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Methods for the Identification, Assessment (19) TZZ__ _T (11) EP 1 581 629 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/68 (2006.01) 01.04.2015 Bulletin 2015/14 (86) International application number: (21) Application number: 03796633.0 PCT/US2003/038539 (22) Date of filing: 04.12.2003 (87) International publication number: WO 2004/053066 (24.06.2004 Gazette 2004/26) (54) METHODS FOR THE IDENTIFICATION, ASSESSMENT, AND TREATMENT OF PATIENTS WITH PROTEASOME INHIBITION THERAPY VERFAHREN ZUR IDENTIFIZIERUNG, BEURTEILUNG UND BEHANDLUNG VON PATIENTEN MIT EINER PROTEASOMEN INHIBITIONS THERAPIE PROCEDESPOUR IDENTIFIER, EVALUER ET TRAITER DES PATIENTS SUIVANT UNE THERAPIE D’INHIBITION DE PROTEASOME (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • "Affymetrix GeneChip Human Genome U95 Set HU IE IT LI LU MC NL PT RO SE SI SK TR HG-U95A" GENBANK GEO, 11 March 2002 Designated Extension States: (2002-03-11), XP002293987 AL LT LV MK • AN W G ET AL: "PROTEASE INHIBITOR- INDUCED APOPTOSIS: ACCUMULATION OF WT (30) Priority: 06.12.2002 US 431514 P P53, P21WAF1/CIP1, AND INDUCTION OF APOPTOSIS ARE INDEPENDENT MARKERS OF (43) Date of publication of application: PROTEASOME INHIBITION" LEUKEMIA, 05.10.2005 Bulletin 2005/40 MACMILLAN PRESS LTD, US, vol. 14, no. 7, July 2000 (2000-07), pages 1276-1283, XP009081378 (73) Proprietor: MILLENNIUM PHARMACEUTICALS, ISSN: 0887-6924 INC. • AGHAJANIAN CAROL ET AL: "A phase I trial of Cambridge, MA 02139 (US) the novel proteasome inhibitor PS341 in advanced solid tumor malignancies." CLINICAL (72) Inventors: CANCER RESEARCH : AN OFFICIAL JOURNAL • MULLIGAN, George OFTHE AMERICAN ASSOCIATION FOR CANCER Lexington, MA 02421 (US) RESEARCH AUG 2002, vol. 8, no. 8, August 2002 • BRYANT, Barbara, M. (2002-08), pages 2505-2511, XP002427558 ISSN: Cambridge, MA 02139 (US) 1078-0432 • MORRISSEY, Michael P. • ZIMMERMANN J ET AL: "Proteasome inhibitor Brighton, MA 02135 (US) induced gene expression profiles reveal • BOLT, Andrew overexpression of transcriptional regulators Cambridge, MA 02138 (US) ATF3, GADD153 and MAD1." ONCOGENE 8 JUN • DAMOKOSH, Andrew, I. 2000, vol. 19, no. 25, 8 June 2000 (2000-06-08), West Hartford, CT 06107 (US) pages 2913-2920, XP002427559 ISSN: 0950-9232 • ADAMS J. ET AL.: ’Protease Inhibitors: A Novel (74) Representative: Lock, Graham James et al Class of Potent and Effective Antitumor Agents’ Fry Heath & Spence LLP CANCERRESEARCH vol. 59, 01 June 1999, pages The Gables 2615 - 2622, XP002168152 Massetts Road • ADAMS J. ET AL.: ’J. Development of The Horley Proteasome Inhibitor PS- 341’ THE ONCOLOGIST Surrey RH6 7DQ (GB) vol. 7, February 2002, pages 9 - 16, XP003000262 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 1 581 629 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 581 629 B1 • LIGHTCAP E.S. ET AL.: ’Proteasome Inhibition • SUDIMACK J ET AL: "TARGETED DRUG Measurements’ CLINICAL APPLICATION. DELIVERY VIA THE FOLATE RECEPTOR", CLINICAL CHEMISTRY vol. 46, no. 5, 2000, pages ADVANCED DRUG DELIVERY REVIEWS, 673 - 683, XP003000263 ELSEVIER, AMSTERDAM, NL, vol. 41, no. 2, 1 • HOCHWALD ET AL: ’Antineoplastic Therapy in January 2000 (2000-01-01), pages 147-162, Colorectal Cancer Through Proteasome XP000990851, ISSN: 0169-409X, DOI: Inhibition’ THE AMERICAN SURGEON vol. 69, no. 10.1016/S0169-409X(99)00062-9 1, January 2003, pages 15 - 23, XP008068421 2 EP 1 581 629 B1 Description CROSS-REFERENCES TO RELATED APPLICATIONS 5 [0001] This application claims the benefit of U.S. Provisional Application Number 60/431,514, filed December 6, 2002. BACKGROUND OF THE INVENTION [0002] Proteasomeinhibition represents an importantrecently developed strategy incancer treatment. The proteasome 10 is a multi-enzyme complex present in all cells which plays a role in degradation of proteins involved in regulation of the cell cycle. For example, Kinget al., demonstrated that the ubiquitin-proteasome pathway plays an essential role in regulating cell cycle, neoplastic growth and metastasis. A number of key regulatory proteins, including p53, cyclins, and the cyclin-dependent kinases p21 and p27 KIP1, are temporally degraded during the cell cycle by the ubiquitin-proteasome pathway. The ordered degradation of these proteins is required for the cell to progress through the cell cycle and to 15 undergo mitosis. See, e.g., Science 274:1652-1659 (1996). Furthermore, the ubiquitin-proteasome pathway is required for transcriptional regulation. Palombella et al., teach that the activation of the transcription factor NF-kB is regulated by proteasome-mediated degradation of the inhibitor protein IkB. See International Patent Application Publication No. WO 95/25533. In turn, NF-kB plays a central role in the regulation of genes involved in the immune and inflammatory responses. For example, Read et al. demonstrated that the ubiquitin-proteasome pathway is required for expression of 