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WO2007109026A2 - Compositions de pten et méthodes servant à détecter le cancer du sein - Google Patents

Compositions de pten et méthodes servant à détecter le cancer du sein Download PDF

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Publication number
WO2007109026A2
WO2007109026A2 PCT/US2007/006338 US2007006338W WO2007109026A2 WO 2007109026 A2 WO2007109026 A2 WO 2007109026A2 US 2007006338 W US2007006338 W US 2007006338W WO 2007109026 A2 WO2007109026 A2 WO 2007109026A2
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WIPO (PCT)
Prior art keywords
tumor
pten
gene expression
profile
domain containing
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Ceased
Application number
PCT/US2007/006338
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English (en)
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WO2007109026A3 (fr
Inventor
Ramon Parsons
Lao Saal
Ake Borg
Sofia Gruvberger-Saal
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Columbia University in the City of New York
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Columbia University in the City of New York
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Publication of WO2007109026A2 publication Critical patent/WO2007109026A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007109026A3 publication Critical patent/WO2007109026A3/fr
Ceased legal-status Critical Current

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    • 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
    • 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
    • C12Q2600/112—Disease subtyping, staging or classification
    • 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
    • C12Q2600/118—Prognosis of disease development
    • 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
    • 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
    • C12Q2600/158—Expression markers

Definitions

  • Another aspect of the invention provides a method for identifying whether a tumor has a high potential for malignancy, the method comprising: (a) determining gene expression level in a sample of tumor cells of (i) stathmin/oncoprotein 18, (ii) PIK3CA, and (iii) one or more genes selected from the group consisting of phosphatase and tensin homolog (mutated in multiple advanced cancers 1), AAA domain containing 1, DEP domain containing 1, cadherin 12 type 2 (N-cadherin 2), karyopherin alpha 2 (RAG cohort 1, importin alpha 1), Rac GTPase activating protein 1, kinesin family member 14, carboxypeptidase Z, centromere protein E, retinoic acid induced 2, kinesin family member 4A, chromosome 20 open reading frame 129, baculoviral IAP repeat-containing 3, Discs large homolog 7 (Drosophila), chromosome 6 open reading frame 173, and AAA domain containing
  • the invention provides results that show that therapy to the PTEN pathway components may be effective. Furthermore, for BRCAl germline carriers, the risk of cancer is much higher than in the general population, and many people opt to have prophylactic bilateral mastectomy and/or oophorectomy to reduce their risk.
  • a low-dose or infrequent regimen of anti-PTEN pathway therapy e.g., rapamycin
  • the invention provides a method for delaying or preventing the onset of cancer in a subject, the method comprising administering to the subject an effective amount of a compound that increases expression of one or more genes selected from the group consisting of phosphatase and tensin homolog (mutated in multiple advanced cancers 1), AAA domain containing 1, and retinoic acid induced 2.
  • stathmin be used in connection with the PTEN gene signature to predict poor outcome tumors.
  • stathmin itself can be used to reliably identify tumors with poor outcome.
  • the signature genes can also serve as potential therapeutic targets. Inhibition of stathmin, which regulates MT dynamics, could have inhibitory effects on mitosis and/or cell migration. Additionally, studies have shown overexpression of stathmin to affect sensitivity to MT-stabilizing drugs and MT-destabilizing drugs (Orr et al., 2003). Therefore, studies can be designed to determine whether MT-targeting therapies, in combination with PI3 -K- targeted therapies, would be synergistic against rapidly proliferating P13-K pathway- activated tumors. Some of the signature genes encode cell surface proteins, which may be useful as molecular beacons of pathway activation that could be imaged non-invasively using labeled antibodies to monitor disease progression and response to targeted therapies. The future of cancer management is quickly moving towards pathway-based profiling and directed therapy. Moreover, the gains in pathway-specific treatment of cancer are likely to translate to other diseases, as for example the PI3-K pathway is involved in a vast array of human ailments.
  • RNA Preparation and Microarray Hybridization Total RNA was extracted from ⁇ 100 mg grossly dissected frozen tumor tissue by pulverization in a microdismembrator chilled on dry ice, immediately followed by homogenization in TRlzol reagent according to manufacturer's instructions (Invitrogen, Carlsbad, CA). RNA was purified a second round using the RNeasy kit (Qiagen, Hilden, Germany), and the final yield and purity was assessed using a Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA).
  • Data within each array was normalized using a BASE plug-in implementation of the LOWESS algorithm, whereby the 48 subarrays were grouped into 6 groups spatially lengthwise along the slide (8 pins per group, i.e. 2 rows of 4) and the data within each pin- group smoothed independently. The data matrix was then exported and further filtered to remove all rows (features) with missing data in >20% of assays.
  • EXAMPLE 2 A PTEN GENE EXPRESSION SIGNATURE IN HUMAN BREAST
  • the pi 10a catalytic subunit of PI3K encoded by PIKSCA is a transforming oncogene (Chang et al, 1997), the 3q26 region where PlKiCA is located is amplified in tumors (Shayesteh et al, 1999; Ma et al, 2000), and recently, the PIK3CA gene was shown to have activating mutations in five types of cancer (Samuels et al, 2004).
  • PIK3CA mutations were significantly associated with lower tumor grade, lower S-phase fraction, and negative Ki67 staining. This may indicate that, in vivo, PIK3CA mutation is a less potent driver of cell proliferation than, for example, PTEN alteration. It was previously reported that PIK3CA mutations were positively associated to ER, lymph node status, and HER2 status (Saal et al, 2005). The different results for association to ER and node status may be due to the fact that the present study is underpowered compared to the prior report; moreover the strongest association had been seen within a subset of over 150 stage II Swedish BCs. Thus, stage and population effects may also have influenced the present results.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Hospice & Palliative Care (AREA)
  • Biophysics (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Cette invention se rapporte à des signatures génétiques et à des méthodes d'utilisation de celles-ci pour identifier une tumeur présentant un fort potentiel de malignité chez un sujet sur la base de l'activation de la voie de signalisation PTEN. Cette invention concerne également des méthodes d'utilisation des signatures génétiques pour déterminer l'efficacité de traitements anti-tumeur. Les signatures génétiques et les méthodes de cette invention peuvent être utilisées pour évaluer le potentiel de malignité de tumeurs du cancer du sein, y compris du cancer du sein de type basal non héréditaire et du cancer du sein de type basal lié à BRCA1 héréditaire. Cette invention concerne également des méthodes permettant d'identifier des composés régulant les voies de signalisation PTEN par évaluation des niveaux d'expression d'un ou plusieurs gènes dans la signature génétique.
PCT/US2007/006338 2006-03-15 2007-03-13 Compositions de pten et méthodes servant à détecter le cancer du sein Ceased WO2007109026A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78250306P 2006-03-15 2006-03-15
US60/782,503 2006-03-15

