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Ep 2618146 A2 (19) TZZ __ T (11) EP 2 618 146 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: (2006.01) 24.07.2013 Bulletin 2013/30 G01N 33/50 (21) Application number: 13164311.6 (22) Date of filing: 24.02.2009 (84) Designated Contracting States: • Harvey, Jeanne AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Livermore, CA 94550 (US) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • Kim, Phillip PT RO SE SI SK TR Irvine, CA 92612 (US) Designated Extension States: • Liu, Xinjun AL BA RS San Diego, CA 92130 (US) •Liu,Limin (30) Priority: 25.02.2008 US 31319 P San Diego, CA 92130 (US) 17.10.2008 US 106404 P • Barham, Robert 24.10.2008 US 108384 P San Marcos, CA 92078 (US) 25.11.2008 US 117908 P • Neri, Bruce 23.12.2008 US 140558 P Carlsbad, CA 92008 (US) (62) Document number(s) of the earlier application(s) in (74) Representative: Rupp, Christian accordance with Art. 76 EPC: Mitscherlich & Partner 12183659.7 / 2 602 623 Patent- und Rechtsanwälte 09715619.4 / 2 250 498 Sonnenstraße 33 80331 München (DE) (71) Applicant: Nestec S.A. 1800 Vevey (CH) Remarks: This application was filed on 18-04-2013 as a (72) Inventors: divisional application to the application mentioned • Singh, Sharant under INID code 62. Santa Fe, CA 92067 (US) (54) Drug selection for breast cancer therapy using antibody-based arrays (57) The present invention provides compositions nal transduction pathways derived from use of the inven- and methods for detecting the activation states of com- tion can be used for cancer diagnosis, prognosis, and in ponents of signal transduction pathways in tumor cells. the design of cancer treatments. Information on the activation states of components of sig- EP 2 618 146 A2 Printed by Jouve, 75001 PARIS (FR) EP 2 618 146 A2 Description CROSS-REFERENCES TO RELATED APPLICATIONS 5 [0001] The present application claims priority to U.S. Provisional Application No. 61/031,319, filed February 25, 2008, U.S. Provisional Application No. 61/106,404, filed October 17, 2008, U.S. Provisional Application No. 61/108,384, filed October 24, 2008, U.S. Provisional Application No. 61/117,908, filed November 25, 2008, and U.S. Provisional Application No. 61/140,558, filed December 23, 2008, the disclosures of which are herein incorporated by reference in their entirety for all purposes. 10 BACKGROUND OF THE INVENTION [0002] 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. 15 Accordingly, derangements in normal signal transduction in cells can lead to a number of disease states such as diabetes, heart disease, autoimmunity, and cancer. [0003] One well characterized signal transduction pathway is the MAP kinase pathway, which is responsible for trans- ducing the signal from epidermal growth factor (EGF) to the promotion of cell proliferation in cells ( see, Figure 1). EGF binds to a transmembrane receptor-linked tyrosine kinase, the epidermal growth factor receptor (EGFR), which is acti- 20 vated 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 kinases activation is the autophosphorylation of EGFR on tyrosine residues. The phosphorylated tyrosine residues on the activated EGFR provide a 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 25 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. [0004] Following activation, Ras binds to and activates the protein kinase activity of RAF kinase, a serine/threonine- 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 30 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 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- 35 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. [0005] 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 40 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 cancer. [0006] Cetuximab is an example of a monoclonal antibody inhibitor, which binds to the extracellular ligand-binding 45 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 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. 50 [0007] 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 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. 55 [0008] 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 good indicator of the efficacy of various cancer treatments. Accordingly, in addition to fulfilling other needs, the present 2 EP 2 618 146 A2 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. 5 BRIEF SUMMARY OF THE INVENTION [0009] The present invention provides compositions and methods for detecting the activation states of components of signal transduction pathways in tumor cells(e.g., circulating cells of a breast tumor). Information on the activation states of components of signal transduction pathways derived from practice of the present invention can be used for 10 cancer diagnosis, prognosis, and in the design of cancer treatments. [0010] In one aspect, the present invention provides a method for selecting a suitable anticancer drug for the treatment of a breast tumor, the method comprising: (a) isolating cells of a breast tumor after administration of an anticancer drug, or prior to incubation with an anticancer 15 drug; (b) lysing the isolated cells to produce a cellular extract; (c) detecting an activation state of one or more analytes in the cellular extract using an assay comprising a plurality of dilution series of capture antibodies specific for the one or more analytes, wherein the capture antibodies are restrained on a solid support; and 20 (d) determining whether the anticancer drug is suitable or unsuitable for the treatment of the breast tumor by com- paring the activation state detected for the one or more analytes with a reference activation profile generated in the absence of the anticancer drug. [0011] In a preferred embodiment, the method for selecting a suitable anticancer drug for the treatment of a breast 25 tumor comprises: (a) isolating cells of a breast tumor after administration of an anticancer drug, or prior to incubation with an anticancer drug; (b) lysing the isolated cells to produce a cellular extract; 30 (c) detecting an activation state of one or more analytes in the cellular extract using an assay comprising a plurality of dilution series of capture antibodies specific for the one or more analytes, wherein the capture antibodies are restrained on a solid support; (d) comparing the activation state detected for the one or more analytes with a reference activation profile generated in the absence of the anticancer drug; and 35 (e) indicating that the anticancer drug is suitable for the treatment of the breast tumor when the activation state detected for the one or more analytes is substantially decreased compared to the reference activation profile.
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