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  • 1
    Language: English
    In: Immunity (Cambridge, Mass.), 2016-03-15, Vol.44 (3), p.609-621
    Description: Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8+ T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8+ T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8+ T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy. •Pharmacologic inhibition of MEK potentiates rather than hinders anti-tumor T cells•MEK inhibitors nonetheless suppress anti-tumor priming in lymph nodes in vivo•MEK inhibitors potentiate anti-tumor T cells by impairing TCR-driven apoptosis•MEK inhibition combines with anti-PD-L1 treatment to yield durable tumor regression MEK is a critical signaling component for both Ras-pathway-mutated tumors and normal T cells. Mellman and colleagues demonstrate that MEK inhibitors potentiate rather than suppress T-cell-based anti-tumor immunity and can combine successfully with anti-PD-L1 immunotherapy.
    Subject(s): Animals ; Antibodies, Monoclonal - administration & dosage ; Antigens ; Apoptosis ; Azetidines - administration & dosage ; Azetidines - pharmacology ; B7-H1 Antigen - immunology ; Cancer ; Carcinoma - immunology ; Carcinoma - therapy ; CD8-Positive T-Lymphocytes - drug effects ; CD8-Positive T-Lymphocytes - immunology ; Cell Cycle Checkpoints - drug effects ; Cell Line, Tumor ; Chemotherapy ; Clinical trials ; Colonic Neoplasms - immunology ; Colonic Neoplasms - therapy ; Cytotoxicity ; Drug Synergism ; Drug Therapy ; Drug Therapy, Combination ; Extracellular Signal-Regulated MAP Kinases ; Flow cytometry ; Humans ; Immunotherapy ; Kinases ; Lymphatic system ; Lymphocyte Activation - drug effects ; Lymphocytes ; Melanoma ; Metastasis ; Mice ; Mice, Inbred BALB C ; Mitogens ; Molecular Targeted Therapy ; Mutation ; Neoplasm Transplantation ; Peptides ; Piperidines - administration & dosage ; Piperidines - pharmacology ; Protein kinases ; T cell receptors ; T cells ; Tumors
    ISSN: 1074-7613
    E-ISSN: 1097-4180
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
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  • 2
    Language: English
    In: Nature medicine, 2015-05, Vol.21 (5), p.431-439
    Description: Much has been written about the advantages and disadvantages of various oncology model systems, with the overall finding that these models lack the predictive power required to translate preclinical efficacy into clinical activity. Despite assertions that some preclinical model systems are superior to others, no single model can suffice to inform preclinical target validation and molecule selection. This perspective provides a balanced albeit critical view of these claims of superiority and outlines a framework for the proper use of existing preclinical models for drug testing and discovery. We also highlight gaps in oncology mouse models and discuss general and pervasive model-independent shortcomings in preclinical oncology work, and we propose ways to address these issues.
    Subject(s): Animal experimentation ; Animals ; Biomarkers ; Cancer ; Care and treatment ; Cell Line, Tumor ; Disease Models, Animal ; Drug Design ; Drug Industry ; Drug therapy ; Genetic Engineering ; Humans ; Immune System ; Innovations ; Mice ; Mice, Transgenic ; Models ; Neoplasm Transplantation ; Neoplasms - immunology ; Neoplasms - therapy ; Oncology ; Predictive Value of Tests ; Retrospective Studies ; Rodents ; Translational Medical Research - methods
    ISSN: 1078-8956
    E-ISSN: 1546-170X
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 3
    Language: English
    In: Science (American Association for the Advancement of Science), 2009-10-23, Vol.326 (5952), p.572-574
    Description: The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.
