated binder-1 (Gab1) as critical for the morphogenic program. Gab1 is a scaffold protein that acts to diversify the signal downstream from the Met receptor through its ability to couple with multiple signal transduction pathways. Gab1 contains a pleckstrin homology (PH) domain with specificity for phosphatidylinositol 3,4,5-trisphosphate. The phospholipid binding capacity of the Gab1 PH domain is required for the localization of Gab1 at sites of cell-cell contact in colonies of epithelial cells and for epithelial morphogenesis, suggesting that PH domain-dependent subcellular localization of Gab1 is a prerequisite for function. We have investigated the requirement for membrane localization of Gab1 for biological activity. We show that substitution of the Gab1 PH domain with the myristoylation signal from the c-Src protein is sufficient to replace the Gab1 PH domain for epithelial morphogenesis. The membrane targeting of Gab1 enhances Rac activity in the absence of stimulation and switches a nonmorphogenic noninvasive response to epidermal growth factor to a morphogenic invasive program. These results suggest that the subcellular localization of Gab1 is a critical determinant for epithelial morphogenesis and invasiveness.
Subject(s)
Phosphoproteins/metabolism , Actins/metabolism , Animals , Blood Proteins/chemistry , CSK Tyrosine-Protein Kinase , Cell Adhesion , Cell Line , Cell Membrane/metabolism , Dogs , Epidermal Growth Factor/pharmacology , Epithelium/drug effects , Epithelium/growth & development , Epithelium/metabolism , Kinetics , Morphogenesis , Mutation , Myristic Acid/metabolism , Phosphoproteins/chemistry , Phosphoproteins/genetics , Phosphorylation , Protein Structure, Tertiary , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-met/chemistry , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Signal Transduction , src-Family KinasesABSTRACT
The Gab family of docking proteins (Gab1 and Gab2) are phosphorylated in response to various cytokines and growth factors. Gab1 acts to diversify the signal downstream from the Met receptor tyrosine kinase through the recruitment of multiple signaling proteins, and is essential for epithelial morphogenesis. To determine whether Gab1 and Gab2 are functionally redundant, we have examined the role of Gab2 in epithelial cells. Both Gab1 and Gab2 are expressed in epithelial cells and localize to cell-cell junctions. However, whereas overexpression of Gab1 promotes a morphogenic response, the overexpression of Gab2 fails to induce this response. We show that Gab2 recruitment to the Met receptor is dependent on the Grb2 adapter protein. In contrast, Gab1 recruitment to Met is both Grb2 dependent and Grb2 independent. The latter requires a novel amino acid sequence present in the Met-binding domain of Gab1 but not Gab2. Mutation of these residues in Gab1 impairs both association with the Met receptor and the ability of Gab1 to promote a morphogenic response, whereas their insertion into Gab2 increases Gab2 association with Met, but does not confer on Gab2 the ability to promote epithelial morphogenesis. We propose that the Grb2-independent recruitment of Gab proteins to Met is necessary but not sufficient to promote epithelial morphogenesis.