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Biomarkers for Determining Sensitivity of Breast

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Biomarkers for Determining Sensitivity of Breast (19) TZZ ¥Z¥_T (11) EP 2 430 443 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: G01N 33/50 (2006.01) G01N 33/532 (2006.01) 27.06.2018 Bulletin 2018/26 G01N 33/533 (2006.01) G01N 33/535 (2006.01) G01N 33/543 (2006.01) G01N 33/574 (2006.01) (21) Application number: 10720095.8 (86) International application number: (22) Date of filing: 13.05.2010 PCT/US2010/034814 (87) International publication number: WO 2010/132723 (18.11.2010 Gazette 2010/46) (54) BIOMARKERS FOR DETERMINING SENSITIVITY OF BREAST CANCER CELLS TO HER2-TARGETED THERAPY BIOMARKER ZUR BESTIMMUNG DER EMPFINDLICHKEIT VON BRUSTKREBSZELLEN GEGENÜBER EINER AUF HER2 GERICHTETEN THERAPIE BIOMARQUEURS PERMETTANT DE DÉTERMINER LA SENSIBILITÉ DE CELLULES CANCÉREUSES DU SEIN À UN TRAITEMENT CIBLANT LE RÉCEPTEUR HER2 (84) Designated Contracting States: • KIRKLAND, Richard AL AT BE BG CH CY CZ DE DK EE ES FI FR GB San Diego GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO California 92111 (US) PL PT RO SE SI SK SM TR • LEE, Tani Designated Extension States: San Diego BA ME RS California 92117 (US) • YBARRONDO, Belen (30) Priority: 14.05.2009 US 178458 P San Diego 22.05.2009 US 180787 P California 92107 (US) 15.06.2009 US 187246 P • SINGH, Sharat 24.07.2009 US 228522 P Rancho Santa Fe 20.08.2009 US 235646 P California 92127 (US) 11.09.2009 US 241804 P 19.11.2009 US 262856 P (74) Representative: J A Kemp 30.11.2009 US 265227 P 14 South Square Gray’s Inn (43) Date of publication of application: London WC1R 5JJ (GB) 21.03.2012 Bulletin 2012/12 (56) References cited: (73) Proprietor: Pierian Holdings, Inc. WO-A1-2009/108637 WO-A2-2008/036802 Franklin, TN 37067 (US) WO-A2-2009/012140 (72) Inventors: • BERNS KATRIEN ET AL: "A functional genetic • KIM, Phillip approach identifies the PI3K pathway as a major Irvine determinant of trastuzumab resistance in breast California 92612 (US) cancer." CANCER CELL OCT 2007 LNKD- • LIU, Xinjun PUBMED:17936563, vol. 12, no. 4, October 2007 San Diego (2007-10), pages 395-402, XP002592491 ISSN: California 92130 (US) 1535-6108 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 430 443 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 430 443 B1 • SCALTRITI MAURIZIO ET AL: "Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer" NATIONAL CANCER INSTITUTE. JOURNAL (ONLINE), OXFORD UNIVERSITY PRESS, GB LNKD- DOI:10.1093/JNCI/DJK134, vol. 99, no. 8, 18 April 2007 (2007-04-18) , pages 628-638, XP002540506 ISSN: 1460-2105 2 EP 2 430 443 B1 Description BACKGROUND OF THE INVENTION 5 [0001] The process of signal transduction in cells is responsible for a variety of biological functions including cell division and death, metabolism, immune cell activation, neurotransmission, and sensory perception to name but a few. Accordingly, derangements in normal signal transduction in cells can lead to a number of disease states such as diabetes, heart disease, autoimmunity, and cancer. [0002] One well characterized signal transduction pathway is the MAP kinase pathway, which is responsible for trans- 10 ducing the signal from epidermal growth factor (EGF) to the promotion of cell proliferation in cells ( see, Figure 1 of PCT Publication No. WO2009/108637). EGF binds to a transmembrane receptor-linked tyrosine kinase, the epidermal growth factor receptor (EGFR), which is activated by the binding of EGF. The binding of EGF to EGFR activates the tyrosine kinase activity of the cytoplasmic domain of the receptor. One consequence of this kinase activation is the autophos- phorylation of EGFR on tyrosine residues. The phosphorylated tyrosine residues on the activated EGFR provide a 15 docking site for the binding of SH2 domain containing adaptor proteins such as GRB2. In its function as an adaptor, GRB2 further binds to a guanine nucleotide exchange factor, SOS, by way of an SH3 domain on GRB2. The formation of the complex of EGFR-GRB2-SOS leads to SOS activation of a guanine nucleotide exchange factor that promotes the removal of GDP from Ras. Upon removal of GDP, Ras binds GTP and becomes activated. [0003] Following activation, Ras binds to and activates the protein kinase activity of RAF kinase, a serine/threonine- 20 specific protein kinase. What follows is the activation of a protein kinase cascade that leads to cell proliferation. In outlin e, RAF kinase then phosphorylates and activates MEK, another serine/threonine kinase. Activated MEK phosphorylates and activates mitogen-activated protein