20 cell adhesion molecules, such as E-selectin, ICAM-1, and VCAM-1. See Immunity 2:493-506 (1995). Additional findings further support the role for proteasome inhibition in cancer therapy, as Zetter found that cell adhesion molecules are involved in tumor metastasis and angiogenesis in vivo, by directing the adhesion and extravastation of tumor cells to and from the vasculature to distant tissue sites within the body. See, e.g., Seminars in Cancer Biology 4:219-229 (1993). Moreover, Beg and Baltimore, found that NF-kB is an anti-apoptotic factor, and inhibition of NF-kB activation makes 25 cells more sensitive to environmental stress and cytotoxic agents. See Science 274:782 (1996). [0003] Adams et al. have described peptide boronic ester and acid compounds useful as proteasome inhibitors. See, e.g., U.S. Patent No. 5,780,454 (1998), U.S. Patent No. 6,066,730 (2000), and U.S. Patent No. 6,083,903 (2000). They describe the use of the disclosed boronic ester and boronic acid compounds to reduce the rate of muscle protein degradation, to reduce the activity of NF-kB in a cell, to reduce the rate of degradation of p53 protein in a cell, to inhibit 30 cyclin degradation in a cell, to inhibit the growth of a cancer cell, and to inhibit NF-kB dependent cell adhesion. Adams et al. have described one of the compounds, N-pyrazinecarbonyl-L-phenylalanine-L-leucineboronic acid (PS-341, now know as bortezomib) as having demonstrated antitumor activity in human tumor xenograft models. This particular com- pound has recently received approval for treatment of patients having relapsed refractory multiple myeloma, and is presently undergoing clinical trials in additional indications, including additional hematological cancers as well as solid 35 tumors. [0004] Because the proteasome plays a pervasive role in normal physiology as well as pathology, it is important to optimize (e.g., avoid excessive) proteasome inhibition when using proteasome inhibitors as therapeutic agents. Moreover, one of the continued problems with therapy in cancer patients is individual differences in response to therapies. With the narrow therapeutic index and the toxic potential of many available cancer therapies, this potentially contributes to 40 many patients undergoing unnecessary ineffective and even harmful therapy regimens. If a designed therapy could be optimized to treat individual patients, such situations could be reduced or even eliminated. Accordingly, there is a need to identify particular cancer patients against which proteasome inhibitors are particularly effective, either alone or in combination with other chemotherapies. Also, there is a need to identify particular patients who respond well to treatment with a proteasome inhibitor (responders) versus those patient who do not respond to proteasome treatment (non- 45 responders). It would therefore be beneficial to provide for the diagnosis, staging, prognosis, and monitoring of cancer patients, including, e.g., hematological cancer patients (e.g., multiple myeloma, leukemias, lymphoma, etc) as well as solid tumor cancer patients, who would benefit from proteasome inhibition therapies; or to indicate a predisposition of such patients to such preventative measures. The present invention is directed towards these needs. 50 DESCRIPTION OF THE INVENTION [0005] The present invention is directed to the methods and kit defined in the appended claims. These methods typically include the determining the level of expression of two or more predictive markers in a patient’s tumor (e.g., a patient’s cancer cells), and identifying whether expression in the sample includes a pattern or profile of expression of a 55 selected predictive marker or marker set which correlates with response or non-response to proteasome inhibition therapy. [0006] The provided methods of the invention can eliminate ineffective or inappropriate use of proteasome inhibition therapy regimens. 3 EP 1 581 629 B1 [0007] The present methods and compositions are designed for use in diagnostics and therapeutics for a patient suffering from cancer. The cancer can be of the liquid or solid tumor type. Liquid tumors include tumors of hematological origin,including, e.g.,myelomas (e.g., multiple myeloma),leukemias (e.g.,Waldenstrom’s syndrome, chronic lymphocytic leukemia, other leukemias), and lymphomas (e.g., B-cell lymphomas, non-Hodgkins lymphoma). Solid tumors can orig- 5 inate in organs, and include cancers such as lung, breast, prostate, ovary, colon, kidney, and liver. [0008] Therapeutic agents for use in the methods of the invention include a new class of therapeutic agents known as proteosome inhibitors. One example of a proteosome inhibitor that was recently approved for treatment of relapsed refractory multiple myeloma patients and is presently being tested in clinical trials for additional indications is bortezomib.
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