WO2007123722A2 - Procedes de prevision et de pronostic de cancer, et surveillance d'une therapie anticancereuse - Google Patents

Procedes de prevision et de pronostic de cancer, et surveillance d'une therapie anticancereuse Download PDF

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Publication number
WO2007123722A2
WO2007123722A2 PCT/US2007/007965 US2007007965W WO2007123722A2 WO 2007123722 A2 WO2007123722 A2 WO 2007123722A2 US 2007007965 W US2007007965 W US 2007007965W WO 2007123722 A2 WO2007123722 A2 WO 2007123722A2
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WIPO (PCT)
Prior art keywords
sorafenib
mmp
subject
amount
cell
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Ceased
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PCT/US2007/007965
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English (en)
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WO2007123722A3 (fr
Inventor
Scott Wilhelm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharmaceuticals Corp
Bayer Healthcare LLC
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Bayer Pharmaceuticals Corp
Bayer Healthcare LLC
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Priority to CA002648106A priority Critical patent/CA2648106A1/fr
Priority to JP2009503038A priority patent/JP2009532029A/ja
Priority to EP07754481A priority patent/EP2002264A2/fr
Publication of WO2007123722A2 publication Critical patent/WO2007123722A2/fr
Publication of WO2007123722A3 publication Critical patent/WO2007123722A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
    • G01N33/5759—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites involving compounds localised on the membrane of tumour or cancer cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
    • G01N33/57585—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites involving compounds identifiable in body fluids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds

Definitions

  • the invention pertains to a method of determining the phenotype of cells, comprising detecting the differential expression, relative to normal cells, of at least one polypeptide, wherein the protein is differentially expressed by at least a factor of two, at least a factor of five, at least a factor of twenty, an up to at least a factor of fifty.
  • the polypeptide is MMP-1, MMP-10, IL- 6, IL-8, IL-10, CSF-2, SLCO4A1 , and/or FOS-like antigen.
  • the present invention also relates to a combination of a multi-kinase inhibitor (see below for examples) and a prodrug that is selectively activated in hypoxic tissues.
  • a multi-kinase inhibitor see below for examples
  • a prodrug that is selectively activated in hypoxic tissues.
  • quinone bioreduct ⁇ ve prodrugs are selectively activated in tissues where they can exert a cytotoxic effect. See, e.g., Seow et al., Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9282-7.
  • An "address" on an array refers to a location at which an element, for example, an oligonucleotide, is attached to the solid surface of the array.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • the term "gene” refers to a nucleic acid sequence that comprises control and coding sequences necessary for the production of a polypeptide or precursor.
  • the polypeptide can be encoded by a full length coding sequence or by any portion of the coding sequence.
  • the gene may be derived in whole or in part from any source known to the art, including a plant, a fungus, an animal, a bacterial genome or episome, eukaryotic, nuclear or plasmid DNA, cDNA, viral DNA, or chemically synthesized DNA.
  • a gene may contain one or more modifications in either the coding or the untranslated regions which could affect the biological activity or the chemical structure of the expression product, the rate of expression, or the manner of expression control.
  • Hybridization also includes the formation of duplexes which contain certain mismatches, provided that the two strands are still forming a double-stranded helix.
  • “Stringent hybridization conditions” refers to hybridization conditions resulting in essentially specific hybridization.
  • nucleic acid refers to polynucleotides such as deoxyribonucleic acid (DNA) and, where appropriate, ribonucleic acid (RNA).
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • Chromosomes, cDNAs, mRNAs, rRNAs, and ESTs are representative examples of molecules that may be referred to as nucleic acids.
  • Small molecule refers to a composition with a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids, or other organic or inorganic molecules. Many pharmaceutical companies have extensive libraries of chemical and/or biological mixtures, often fungal, bacterial, or algal extracts, which can be screened with any of the assays of the invention to identify compounds that modulate a bioactivity.
  • the invention provides a method comprising incubating a cell expressing the marker nucleic acids with a test compound and measuring the mRNA or protein level.
  • the invention further provides a method for quantitatively determining the level of expression of the marker nucleic acids in a cell population, and a method for determining whether an agent is capable of increasing or decreasing the level of expression of the marker nucleic acids in a cell population.
  • Determining gene expression levels may be accomplished utilizing microarrays. Generally, the following steps may be involved: (a) obtaining an mRNA sample from a subject and preparing labeled nucleic acids therefrom (the "target nucleic acids” or “targets”); (b) contacting the target nucleic acids with an array under conditions sufficient for the target nucleic acids to bind to the corresponding probes on the array, for example, by hybridization or specific binding; (c) optional removal of unbound targets from the array; (d) detecting the bound targets, and (e) analyzing the results, for example, using computer based analysis methods.
  • “nucleic acid probes” or “probes” are nucleic acids attached to the array
  • target nucleic acids are nucleic acids that are hybridized to the array.
  • a “non-invasive” sampling means is one in which the nucleic acid molecules are recovered from an internal or external surface of the animal.
  • Examples of such "non-invasive” sampling means include, for example, “swabbing,” collection of tears, saliva, urine, fecal material, sweat or perspiration, hair.
  • RNA may be extracted from tissue or cell samples by a variety of methods, for example, guanidium thiocyanate lysis followed by CsCI centrifugation (Chirgwin, et al., Biochemistry 18:5294-5299, 1979).
  • RNA from single cells may be obtained as described in methods for preparing cDNA libraries from single cells (see, e.g., Dulac, Curr. Top. Dev. Biol. 36:245, 1998; Jena, et al., J. Immunol. Methods 190:199, 1996).
  • RNA sample can be further enriched for a particular species.
  • poly(A)+ RNA may be isolated from an RNA sample.