    Subject(s): Amino Acid Sequence ; Amino Acid Substitution ; Amino acids ; Anilides - metabolism ; Anilides - pharmacology ; Anilides - therapeutic use ; Animals ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Basal cell carcinoma ; Biological and medical sciences ; Biopsies ; Brain cancer ; Brain Neoplasms - drug therapy ; Brain Neoplasms - genetics ; Brain Neoplasms - pathology ; Cancer ; Cell Line, Tumor ; Cellular biology ; Cinnamates - pharmacology ; Development and progression ; Diagnosis ; Drug resistance ; Drug Resistance, Neoplasm ; Gene mutations ; Genetic aspects ; Genetic mutation ; Genotype & phenotype ; Hedgehog Proteins - antagonists & inhibitors ; Hedgehog Proteins - genetics ; Hedgehog Proteins - metabolism ; Humans ; Identification and classification ; Inhibitor drugs ; Medical sciences ; Medulloblastoma ; Medulloblastoma - drug therapy ; Medulloblastoma - genetics ; Medulloblastoma - pathology ; Mice ; Molecular Sequence Data ; Mutant Proteins - antagonists & inhibitors ; Mutant Proteins - chemistry ; Mutant Proteins - metabolism ; Mutation ; Mutation, Missense ; Neoplasm Metastasis ; Neurology ; Patched Receptors ; Protein Conformation ; Pyridines - metabolism ; Pyridines - pharmacology ; Pyridines - therapeutic use ; Receptors ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; Receptors, G-Protein-Coupled - antagonists & inhibitors ; Receptors, G-Protein-Coupled - chemistry ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Relapse ; Reports ; Resistance mechanisms ; Signal Transduction ; Smoothened Receptor ; Tumors ; Tumors of the nervous system. Phacomatoses ; Veratrum Alkaloids - pharmacology
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 4
    Language: English
    In: Nature (London), 2018-10, Vol.562 (7727), p.429-433
    Description: Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC) , residual disease persists in some patients and may contribute to relapse when treatment is discontinued . Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1-Trp53 mouse model of BCC and found that mice treated with vismodegib harbour quiescent residual tumours that regrow upon cessation of treatment. Profiling experiments revealed that residual BCCs initiate a transcriptional program that closely resembles that of stem cells of the interfollicular epidermis and isthmus, whereas untreated BCCs are more similar to the hair follicle bulge. This cell identity switch was enabled by a mostly permissive chromatin state accompanied by rapid Wnt pathway activation and reprogramming of super enhancers to drive activation of key transcription factors involved in cellular identity. Accordingly, treatment of BCC with both vismodegib and a Wnt pathway inhibitor reduced the residual tumour burden and enhanced differentiation. Our study identifies a resistance mechanism in which tumour cells evade treatment by adopting an alternative identity that does not rely on the original oncogenic driver for survival.
    Subject(s): Anilides - administration & dosage ; Anilides - pharmacology ; Anilides - therapeutic use ; Animals ; Basal cell carcinoma ; Cancer ; Carcinoma, Basal Cell - drug therapy ; Carcinoma, Basal Cell - metabolism ; Carcinoma, Basal Cell - pathology ; Cell Differentiation - drug effects ; Cell Proliferation - drug effects ; Enzyme inhibitors ; Epidermal Cells - drug effects ; Epidermal Cells - metabolism ; Epidermal Cells - pathology ; Genetic transcription ; Hair Follicle - drug effects ; Hair Follicle - metabolism ; Hair Follicle - pathology ; Hedgehog Proteins - antagonists & inhibitors ; Hedgehog Proteins - metabolism ; Humans ; Mice ; Oncology, Experimental ; Pyridines - administration & dosage ; Pyridines - pharmacology ; Pyridines - therapeutic use ; Research ; Signal Transduction - drug effects ; Skin Neoplasms - drug therapy ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; Smoothened Receptor - metabolism ; Stem Cells - drug effects ; Stem Cells - metabolism ; Stem Cells - pathology ; Wnt Signaling Pathway - drug effects
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Get It Now
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  • 5
    Language: English
    In: The New England journal of medicine, 2009-09-17, Vol.361 (12), p.1173-1178
    Description: The hedgehog pathway is essential for certain aspects of embryonic differentiation. Abnormalities of this pathway have been found in some cases of medulloblastoma. This report describes a patient with a very advanced metastatic medulloblastoma that had such molecular abnormalities. The patient was treated with a small-molecule inhibitor of the hedgehog pathway. The response of the tumor to the agent was dramatic but transitory. This report describes a patient with a very advanced metastatic medulloblastoma that had molecular abnormalities of the hedgehog pathway. The response of the tumor to GDC-0449 was dramatic but transitory. Medulloblastoma is a malignant tumor of the cerebellum. The median age at diagnosis is 5 years, with the age range extending into young adulthood. Primary management consists of surgical resection followed by radiation therapy and chemotherapy. Current therapies have serious short-term and long-term adverse effects, including postoperative mutism, neurocognitive deficits, endocrinopathies, sterility, and the risk of secondary high-grade glioma or meningioma. 1 Patients with recurrent disease after primary therapy have a particularly poor prognosis, with a median survival of less than 6 months; the 2-year survival rate among these patients is approximately 9%. 2 The hedgehog pathway is an essential embryonic signaling . . .
