WO2016011065A1 - Détection de l'expression dixdc1 (protéine contenant le domaine dix-1) pour déterminer si une tumeur peut répondre aux inhibiteurs fak et src kinase - Google Patents

Détection de l'expression dixdc1 (protéine contenant le domaine dix-1) pour déterminer si une tumeur peut répondre aux inhibiteurs fak et src kinase Download PDF

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Publication number
WO2016011065A1
WO2016011065A1 PCT/US2015/040432 US2015040432W WO2016011065A1 WO 2016011065 A1 WO2016011065 A1 WO 2016011065A1 US 2015040432 W US2015040432 W US 2015040432W WO 2016011065 A1 WO2016011065 A1 WO 2016011065A1
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dixdcl
sample
cancer
protein
expression
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PCT/US2015/040432
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Reuben J. Shaw
Jonathan M. GOODWIN
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Salk Institute For Biolofical Studies
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    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2440/00—Post-translational modifications [PTMs] in chemical analysis of biological material
    • G01N2440/14—Post-translational modifications [PTMs] in chemical analysis of biological material phosphorylation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Trp53, Rb, pl6/Cdkn2a Carretero et al., Cancer Cell 17, 547-559, 2010; Contreras et al., Dis Model Mech 3, 181-193, 2010; Ji et al., Nature 448, 807-810, 2007; Liu et al., Cancer Cell 21, 751-764, 2012).
  • the enhanced metastatic potential of Lkbl -deficient tumors is also notable for occurring in cancers across multiple lineages, namely endometrium, lung, and melanoma (Contreras et al, Cancer Res. 68, 759-766, 2008; Ji et al., Nature 448, 807-810, 2007; Liu et al., Cancer Cell 21, 751-764, 2012).
  • FIG. 1G LKBl is the master upstream activating kinase of the AMPKR kinase family.
  • siRNA oligos targeting AMPKR subfamilies were transfected into U20S at a final concentration of 20 ⁇ for 72 hours. Lysates were analyzed by western blotting with indicated antibodies.
  • FIG. 4F siRNA knockdown for indicated genes (20 ⁇ final) was performed in U20S cells for 72 hrs. Lysates were immunoblotted with indicated antibodies. Key: Control RNAi (Con), AMPKal and AMPKa2 (A12), MARKl (Ml), MARK2 (M2), MARK3 (M3), MARK4 (M4), MARKl and MARK4 (M14), MARK2 and MARK3 (M23).
  • FIGS. 6A-6G Hyperactivation of FAK upon loss of LKB1 or DIXDCl is responsible for Snail induction.
  • FIG. 11 A RT-PCR analysis of a panel of T nonMet and TMet cell lines for Dixdcl mRNA levels. * p ⁇ .01 relative to 802T4.
  • FIG. 1 IF. MTT growth assay comparing proliferation rates of T nonMet shGFP and shDixdcl cells from FIG. 10B. p > 0.9 using unpaired Student's t-test.
  • FIGS. 13A-13D DIXDCl is frequently downregulated in human cancer.
  • SEQ ID NO: 37 is an shRNA for hDIXDCl 3'utr hairpin.
  • DIXDCl is involved in focal adhesion maturation. It was observed that loss of DIXDCl results in an accumulation of nascent focal adhesions, which are documented to possess enhanced tractile strength in motile cells compared to mature adhesions (Beningo et al., J Cell Biol 153, 881-888, 2001). Furthermore, these nascent peripheral adhesions were largely absent for zyxin staining, a protein known to mark mature adhesions as well as decrease adhesion strength and cell migration ability (Sperry et al., J. Cell. Phys.
  • the DIXDCl protein-specific binding agent or a DIXDCl nucleic acid probe are allowed to interact with the sample (or proteins or nucleic acids isolated from the sample) under conditions that permit binding of the DIXDCl protein-specific binding agent to DIXDCl proteins in the sample or that permit binding of the DIXDCl nucleic acid probe to DIXDCl nucleic acids (e.g. , genomic DNA, mRNA, and the like) in the sample (if DIXDCl proteins/nucleic acids are present in the sample).
  • DIXDCl protein or DIXDCl nucleic acid molecule expression indicates that the cancer is sensitive to a FAK inhibitor and/or Src inhibitor.
  • the disclosed diagnostic methods can be used in companion diagnostic assays with FAK and/or Src inhibitors. That is, the disclosed methods can be used to identify cancers that will be sensitive to a FAK and/or Src inhibitor. For example, cancers with decreased DIXDCl expression or decreased phosphorylation (e.g., at Ser 592), are cancers which are predicted to be responsive to FAK and/or Src inhibitors. In addition, cancers with decreased DIXDCl expression or decreased phosphorylation, are cancers which are predicted to metastasize.
  • FAK inhibitors include a family of compounds that can be used to reduce (e.g., down regulate) FAK activity, for example by reducing FAK nucleic acid and/or FAK expression.
  • Examples of such compounds include inhibitory nucleic acid molecules and small molecule inhibitors, such as those that specifically block FAK kinase activity.
  • program modules include routines, programs, libraries, objects, classes, components, data structures, etc. that perform particular tasks or implement particular abstract data types.
  • the functionality of the program modules may be combined or split between program modules as desired in various embodiments.
  • Computer- executable instructions for program modules may be executed within a local or distributed computing system.
  • the computer-executable instructions can be executable code that results from compilation into instructions directly executable on a processor, interpreted code such as a script, byte codes or other intermediate representation of software instructions, or logic or formulas adapted for execution in a spreadsheet or other tool.
  • the computer-executable instructions can be specified in any of various computer languages, such as C, C++, Java, Perl, JavaScript, Adobe Flash, or any other suitable language.
  • a core function of Snail family transcription factors is to create a cellular state favorable to cell migration and invasion (Thiery et al., Cell 139, 871-890, 2009). Snail mediates this through repression of the E-cadherin promoter, but also through transcriptional induction (Rembold et al., Genes Dev 28, 167-181, 2014) of mRNAs for extracellular matrix components, metalloproteinases, and numerous secreted growth factors, including the noncanonical Wnt ligands, Wnt5a and Wnt5b (Moreno-Bueno et al., Cancer Res 66, 9543-9556, 2006; Ren et al.,
  • DIXDCl is a novel substrate of MARKl and MARK that suppresses Snail levels
  • This example describes methods used to further dissect the mechanism by which
  • the optimal substrate motif was determined for all four MARK kinases using the same method, and nearly identical profiles were observed (FIGS. 3B and 4A).
  • the optimal in vitro peptide phosphorylation sequence for the MARK kinases ("MARK motif) was also quite similar to a previously described AMPK motif (Gwinn et al., Mol Cell 30, 214-226, 2008) (FIG. 4A). This common consensus sequence includes strong preferences for aliphatic residues at positions -5 and +4 relative to the phosphorylation site, as well as for a basic residue at position -3.
  • DIXDCl is most significantly deleted independent of a peak region in metastatic cutaneous melanoma, lung cancer, and cervical squamous cell carcinoma, of which melanoma and lung cancer represent well-defined settings where loss of Lkbl in GEMM models modulates metastasis and FAK/Src signaling (Liu et al., Cancer Cell 21, 751-764, 2012) (FIG. 12A).
  • CONEXIC a new algorithm that combines gene expression and copy number alterations to identify driver events in melanoma
  • suppression of DIXDCl was identified as one of the top 30 drivers in this tumor type (Akavia et al., Cell 143, 1005-1017, 2010).