  • the RNA population may be enriched for sequences of interest by primer-specific cDNA synthesis, or multiple rounds of linear amplification based on cDNA synthesis and template-directed in vitro transcription (see, e.g., Wang, et al., Proc. Natl. Acad. Sci. USA 86:9717, 1989; Dulac, et al., supra; Jena, et al., supra).
  • Assays can be utilized which permit quantification and/or presence/absence detection of a target nucleic acid in a sample. Assays can be performed at the single- cell level, or in a sample comprising many cells, where the assay is "averaging" expression over the entire collection of cells and tissue present in the sample. Any suitable assay format can be used, including, but not limited to, e.g., Southern blot analysis, Northern blot analysis, polymerase chain reaction ("PCR”) (e.g., Saiki et al., Science, 241:53, 1988; U.S. Pat. Nos.
  • PCR polymerase chain reaction
  • any method suitable for single cell analysis of gene or protein expression can be used, including in situ hybridization, immunocytochemistry, MACS, FACS, flow cytometry, etc.
  • expression products can be measured using antibodies, PCR, or other types of nucleic acid amplification (e.g., Brady et al., Methods MoI. & Cell. Biol. 2, 17-25, 1990; Eberwine et al., 1992, Proc. Natl. Acad. ScL,- 89, 3010-3014, 1992; U.S. Pat. No. 5,723,290).
  • nucleic acid amplification e.g., Brady et al., Methods MoI. & Cell. Biol. 2, 17-25, 1990; Eberwine et al., 1992, Proc. Natl. Acad. ScL,- 89, 3010-3014, 1992; U.S. Pat. No. 5,723,290.
  • a microarray may contain from 2 to 20 probes corresponding to one gene and preferably about 5 to 10.
  • the probes may correspond to the full-length RNA sequence or complement thereof of genes characteristic of small molecule efficacy, or the probe may correspond to a portion thereof, which portion is of sufficient length to permit specific hybridization.
  • Such probes may comprise from about 50 nucleotides to about 100, 200, 500, or 1000 nucleotides or more than 1000 nucleotides.
  • Various algorithms are available for analyzing gene expression data, for example, the type of comparisons to perform.
  • a preferred embodiment for identifying such groups of genes involves clustering algorithms (for reviews of clustering algorithms, see, e.g., Fukunaga, 1990, Statistical Pattern Recognition, 2nd Ed., Academic Press, San Diego; Everitt, 1974, Cluster Analysis, London: Heinemann Educ. Books; Hartigan, 1975, Clustering Algorithms, New York: Wiley; Sneath and Sokal, 1973, Numerical Taxonomy, Freeman; Anderberg, 1973, Cluster Analysis for Applications, Academic Press: New York).
  • Expression patterns may be used to derive a panel of biomarkers that can be used to predict the efficacy of drug treatment in the patients.
  • the biomarkers may consist of gene expression levels from microarray experiments on RNA isolated from biological samples, RNA isolated from frozen samples of tumor biopsies, or mass spectrometry-derived protein masses in the serum.
  • chemotherapeutic agents include, but are not limited to, e.g., alkylating agents (e.g., cyclophosphamide, ifosfamide, melphalan, chlorambucil, aziridines, epoxides, alkyl sulfonates), cisplatin and its analogues (e.g., carboplatin, oxaliplatin), antimetabolitites (e.g., methotrexate, 5-fluorouracil, capecitabine, cytarabine, gemcitabine, fludarabine), toposiomerase interactive agents (e.g., camptothecin, irinotecan, topotecan, etoposide, teniposide, doxorubicin, daunorubicin), antimicrotubule agents (e.g., vinca alkaloids, such as vincristine, vinblastine, and vinorelbine; taxanes, such
  • human tissue samples may be screened for the presence and/or absence of biomarkers identified herein.
  • samples could consist of needle biopsy cores, surgical resection samples, lymph node tissue, or serum.
  • these methods include obtaining a biopsy, which is optionally fractionated by cryostat sectioning to enrich tumor cells to about 80% of the total cell population.
  • nucleic acids extracted from these samples may be amplified using techniques well known in the art. The levels of selected markers detected would be compared with statistically valid groups of metastatic, non-metastatic malignant, benign, or normal tissue samples.
  • An indicator moiety, or label group may be attached to the subject antibodies and is selected so as to meet the needs of various uses of the method which are often dictated by the availability of assay equipment and compatible immunoassay procedures. General techniques to be used in. performing the various immunoassays noted above are known to those of ordinary skill in the art.
  • one aspect of the present invention relates to diagnostic assays for determining, in the context of cells isolated from a patient, if the level of a marker polypeptide is significantly reduced in the sample cells.
  • the term "significantly reduced” refers to a cell phenotype wherein the cell possesses a reduced cellular amount of the marker polypeptide relative to a normal cell of similar tissue origin.
  • a cell may have less than about 50%, 25%, 10%, or 5% of the marker polypeptide compared to that of a normal control cell.
  • tumor cells of the same type may not show uniformly increased expression of individual oncogenes or uniformly decreased expression of individual tumor suppressor genes.