    Subject(s): Abridged Index Medicus ; Adult ; Analysis ; Anilides ; Antineoplastic Agents - therapeutic use ; Benzimidazoles - therapeutic use ; Biological and medical sciences ; Care and treatment ; Case studies ; Cerebellar Neoplasms - drug therapy ; Cerebellar Neoplasms - metabolism ; Cerebellar Neoplasms - pathology ; Enzyme inhibitors ; Evaluation ; Gene Expression ; Gene mutations ; General aspects ; Health aspects ; Hedgehog Proteins - antagonists & inhibitors ; Humans ; Male ; Medical sciences ; Medulloblastoma ; Medulloblastoma - drug therapy ; Medulloblastoma - metabolism ; Medulloblastoma - secondary ; Neurology ; Patched Receptors ; Patched-1 Receptor ; Polymerase Chain Reaction ; Pyridines ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; RNA, Messenger - metabolism ; Signal Transduction - drug effects ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumors of the nervous system. Phacomatoses ; Zinc Finger Protein GLI1
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 6
    Language: English
    In: Nature, 2008, Vol.455 (7211), p.406-410
    Description: Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.
    Subject(s): Animal models in research ; Animals ; Biological and medical sciences ; Cancer ; Carcinogenesis, carcinogens and anticarcinogens ; Cell Line ; Cell lines ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; General aspects ; Hedgehog Proteins - metabolism ; Humans ; Ligands ; Medical sciences ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neoplasms - genetics ; Neoplasms - metabolism ; Paracrine Communication - physiology ; Physiological aspects ; Receptors, G-Protein-Coupled - deficiency ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Research ; Signals and signaling ; Smoothened Receptor ; Stromal Cells - metabolism ; Tumors
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    E-ISSN: 1476-4679
    Source: Academic Search Ultimate
    Source: Nature Journals Online
    Source: Get It Now
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  • 7
    Language: English
    In: Science signaling, 2018-09-11, Vol.11 (547)
    Description: The Hippo signaling pathway regulates organ size and plays critical roles in maintaining tissue growth, homeostasis, and regeneration. Dysregulated in a wide spectrum of cancers, in mammals, this pathway is regulated by two key effectors, YAP and TAZ, that may functionally overlap. We found that TAZ promoted liver inflammation and tumor development. The expression of TAZ, but not YAP, in human liver tumors positively correlated with the expression of proinflammatory cytokines. Hyperactivated TAZ induced substantial myeloid cell infiltration into the liver and the secretion of proinflammatory cytokines through a TEAD-dependent mechanism. Furthermore, tumors with hyperactivated YAP and TAZ had distinct transcriptional signatures, which included the increased expression of inflammatory cytokines in TAZ-driven tumors. Our study elucidated a previously uncharacterized link between TAZ activity and inflammatory responses that influence tumor development in the liver.
    Subject(s): Cytokines ; Effectors ; Hepatocytes ; Homeostasis ; Infiltration ; Inflammation ; Kinases ; Liver ; Metastases ; Myeloid cells ; Regeneration ; Ribonucleic acid ; RNA ; Signal transduction ; Signatures ; Tumor cells ; Tumors ; Xenografts ; Xenotransplantation ; Yes-associated protein
    ISSN: 1945-0877
    E-ISSN: 1937-9145
    Source: Science Magazine
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  • 8
    Language: English
    In: The Journal of biological chemistry, 2009-12-11, Vol.284 (50), p.34553-34560
    Description: Proapoptotic receptor agonists cause cellular demise through the activation of the extrinsic and intrinsic apoptotic pathways. Inhibitor of apoptosis (IAP) proteins block apoptosis induced by diverse stimuli. Here, we demonstrate that IAP antagonists in combination with Fas ligand (FasL) or the death receptor 5 (DR5) agonist antibody synergistically stimulate death in cancer cells and inhibit tumor growth. Single-agent activity of IAP antagonists relies on tumor necrosis factor-α signaling. By contrast, blockade of tumor necrosis factor-α does not affect the synergistic activity of IAP antagonists with FasL or DR5 agonist antibody. In most cancer cells, proapoptotic receptor agonist-induced cell death depends on amplifying the apoptotic signal via caspase-8-mediated activation of Bid and subsequent activation of the caspase-9-dependent mitochondrial apoptotic pathway. In the investigated cancer cell lines, induction of apoptosis by FasL or DR5 agonist antibody can be inhibited by knockdown of Bid. However, knockdown of X chromosome-linked IAP (XIAP) or antagonism of XIAP allows FasL or DR5 agonist antibody to induce activation of effector caspases efficiently without the need for mitochondrial amplification of the apoptotic signal and thus rescues the effect of Bid knockdown in these cells.