Publications (2)

Publication Number Publication Date
WO2007109026A2 true WO2007109026A2 (fr) 2007-09-27
WO2007109026A3 WO2007109026A3 (fr) 2008-11-20

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PCT/US2007/006338 Ceased WO2007109026A2 (fr) 2006-03-15 2007-03-13 Compositions de pten et méthodes servant à détecter le cancer du sein

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WO (1) WO2007109026A2 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009103790A3 (fr) * 2008-02-21 2009-11-12 Universite Libre De Bruxelles Procédé et trousse de détection des gènes associés à la mutation du pik3ca et impliqués dans l’activation de la voie pi3k/akt dans les sous-types er-positifs et her2-positifs avec des implications cliniques.
WO2011022316A1 (fr) * 2009-08-20 2011-02-24 The Regents Of The University Of Colorado, A Body Corporate Arnmi dérégulés dans un cancer du sein triple-négatif
EP2380991A1 (fr) * 2010-04-20 2011-10-26 Universitätsklinikum Hamburg-Eppendorf Procédé pour déterminer le potentiel métastatique d'une tumeur
EP2588110A4 (fr) * 2010-07-02 2014-04-16 Univ Health Network Méthodes de ciblage de maladies a mutation de pten et compositions prévues à cet effet
EP2823065A4 (fr) * 2012-03-09 2016-03-02 Insight Genetics Inc Procédés et compositions associés au diagnostic et au traitement de cancers associés à un récepteur tyrosine kinase
US9796703B2 (en) 2010-04-06 2017-10-24 University Health Network Synthesis of chiral 2-(1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-ones
USRE47731E1 (en) 2009-04-06 2019-11-19 University Health Network Kinase inhibitors and method of treating cancer with same
EP4352265A4 (fr) * 2021-06-04 2025-10-08 Cedars Sinai Medical Center Utilisation de l'expression de cellules cancéreuses de la cadhérine 12 et de la cadhérine 18 pour traiter des cancers de la vessie