  • the invention provides for a battery of tests utilizing a number of probes of the invention, in order to improve the reliability and/or accuracy of the diagnostic test.
  • nucleic acid molecules may be used to generate microarrays on a solid surface (e.g., a membrane) such that the arrayed nucleic acid molecules may be used to determine if any of the nucleic acids are differentially expressed between normal cells or tissue and cancerous cells or tissue.
  • the nucleic acid molecules of the invention may be cDNA or may be used to generate cDNA molecules to be subsequently amplified by PCR and spotted on nylon membranes. The membranes may then be reacted with radiolabeled target nucleic acid molecules obtained from equivalent samples of cancerous and normal tissue or cells.
  • Sorafenib, and other agents in accordance with the present invention can also produce an biologically effective dose (BED) prior to achieving a substantial therapeutic effect.
  • BED biologically effective dose
  • the latter can occur, e.g., when dosages of sorafenib are sufficient for it to interact with its kinase targets, but not adequate to effectively treat the disease or disorder.
  • the presenting invention also provides methods for determining the efficacy of an agent in treating a tumor in a subject who has been administered an agent (such as sorafenib or sutent), comprising, measuring the amount of tumor hypoxia in said subject, wherein said amount is indicative of whether a therapeutically effective amount of sorafenib has been administered.
  • Tissue hypoxia can be defined as decrease in oxygen utilization, such that cells are experiencing anaerobic respiration.
  • Various methods can be utilized to determine hypoxia. For example, global measurements include, e.g., blood lactate, pH, oxygen transport/oxygen consumption, mixed venous oxygen saturation, venous arterial carbon dioxide gradient, etc. In addition to global measurements, regional hypoxia can also be measured.
  • an expression pattern can be used as a unique identifier to characterize the status of the tissue with respect to its sorafenib response. It can be used as a point of reference to compare and characterize a cellular response to a multi-kinase inhibitor.
  • the fingerprint can be used to determine whether a compound of interest has the same pharmacological activity of sorafenib.
  • a pattern of differential gene expression can be determined for a test compound. The closer the pattern match, the more closely the compound mirrors the pharmacological profile of sorafenib. Such compounds can be used for any indication that sorafenib is utilized for.
  • MMP-1, MMP-10, IL-6, IL-8, IL-10, CSF-2, SLCO4A1, and/or FOS-like antigen mRNA and protein may be detected in plasma.
  • changes in the baseline plasma concentration of MMP-1 , MMP-10, IL-6, IL-8, IL- 10, CSF-2, SLCO4A1, and/or FOS-like antigen may be monitored in patients with cancer.
  • MMP-1, MMP-10, IL-6, IL-8, IL-10, CSF-2, SLCO4A1, and/or FOS-like antigen protein levels may also be monitored by quantitative immunohistochemistry using paraffin-embedded tumor biopsies.
  • Another approach to monitor treatment is an evaluation of serum proteomic spectra.
  • plasma samples may be subjected to mass spectroscopy (e.g., surface-enhanced laser desorption and ionization) and a proteomic spectra may be generated for each patient.
  • mass spectroscopy e.g., surface-enhanced laser desorption and ionization
  • a set of spectra, derived from analysis of plasma from patients before and during treatment may be analyzed by an iterative searching algorithm, which can identify a proteomic pattern that completely discriminates the treated samples from the untreated samples. The resulting pattern may then be used to predict the clinical benefit following treatment.
  • FIG. 1 shows outline for gene regulation/protein expression studies.
  • Tumor samples were snap-frozen and homogenized in lysis buffer [4OmM Tris, pH7.4, 10% glycerol, 5OmM b-glycerol phosphate, 5mM EGTA, 2mM EDTA, 1mM sodium orthovanadate, 1OmM sodium fluoride, 0.3% Triton-X-100, and a protease inhibitor cocktail (Roche; Indianapolis, IN)].
  • lysis buffer 4OmM Tris, pH7.4, 10% glycerol, 5OmM b-glycerol phosphate, 5mM EGTA, 2mM EDTA, 1mM sodium orthovanadate, 1OmM sodium fluoride, 0.3% Triton-X-100, and a protease inhibitor cocktail (Roche; Indianapolis, IN)].
  • IL-6, IL-8 and VEGF were determined using specific assay kits from MesoScale Diagnostics (Gaithersburg, MD) following conditions from the manufacturer.
  • MMP-1 and MMP-10 protein levels were determined in an immunoassay ELISA from R&D Systems (Minneapolis, MN) following the protocols from the vendor.
  • Tumor protein levels of IL-6, IL-8, MMP-1 , and MMP-10 were elevated by sorafenib treatment (QDX 3) at different doses tested. Statistically significant elevation of the levels of all four proteins was observed at 24 hours after the third dose (15, 30 and 60 mg/kg doses). Trends in elevation of II-6, IL-8 and MMP-10 levels in plasma were observed removed from Sorafenib-treated animals.

