Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but ...exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody-drug conjugates, is a viable alternative. A panel of patient-derived ovarian cancer xenografts (PDX), similar in genetics and chemotherapy responsiveness to human tumors, was exposed to 21 monotherapies and combination therapies. Three monotherapies and one combination were found to be active in different subsets of PDX. Analysis of gene expression data identified biomarkers associated with responsiveness to each of the three targeted therapies, none of which directly inhibits an oncogenic driver. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. The distribution of biomarker positivity in The Cancer Genome Atlas data suggests the potential for a similar precision approach in human patients. SIGNIFICANCE: This study exploits a panel of patient-derived xenografts to demonstrate that most ovarian tumors can be matched to effective biomarker-guided treatments.
There is a compelling need for new therapeutic strategies for glioblastoma multiforme (GBM). Preclinical target and therapeutic discovery for GBMs is primarily conducted using cell lines grown in ...serum-containing media, such as U-87 MG, which do not reflect the gene expression profiles of tumors found in GBM patients. To address this lack of representative models, we sought to develop a panel of patient-derived GBM models and characterize their genomic features, using RNA sequencing (RNA-seq) and growth characteristics, both when grown as neurospheres in culture, and grown orthotopically as xenografts in mice. When we compared these with commonly used GBM cell lines in the Cancer Cell Line Encyclopedia (CCLE), we found these patient-derived models to have greater diversity in gene expression and to better correspond to GBMs directly sequenced from patient tumor samples. We also evaluated the potential of these models for targeted therapy, by using the genomic characterization to identify small molecules that inhibit the growth of distinct subsets of GBMs, paving the way for precision medicines for GBM.
To describe quality-of-life outcomes; determine relationships between quality of life and demographic, physical, psychosocial, and clinical variables; and identify predictors of quality of life at 1 ...month after implantation of a left ventricular assist device.
Patients who received either an implantable pneumatic (n = 38) or a vented electric (n = 54) left ventricular assist device as a bridge to heart transplantation between August 1, 1994, and August 31, 1999, completed 6 instruments used to measure quality of life andfactors related to quality of life. Data were analyzed by using descriptive statistics, Pearson correlations, Mann-Whitney U tests, and forward, stepwise multiple regression.
Overall satisfaction with quality of life was quite high as determined from the total score on the Quality of Life Index (mean = 0.69). Patients were very satisfied with the implantation and thought that they would do well after future heart transplant surgery. Patients had a moderate level of stress. Significant predictors of overall quality of life were psychological symptoms, stress, and race; these accounted for 46% of variance in quality of life.
Patients were satisfied with their quality of life at 1 month after implantation of a left ventricular assist device. However, they were least satisfied with their health and functioning and yet were optimistic about how well they thought they would do after heart transplantation. Psychological factors were the strongest predictors of satisfaction with overall quality of life.
Soellner published on the interplay between allosteric and adenosine triphosphate (ATP)‐competitive inhibitors of ABL kinase, showing that the latter preferably binds to different conformational ...states of ABL compared to allosteric agents that specifically target the ABL myristate pocket (STAMP) and deducing that asciminib cannot bind to ABL simultaneously with ATP‐competitive drugs. These results are to some extent in line with ours, although our analyses of dose–response matrices from combinations of asciminib with imatinib, nilotinib or dasatinib, show neither synergy nor antagonism, but suggest additive antiproliferative effects on BCR‐ABL‐dependent KCL22 cells. Furthermore, our X‐ray crystallographic, solution nuclear magnetic resonance (NMR), and isothermal titration calorimetry studies show that asciminib can bind ABL concomitantly with type‐1 or ‐2 ATP‐competitive inhibitors to form ternary complexes. Concomitant binding of asciminib with imatinib, nilotinib, or dasatinib might translate to benefit some chronic myeloid leukaemia patients.
Soellner published on the interplay between allosteric and adenosine triphosphate (ATP)‐competitive inhibitors of ABL kinase, showing that the latter preferably binds to different conformational states of ABL compared to allosteric agents that specifically target the ABL myristate pocket (STAMP) and deducing that asciminib cannot bind to ABL simultaneously with ATP‐competitive drugs. These results are to some extent in line with ours, although our analyses of dose‐response matrices from combinations of asciminib with imatinib, nilotinib or dasatinib, show neither synergy nor antagonism, but suggest additive antiproliferative effects on BCR‐ABL‐dependent KCL22 cells. Furthermore, our X‐ray crystallographic, solution nuclear magnetic resonance (NMR), and isothermal titration calorimetry studies show that asciminib can bind ABL concomitantly with type‐1 or ‐2 ATP‐competitive inhibitors to form ternary complexes.