    Subject(s): Animals ; Apoptosis - physiology ; BH3 Interacting Domain Death Agonist Protein - genetics ; BH3 Interacting Domain Death Agonist Protein - metabolism ; Caspases - metabolism ; Cell Death - physiology ; Cell Line, Tumor ; Etanercept ; Fas Ligand Protein - metabolism ; Humans ; Immunoglobulin G - genetics ; Immunoglobulin G - metabolism ; Mechanisms of Signal Transduction ; Mice ; Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists ; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism ; Receptors, Tumor Necrosis Factor - genetics ; Receptors, Tumor Necrosis Factor - metabolism ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Signal Transduction - physiology ; Transplantation, Heterologous ; Tumor Necrosis Factor-alpha - metabolism ; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors ; X-Linked Inhibitor of Apoptosis Protein - genetics ; X-Linked Inhibitor of Apoptosis Protein - metabolism
    ISSN: 0021-9258
    E-ISSN: 1083-351X
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Journal of pharmaceutical sciences, 2015-04, Vol.104 (4), p.1508-1521
    Description: Advanced tissue composition-based models can predict the tissue–plasma partition coefficient (Kp) values of drugs under in vivo conditions on the basis of in vitro and physiological input data. These models, however, focus on healthy tissues and do not incorporate data from tumors. The objective of this study was to apply a tissue composition-based model to six marketed antineoplastic drugs (docetaxel, DOC; doxorubicin, DOX; gemcitabine, GEM; methotrexate, MTX; topotecan, TOP; and fluorouracil, 5-FU) to predict their Kp values in three human tumor xenografts (HCT-116, H2122, and PC3) as well as in healthy tissues (brain, muscle, lung, and liver) under steady-state in vivo conditions in female NCR nude mice. The mechanisms considered in the tissue/tumor composition-based model are the binding to lipids and to plasma proteins, but the transporter effect was also investigated. The method consisted of analyzing tissue composition, performing the pharmacokinetics studies in mice, and calculating the corresponding in vivo Kp values. Analyses of tumor composition indicated that the tumor xenografts contained no or low amounts of common transporters by contrast to lipids. The predicted Kp values were within twofold and threefold of the measured values in 77% and 93% of cases, respectively. However, predictions for brain for each drug, for liver for MTX, and for each tumor xenograft for GEM were disparate from the observed values, and, therefore, not well served by the model. Overall, this study is the first step toward the mechanism-based prediction of Kp values of small molecules in healthy and tumor tissues in mouse when no transporter and permeation limitation effect is evident. This approach will be useful in selecting compounds based on their abilities to penetrate human cancer xenografts with a physiologically based pharmacokinetic (PBPK) model, thereby increasing therapeutic index for chemotherapy in oncology study.
    Subject(s): ADME ; Animals ; Antimitotic agents ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - blood ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Cancer ; Chemotherapy ; Colonic Neoplasms - blood ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; disposition ; distribution ; Dogs ; Drug wholesalers ; Female ; HCT116 Cells ; Heterografts ; Humans ; Infusions, Intravenous ; Lung Neoplasms - blood ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Madin Darby Canine Kidney Cells ; Male ; Membrane Transport Proteins - genetics ; Membrane Transport Proteins - metabolism ; Mice, Nude ; Models ; Models, Biological ; oncology ; partition coefficients ; PBPK modeling ; pharmacokinetics ; Prostatic Neoplasms - blood ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Protein binding ; Tissue Distribution ; Transfection ; tumor ; Tumors ; xenograft
    ISSN: 0022-3549
    E-ISSN: 1520-6017
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: ACS medicinal chemistry letters, 2016-04-14, Vol.7 (4), p.351-356
    Description: Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood–brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (16). The discovery and preclinical characterization of this molecule are described within.
    Subject(s): blood−brain barrier penetration ; CNS ; kinase inhibitor ; oncology ; PI3K
    ISSN: 1948-5875
    E-ISSN: 1948-5875
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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