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ISAKOFF S. ET AL.: 'Breast Cancer Associated P1K3CA Mutation Are Oncogenic in Mammary Epithelial Cells' CANCER RESEARCH vol. 65, no. 23, 2005, pages 10992 - 11000 *
WOENCKHAUS J. ET AL.: 'Genomic gain of P1K3CA and increased expression of p11alpha are associated with progression of dysplasia into invasive squamous cell carcinoma' JOURNAL OF PATHOLOGY vol. 198, no. 3, 2002, pages 335 - 342, XP009040955 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009103790A3 (fr) * 2008-02-21 2009-11-12 Universite Libre De Bruxelles Procédé et trousse de détection des gènes associés à la mutation du pik3ca et impliqués dans l’activation de la voie pi3k/akt dans les sous-types er-positifs et her2-positifs avec des implications cliniques.
US8580496B2 (en) 2008-02-21 2013-11-12 Universite Libre De Bruxelles Method and kit for the detection of genes associated with PIK3CA mutation and involved in PI3K/AKT pathway activation in the ER-postitive and HER2-positive subtypes with clinical implications
USRE47731E1 (en) 2009-04-06 2019-11-19 University Health Network Kinase inhibitors and method of treating cancer with same
WO2011022316A1 (fr) * 2009-08-20 2011-02-24 The Regents Of The University Of Colorado, A Body Corporate Arnmi dérégulés dans un cancer du sein triple-négatif
US8507195B2 (en) 2009-08-20 2013-08-13 The Regents Of The University Of Colorado MiRNAs dysregulated in triple-negative breast cancer
US9796703B2 (en) 2010-04-06 2017-10-24 University Health Network Synthesis of chiral 2-(1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-ones
US10358436B2 (en) 2010-04-06 2019-07-23 University Health Network Kinase inhibitors and method of treating cancer
US10077255B2 (en) 2010-04-06 2018-09-18 University Health Network Synthesis of chiral 2-(1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-ones
US9907800B2 (en) 2010-04-06 2018-03-06 University Health Network Kinase inhibitors and method of treating cancer
CN103003445A (zh) * 2010-04-20 2013-03-27 汉堡-艾本德大学医学中心 确定肿瘤转移可能性的方法
WO2011131360A3 (fr) * 2010-04-20 2012-10-18 Universitatsklinikum Hamburg-Eppendorf Procédé de détermination du potentiel métastatique d'une tumeur
EP2380991A1 (fr) * 2010-04-20 2011-10-26 Universitätsklinikum Hamburg-Eppendorf Procédé pour déterminer le potentiel métastatique d'une tumeur
US9402828B2 (en) 2010-07-02 2016-08-02 University Health Network Methods of targeting PTEN mutant diseases and compositions therefor
US8933070B2 (en) 2010-07-02 2015-01-13 University Health Network Methods of targeting PTEN mutant diseases and compositions therefor
EP2588110A4 (fr) * 2010-07-02 2014-04-16 Univ Health Network Méthodes de ciblage de maladies a mutation de pten et compositions prévues à cet effet
EP2823065A4 (fr) * 2012-03-09 2016-03-02 Insight Genetics Inc Procédés et compositions associés au diagnostic et au traitement de cancers associés à un récepteur tyrosine kinase
EP4352265A4 (fr) * 2021-06-04 2025-10-08 Cedars Sinai Medical Center Utilisation de l'expression de cellules cancéreuses de la cadhérine 12 et de la cadhérine 18 pour traiter des cancers de la vessie

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