The molecular chaperone heat shock protein 90 (HSP90) facilitates the appropriate folding of various oncogenic proteins and is necessary for the survival of some cancer cells. HSP90 is therefore an ...attractive drug target, but the efficacy of HSP90 inhibitor may be limited by HSP90 inhibition induced feedback mechanisms. Through pooled RNA interference screens, we identified that heat shock factor 1(HSF1) is a sensitizer of HSP90 inhibitor. A striking combinational effect was observed when HSF1 knockdown plus with HSP90 inhibitors treatment in various cancer cell lines and tumor mouse models. Interestingly, HSF1 is highly expressed in hepatocellular carcinoma (HCC) patient samples and HCC is sensitive to combinational treatment, indicating a potential indication for the combinational treatment. To understand the mechanism of the combinational effect, we identified that a HSF1-target gene DEDD2 is involved in attenuating the effect of HSP90 inhibitors. Thus, the transcriptional activities of HSF1 induced by HSP90 inhibitors provide a feedback mechanism of limiting the HSP90 inhibitor's activity, and targeting HSF1 may provide a new avenue to enhance HSP90 inhibitors activity in human cancers.
Background: Chronic myelogenous leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL) are caused by the t(9;22)(q34;q11.2) chromosome translocation, resulting in fusion of the BCR and ...ABL1 genes on the Philadelphia chromosome to encode constitutively active ABL1 kinase. Despite the dramatic progress made over the past decade with tyrosine kinase inhibitors (TKIs) in the treatment of CML, allogeneic stem cell transplant is considered the only proven curative therapy. To achieve cure or benefit from treatment-free remissions with pharmacologically-based therapies, it is estimated that patients will likely need to achieve a sustained reduction in tumor burden of 4 logs (MR4) or deeper (MR4.5). Currently, only 39% and 18% of patients achieve MR4 by 24 months of treatment with single agent nilotinib or imatinib, respectively. Furthermore, for a subset of CML patients and the majority of Ph+ ALL patients, resistance develops to current TKI’s as a result of emergence of point mutations in the ATP site of the kinase domain. ABL001 is a potent, selective BCR-ABL inhibitor that maintains activity across most mutations, including T315I, with a distinct, allosteric mechanism of action which recently entered Phase I development for the treatment of patients with CML and Ph+ ALL. ABL001 was developed to be dosed in combination with nilotinib to provide greater pharmacological coverage of BCR-ABL disease and prevent the emergence of resistance.
Methods: Based on X-ray crystallography, NMR and molecular modeling, ABL001 is the result of a structure-guided medicinal chemistry program targeting the myristoyl pocket of the ABL1 kinase. In vitro cell based assays were performed using the Ba/F3 isogenic cell system and a panel of over 300 cell lines. KCL-22 cells were used to develop an in vivo xenograft model to assess the efficacy of ABL001 and the PD marker, pSTAT5, was used to monitor the inhibition of BCR-ABL signaling.
Results: In contrast to TKIs that bind to the ATP-site of the ABL1 kinase domain, NMR and X-Ray crystallography studies confirmed that ABL001 binds to a pocket on the BCR-ABL kinase domain that is normally occupied by the myristoylated N-terminus of ABL1. Upon fusion with BCR, this myristoylated N-terminus that serves to autoregulate ABL1 activity is lost. ABL001 functionally mimics the role of the myristoylated N-terminus by occupying its vacant binding site and restores the negative regulation of the kinase activity. Cell proliferation studies demonstrate that ABL001 selectively inhibited the growth of CML and Ph+ ALL cells with potencies ranging from 1-10nM range. In contrast, BCR-ABL-negative cell lines remained unaffected at concentrations 1000-fold higher. With resistance emerging in the clinic to current TKI’s as a result of point mutations in the ATP-site, ABL001 was tested for activity against clinically observed mutations and found to be active in the low nM range. In the KCL-22 mouse xenograft model, ABL001 displayed potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition. The KCL-22 xenograft model was also used to compare the dosing of ABL001 and nilotinib as single agents to dosing a combination of ABL001 and nilotinib. Single agent dosing regimens led to tumor regressions; however, despite continuous dosing, all tumors relapsed within 30-60 days with evidence of point mutations in the resistant tumors. In contrast, animals treated with the combination of ABL001 and nilotinib achieved sustained tumor regression with no evidence of disease relapse either during the 70 days of treatment or for > 150 days after treatment stopped.