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  • Engineering & Computer Science (AREA)
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Abstract

La présente invention concerne des procédés, des systèmes et des trousses permettant d'analyser des échantillons de cancer (tels que ceux dans lesquels la FAK est régulée à la hausse ou activée). Ces procédés peuvent consister à détecter l'expression et/ou la phosphorylation DIXDC1 pour identifier les cancers qui répondront aux inhibiteurs FAK et/ou aux inhibiteurs Src, et pour identifier les cancers qui seront susceptibles de former des métastases.
PCT/US2015/040432 2014-07-15 2015-07-14 Détection de l'expression dixdc1 (protéine contenant le domaine dix-1) pour déterminer si une tumeur peut répondre aux inhibiteurs fak et src kinase WO2016011065A1 (fr)

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Cited By (1)

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CN113817797A (zh) * 2021-08-31 2021-12-21 皖南医学院 一种研究乳酸影响肺癌细胞转移侵袭能力的方法

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WO2011017106A1 (fr) * 2009-07-27 2011-02-10 The Trustees Of Columbia University In The City Of New York Skp2 en tant que biomarqueur de la résistance à la rapamycine
US20110320392A1 (en) * 2009-03-02 2011-12-29 Black Esther P Methods for predicting cancer response to egfr inhibitors
US20130331294A1 (en) * 2007-11-09 2013-12-12 Fox Chase Cancer Center Egfr/nedd9/tgf-beta interactome and methods of use thereof for the identification of agents having efficacy in the treatment of hyperproliferative disorders
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WO2008082730A2 (fr) * 2006-09-19 2008-07-10 Novartis Ag Biomarqueurs de modulation cible, efficacité, diagnostic et/ou pronostic pour les inhibiteurs de la raf
US20100184125A1 (en) * 2007-05-17 2010-07-22 Bristol-Myers Squibb Company Biomarkers and methods for determining sensitivity to insulin growth factor-1 receptor modulators
US20100247528A1 (en) * 2007-09-06 2010-09-30 Kent Hunter Arrays, kits and cancer characterization methods
US20130331294A1 (en) * 2007-11-09 2013-12-12 Fox Chase Cancer Center Egfr/nedd9/tgf-beta interactome and methods of use thereof for the identification of agents having efficacy in the treatment of hyperproliferative disorders
US20110320392A1 (en) * 2009-03-02 2011-12-29 Black Esther P Methods for predicting cancer response to egfr inhibitors
WO2011017106A1 (fr) * 2009-07-27 2011-02-10 The Trustees Of Columbia University In The City Of New York Skp2 en tant que biomarqueur de la résistance à la rapamycine
WO2014030602A1 (fr) * 2012-08-20 2014-02-27 独立行政法人国立がん研究センター Agent pour le traitement du cancer

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UCHINO, K. ET AL.: "Therapeutic effects of microRNA-582-5p and -3p on the inhibition of bladder cancer progression", MOLECULAR THERAPIES, vol. 21, no. 3, 2013, pages 610 - 9, XP055188593, DOI: doi:10.1038/mt.2012.269 *
WANG, L. ET AL.: "DLXDC targets p21 and cyclin D1 via PI3K pathway activation to promote colon cancer cell proliferation", CANCER SCIENCE, vol. 100, no. 10, 2009, pages 1801 - 8 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113817797A (zh) * 2021-08-31 2021-12-21 皖南医学院 一种研究乳酸影响肺癌细胞转移侵袭能力的方法

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