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Abstract

La présente invention concerne également les biomarqueurs et l'utilisation de biomarqueurs dans le cadre de la prévision et du pronostic d'un cancer, ainsi que l'utilisation de biomarqueurs en vue de surveiller l'efficacité d'un traitement anticancéreux.
PCT/US2007/007965 2006-03-31 2007-03-30 Procedes de prevision et de pronostic de cancer, et surveillance d'une therapie anticancereuse Ceased WO2007123722A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002648106A CA2648106A1 (fr) 2006-03-31 2007-03-30 Procedes de prevision et de pronostic de cancer, et surveillance d'une therapie anticancereuse
JP2009503038A JP2009532029A (ja) 2006-03-31 2007-03-30 癌の予報および予後方法および癌治療のモニタリング
EP07754481A EP2002264A2 (fr) 2006-03-31 2007-03-30 Procedes de prevision et de pronostic de cancer, et surveillance d'une therapie anticancereuse

Applications Claiming Priority (4)

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US78769306P 2006-03-31 2006-03-31
US60/787,693 2006-03-31
US90168207P 2007-02-16 2007-02-16
US60/901,682 2007-02-16

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WO2007123722A2 true WO2007123722A2 (fr) 2007-11-01
WO2007123722A3 WO2007123722A3 (fr) 2008-05-08

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009061800A3 (fr) * 2007-11-09 2009-07-16 Genentech Inc Procédés et compositions pour une utilisation de diagnostic chez des patients atteints de cancer
WO2010022227A1 (fr) * 2008-08-20 2010-02-25 Schering Corporation Procédés pour surveiller une thérapie il-10
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
JP2011528014A (ja) * 2008-07-14 2011-11-10 ジーイー・ヘルスケア・リミテッド 治療のモニタリング
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
JP2012506560A (ja) * 2008-10-21 2012-03-15 バイエル ヘルスケア エルエルシー 肝細胞癌と関連するシグネチャ遺伝子の同定
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US20210029131A1 (en) * 2016-12-20 2021-01-28 Google Llc Conditional provision of access by interactive assistant modules
US11822695B2 (en) 2018-08-07 2023-11-21 Google Llc Assembling and evaluating automated assistant responses for privacy concerns
US12175205B2 (en) 2017-05-15 2024-12-24 Google Llc Providing access to user-controlled resources by automated assistants

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2989466B1 (fr) * 2013-04-25 2018-10-31 CBS Bioscience, Co., Ltd Procédé analytique pour augmenter la sensibilité d'une thérapie moléculaire ciblée dans un carcinome hépatocellulaire

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015947A2 (fr) * 2005-07-29 2007-02-08 Bayer Healthcare Llc Methodes et trousses pour la prediction du succes therapeutique, de la survie sans recidive et globale dans des therapies du cancer

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
WO2009061800A3 (fr) * 2007-11-09 2009-07-16 Genentech Inc Procédés et compositions pour une utilisation de diagnostic chez des patients atteints de cancer
JP2011528014A (ja) * 2008-07-14 2011-11-10 ジーイー・ヘルスケア・リミテッド 治療のモニタリング
WO2010022227A1 (fr) * 2008-08-20 2010-02-25 Schering Corporation Procédés pour surveiller une thérapie il-10
JP2012506560A (ja) * 2008-10-21 2012-03-15 バイエル ヘルスケア エルエルシー 肝細胞癌と関連するシグネチャ遺伝子の同定
US20210029131A1 (en) * 2016-12-20 2021-01-28 Google Llc Conditional provision of access by interactive assistant modules
US12175205B2 (en) 2017-05-15 2024-12-24 Google Llc Providing access to user-controlled resources by automated assistants
US11822695B2 (en) 2018-08-07 2023-11-21 Google Llc Assembling and evaluating automated assistant responses for privacy concerns
US11966494B2 (en) 2018-08-07 2024-04-23 Google Llc Threshold-based assembly of remote automated assistant responses

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JP2009532029A (ja) 2009-09-10
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