Conclusion: ABL001 selectively inhibited the proliferation of cells expressing the BCR-ABL fusion gene and was active against clinically important mutations that arise with current TKI therapy in CML. In an in vivo model of CML, the combination of ABL001 and nilotinib resulted in complete and sustained tumor regression with no evidence of disease relapse. These results provide proof-of-principle that simultaneous targeting of the myristoyl pocket and ATP-pocket by ABL001 and nilotinib, respectively, promotes a more sustained overall efficacy and prevents the emergence of resistance via acquisition of point mutations in the respective binding sites. ABL001 is currently being evaluated in a Phase 1 study in patients with CML and Ph+ ALL.
Wylie:Novartis Institutes for Biomedical Research, Inc: Employment. Schoepfer:Novartis Institutes for Biomedical Research: Employment. Berellini:Novartis Institutes for Biomedical Research: Employment. Cai:Novartis Institutes for Biomedical Research: Employment. Caravatti:Novartis Institutes for Biomedical Research: Employment. Cotesta:Novartis Institues for Biomedical Research: Employment. Dodd:Novartis Institutes for Biomedical Research: Employment. Donovan:Novartis Institutes for Biomedical Research: Employment. Erb:Novartis Institutes for Biomedical Research: Employment. Furet:Novartis Institutes for Biomedical Research: Employment. Gangal:Novartis Institutes for Biomedical Research: Employment. Grotzfeld:Novartis Institutes for Biomedical Research: Employment. Hassan:Novartis Institutes for Biomedical Research: Employment. Hood:Novartis Institutes for Biomedical Research: Employment. Iyer:Novartis Institutes for Biomedical Research: Employment. Jacob:Novartis Institutes for Biomedical Research: Employment. Jahnke:Novartis Institutes for Biomedical Research: Employment. Lombardo:Novartis Institutes for Biomedical Research: Employment. Loo:Novartis Institutes for Biomedical Research: Employment. Manley:Novartis Institutes for Biomedical Research: Employment. Marzinzik:Novartis Institutes for Biomedical Research: Employment. Palmer:Novartis Institutes for Biomedical Research: Employment. Pelle:Novartis Institutes for Biomedical Research: Employment. Salem:Novartis Institutes for Biomedical Research: Employment. Sharma:Novartis Institutes for Biomedical Research: Employment. Thohan:Novartis Institutes for Biomedical Research: Employment. Zhu:Novartis Institutes for Biomedical Research: Employment. Keen:Novartis Institutes for Biomedical Research: Employment. Petruzzelli:Novartis Institutes for Biomedical Research: Employment. Vanasse:Novartis: Employment, Equity Ownership. Sellers:Novartis: Employment.
The HeartMate vented electric left ventricular assist device has been approved for use as destination therapy. Thus, the study of quality-of-life outcomes, as well as morbidity and mortality, is ...imperative. The purpose of our study was to describe change with time (from 1 month to 1 year) in patients who received a HeartMate vented electric left ventricular assist device as a bridge to heart transplantation and to identify quality-of-life predictors of survival after left ventricular assist device implantation.
A nonrandom sample of 78 patients who received a HeartMate vented electric left ventricular assist device (primarily middle-aged, white married males) who had quality-of-life data at 1, 2, 3, 6, 9, or 12 months after implant was the subject of this report. The sample size decreased with time primarily because of heart transplantation. Patients completed the following booklets of questionnaires: Quality of Life Index, Rating Question Form, Heart Failure Symptom Checklist, and Sickness Impact Profile. Analyses included both descriptive analyses and modeling procedures (mixed-effects models and Cox proportional hazards models).
Quality-of-life outcomes were fairly good and stable from 1 month to 1 year after HeartMate vented electric left ventricular assist device implantation. Both positive and negative changes were detected in all quality-of-life domains (physical and occupational function, social interaction, somatic sensation, and psychological state) after left ventricular assist device insertion. Items from the physical domain of quality of life, specifically walking and dressing oneself, were significantly associated with the risk of dying after left ventricular assist device implantation.
Identifying poor quality-of-life outcomes within 1 year after left ventricular assist device implantation provides direction to develop strategies to improve outcomes. Physical and occupational rehabilitation, psychosocial intervention, and monitoring symptom distress and physical disability may contribute to improved quality-of-life outcomes and survival after left ventricular assist device implantation.
Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and ...pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.
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