kinase (MAPK). Among the targets for further phosphorylation by MAPK are 40S ribosomal protein S6 kinase (RSK). The phosphorylation of RSK by MAPK results in activation of RSK, which in turn phosphorylates ribosomal protein S6. Another known target of MAPK is the proto-oncogene, c-Myc, a gene important 25 for cell proliferation, which is mutated in a variety of cancers. MAPK also phosphorylates and activates another protein kinase, MNK, which in turn phosphorylates the transcription factor, CREB. Indirectly, MAPK also regulates the transcrip- tion of the Fos gene, which encodes yet another transcription factor involved in cell proliferation. By altering the levels and activities of such transcription factors, MAPK transduces the original extracellular signal from EGF into altered transcription of genes that are important for cell cycle progression. 30 [0004] Given the central role that signal transduction pathways play in cell growth, it is not surprising that many cancers arise as a result of mutations and other alterations in signal transduction components that result in aberrant activation of cell proliferation pathways. For example, overexpression or hyperactivity of EGFR has been associated with a number of cancers, including glioblastoma multiforme, colon cancer, and lung cancer. This has prompted the development of anticancer therapeutics directed against EGFR, including gefitinib and erlotinib for lung cancer, and cetuximab for colon 35 cancer. [0005] Cetuximab is an example of a monoclonal antibody inhibitor, which binds to the extracellular ligand-binding domain of EGFR, thus preventing the binding of ligands which activate the EGFR tyrosine kinase. In contrast, gefitinib and erlotinib are small molecules which inhibit the intracellularly-located EGFR tyrosine kinase. In the absence of kinase activity, EGFR is unable to undergo autophosphorylation at tyrosine residues, which is a prerequisite for binding of 40 downstream adaptor proteins, such as GRB2. By halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished. [0006] Additionally, other studies have shown that about 70% of human melanomas and a smaller fraction of other tumors have a point mutation (V599E) in the Raf gene which leads to persistent activation of the MAPK pathway (see, e.g., Davies et al., Nature, 417:949-954 (2002)). Such results suggest that mutations in particular signal transduction 45 pathways may be characteristic of particular types of tumors and that such specific, altered signal transduction pathways may be a promising target for chemotherapeutic intervention. [0007] Given that different cancer treatments, particularly cancer chemotherapy, may function either directly or indi- rectly by means of either blocking or activating cellular signal transduction pathways that are involved in cell proliferation or death, respectively, the activity of a given signal transduction pathway in a particular form of cancer may serve as a 50 good indicator of the efficacy of various cancer treatments. Accordingly, in addition to fulfilling other needs, the present invention provides a method for evaluating the effectiveness of potential anticancer therapies for an individual patient. As such, the present invention provides methods for assisting a physician in selecting a suitable cancer therapy at the right dose and at the right time for every patient. [0008] WO2008/036802 describes antibody-based arrays for detecting the activation state and/or total amount of a 55 plurality of signal transduction molecules in rare circulating cells. WO2009/012140 and WO2009/108637 describe com- positions and methods for detecting the activation state of components of signal transduction pathways in tumour cells. Berns et al., Cancer Cell, Oct 2007, vol. 12, no. 4, pages 395 - 402 describes a functional genetic approach that identified the PI3K pathjway as a major determinant of trastuzamab resistence in brease cancer. Scaltriti et al., J. Natl. Cancer 3 EP 2 430 443 B1 Inst. Apr 2007, vol. 99, no. 8, pages 628 - 638 compares the sensitivity of tumors expressing p95HER2 and tumors expressing the full-length HER2 receptor to anti-HER2 therapies. BRIEF SUMMARY 5 [0009] The invention provides a method for determining the sensitivity of a breast cancer cell to a compound that modulates HER2 activity, the method comprising: (a) contacting the breast cancer cell with the compound; 10 (b) lysing the breast cancer cell to produce a cellular extract; (c) determining the activation level of HER2 and p95HER2 in the cellular extract; and (d) comparing the activation level of HER2
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