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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 3 September 2009 (03.09.2009) (51) International Patent Classification: A61K 48/00 (2006.01) A61K 33/24 (2006.01) A61P 35/00 (2006.01) (21) International Application Number: PCT/US2009/035 150 (22) International Filing Date: 2 5 February 2009 (25.02.2009) WO 2009/108706 A 3 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (25) Filing Language: (26) Publication Language: (30) Priority Data: 61/03 1,297 2 5 February 2008 (25.02.2008) English English US (71) Applicant (for all designated States except US): THE REGENTS O F THE UNIVERSITY OF COLORADO, A BODY CORPORATE [US/US]; 201 Regents A dmin istrative Center, 3 Sys, Boulder, CO 80309 (US). (72) Inventors; and (75) Inventors/ Applicants (for US only): FORD, Heide, L . [US/US]; 201 Regents Administrative Center, 3 Sys, Published: Boulder, CO 80309 (US). ZHAO, Rui [US/US]; 201 R e — with international search report (Art. 21(3)) gents Administrative Center, 3 Sys, Boulder, CO 80309 f (US). PATRICK, Aaron [US/US]; 201 Regents A dmin — before the expiration o the time limit for amending the claims and to be republished in the event of receipt of istrative Center, 3 Sys, Boulder, CO 80309 (US). amendments (Rule 48.2(h)) (74) Agent: BARRETT, Tamsen; Fulbright & Jaworski LIp., 600 Congress Avenue, Suite 2400, Austin, TX (88) Date of publication of the international search report: 10 December 2009 78701 (US). (54) Title: METHODS FOR INHIBITING SIX 1 AND EYA PROTEINS FIG. 2 (57) Abstract: In some aspects, the invention provides a method of inhibiting interaction of Sixl with Eya2 comprising contacting a cell expressing Sixl and Eya2 with an agent that inhibits binding of Sixl to Eya2 or an agent that inhibits the phostphatase ac t iv i ty of Eya2 on Sixl. In other apsects, the invention provides a method of treating cancer in a subject comprising administering to said subject an effective amount of an agent that inhibits Sixl interaction with Eya2 or an agent that inhibits the phostphatase a c tivity of Eya2 on Sixl. In some embodiments, the invention further provides for the administration of a second cancer therapy t o the patient. In still further aspects, the invention provides a method of identifying a candidate anti-cancer agent. The candidate in hibitor may b e a nucleic acid, a protein, a peptide or a small molecule. INTERNATIONAL SEARCH REPORT PCT7US2009/035150 A. CLASSIFICATION O F SUBJECT MATTER A61K 48/00(2006.01)i, A61P 35/00(2006.01)i, A61K 33/24(2006.01)i According to International Patent Classification (IPC) or t o both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC A61K 48/00, A61P 35/00, A61K 32/24 Documentation searched other than minimum documentation t o the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CA, PubMed, Delphi on "(eya* OR eyes absent homologue) AND (six*)" C. DOCUMENTS CONSIDERED T O B E RELEVANT Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim N o Category* ZHANG, L et a l "Transcriptional Coactivator Drosophila Eyes Absent Homologue 2 I s Upregulated in Epithelial Ovarian Cancer and Promotes Tumor Growth " Cancer Res , Feb 2005, VoI 65, N o 3 Pages 925-931 See the whole document BEHBAKHT, K et a l "Sixl Overexpression i n Ovarian Carcinoma Causes Resistance t o TRAILMediated Apoptosis and I s Associated with Poor Survival" Cancer Res , Apr 2007, VoI 67, N o 7 , Pages 3036-3042 See the whole document A 14, 15, 32-35 14, 15, 32-35 HEANUE, T A et al "Synergistic Regulation of Vertebrate Muscle Development by Dach2, Eya2, and Sixl, Homologs of Genes Required for Drosophila Eye Formation" Genes Dev , Dec 1999, VoI 13, N o 24, Pages 3231-3243 See the whole document OHTO, H et a l "Cooperation of Six and Eya in Activation of Their Target Genes through Nuclear Translocation of Eya" MoI Cell Biol , Oct 1999, VoI 19, N o 10, Pages 6815-6824 See the whole document 14, 15, 32-35 14, 15, 32-35 Further documents are listed in the continuation of Box C * "A" Special categories of cited documents document defining the general state of the art which is not considered t o b e of particular relevance "E" earlier application or patent but published on or after the international filing date "L" document which may throw doubts on priority claim(s) or which i s cited t o establish the publication date of citation or other special reason (as specified) "O" document referring t o an oral disclosure use, exhibition or other means "P" document published prior t o the international filing date but later than the priority date claimed See patent family annex "T" later document published after the international filing date or priority date and not in conflict with the application but cited t o understand the principle or theory underlying the invention "X" document of particular relevance, the claimed invention cannot he considered novel or cannot b e considered t o involve an inventive step when the document i s taken alone "Y" document of particular relevance, the claimed invention cannot be considered t o involve an inventive step when the document i s combined with one or more other such documents, such combination being obvious t o a person skilled in the art "&" document member of the same patent family Date of the actual completion of the international search 15 OCTOBER 2009 (15 10 2009) Date of mailing of the international search report 15 OCTOBER 2009 (15.10.2009) Authorized officer CHANG, Je Hwan Telephone N o 82-42-481-5634 Name and mailing address of the ISA/KR Korean Intellectual Property Office Government Complex-Daejeon, 139 Seonsa-ro, Seogu Daejeon 302-701, Republic of Korea Facsimile N o 82-42-472-7140 Form PCT/ISA/210 (second sheet) (My 2008) INTERNATIONAL SEARCH REPORT Box No. II International application N o PCT/US2009/035150 Observations where certain claims were found unsearchable (Continuation o f item 2 o f first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons 1 l Claims Nos 1-13, 16-3 1 because they relate to subject matter not required t o be searched by this Authority, namely The subject matter of claims 1-13 and 16-31 pertains t o methods for treatment of the human body by therapy, thus relates to a subject matter which this International Searching Authority i s not required, under Article 17(2)(a)(i) of the PCT and Rule 39 l(iv) of the Regulations under the PCT t o search 2 I I Claims Nos because they relate to parts of the international application that do not comply with the prescribed requirements t o such a n extent that no meaningful international search can b e carried out, specifically Claims Nos because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6 4(a) Box No. Ill Observations where unity of invention is lacking (Continuation o f item 3 o f first sheet) This International Searching Authority found multiple inventions in this international application, a s follows 1 A s all required addtional search fees were timely paid by the applicant, this international search report covers all searchable claims A s all searchable claims could b e searched without effort justifying an additional fee, this Authority did not invite payment of any additional fee A s only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos 2 3 N o required additional search fees were timely paid by the applicant Consequently, this international search report is rest π cted t o the invention first mentioned in the claims, it is covered by claims Nos Remark on Protest | I I | The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee I The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation I N o protest accompanied the payment of additional search fees Form PCT/ISA/210 (continuation of first sheet (2)) (July 2008)