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WO 2013/025936 Al 21 February 2013 (21.02.2013) P O P C T

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WO 2013/025936 Al 21 February 2013 (21.02.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/025936 Al 21 February 2013 (21.02.2013) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12N 15/113 (2010.01) A61K 38/17 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/58 (2006.01) A61K 39/395 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/7088 (2006.01) 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, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/US20 12/05 1207 NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 16 August 2012 (16.08.2012) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/525,007 18 August 201 1 (18.08.201 1) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant (for all designated States except US): COR¬ EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, NELL UNIVERSITY [US/US]; 395 Pine Tree Road, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Suite 310, Ithaca, New York 14850 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/ Applicants (for US only): MITTAL, Vivek Published: [IN/US]; 38 Clay Pitts Road, Greenlawn, New York 11740 — with international search report (Art. 21(3)) (US). GAO, Ding Cheng [CN/US]; 465 Main Street, Apt. 4F, New York, New York 10044 (US). — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (74) Agents: PERDOK SHONKA, Monique M. et al; amendments (Rule 48.2(h)) Schwegman, Lundberg & Woessner, P.A., P.O. Box 2938, Minneapolis, Minnesota 55402 (US). — with sequence listing part of description (Rule 5.2(a)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: DETECTION AND TREATMENT OF METASTATIC DISEASE s S-S V n- T - (57) Abstract: The establishment and growth of metastatic tumors can be detected and inhibited by the methods and compositions described herein. As illustrated herein, agents that inhibit the expression or activity of versican, for example, in bone marrow cells effectively halt the growth and establishment of metastatic tumors at distal sites from a primary tumor site. In general, the primary tu- mor is unaffected by versican inhibitors but metastasis is substantially eliminated. Detection a d Treatment of Metastatic Disease This application claims benefit of the filing date of U.S. Provisional Patent Application No. 61/525,007, filed August 18, 20 1, the contents of which is specifically incorporated herein in its entirety. Background Malignant primary tumor cells colonize distal target organs to form micrometastases and in some cases, the micrometastases progress to lethal macrometastases (Townson & Chambers, Cell Cycle 5 : 1744-1 750 (2006); Naumov et al., J Natl Cancer Inst 98: 316-325 (2006)). As a consequence, such metastasis results in more than 90% of human cancer-related deaths (Gupta & Massague, Cell 127: 679-695 (2006)). Rather than dying from problems relating to the primary tumor, most patients die from extensive metastatic tumor growth . Further information on the molecular mechanisms and the extrinsic micro environmental factors that enhance the metastatic potential of primary tumor cells, and of micrometastatic tumor cells at distal sites, would facilitate development of more effective cancer treatments. Summary of the Invention Methods and compositions are described herein for detecting and/or inhibiting the establishment and growth of metastatic tumors. Such methods and compositions can inhibit the expression or activity of versican in cells, and by doing so the inhibitors inhibit the metastasis promoting functions provided by myeloid progenitor cells and descendants of myeloid progenitor ceils. One aspect of the invention is a method of inhibiting establishment or growth of metastatic tumor cells at a site distal from a primary tumor in an animal comprising administering to the animal a composition comprising a versican inhibitor to thereby inhibit establishment or growth of metastati c tumor cells at a site distal from a primary tu r in the animal. In some embodiments, the versican inhibitor may not affect growth of the primary tumor or the animal has undergone surgery to remove the primary tumor. In some embodiments, the versican inhibitor is administered to bone marrow or to a site that can have metastatic tumor cells. The versican inhibitor can inhibit versican expression in bone marrow cells, bone marrow-derived cells or myeloid progenitor ce s of the animal. For example, the versican inhibitor is formulated to target bone marrow, bone marrow-derived cells or myeloid progenitor cells. Such methods can inhibit recruitment of myeloid progenitor cells to a premetastatic or metastatic site in the animal. Such methods can also inhibit TGF- p/Smad2/3 signaling in the animal. ersican inhibitors used in the methods and compositions described herein can include selected from the group consisting of budesonide, one or more hvaluronan oligomers, one or more anti-versiean antibodies, one or more non-functioning versican peptides, one or more versican inhibitory nucleic acids, and combinations thereof. Versican inhibitory nucleic acids used in the methods and compositions described herein can specifically bind to a versican mRNA under physiological conditions and can inhibit expression or translation of a versican mRNA. For example, versican inhibitory nucleic acids used in the methods and compositions described herein can include at least one versican inhibitory nucleic acid with: a sequence comprising 5'-ACACCAGAATTAG AAAGTTCAA-3 ' (shVcnl ; SEQ ID NO:43), or '-AGCACCTTGTCTG ATGGCCAAG-3' (shVcn2; SEQ ID NO:44); an A sequence corresponding to a DNA sequence comprising 5'- ACACCAGAATTAG AAAGTTCAA-3 ' (shVc SEQ ID NO:43), or 5'- AGCACCTTGTCTGATGGCCAAG-3' (shVcn2; SEQ ID NO:44); a DNA or RNA sequence comprising a sequence complementary to 5'- ACACCAGAATTAG AAAGTTCAA-3' (shVcnl; SEQ ID NO:43), or 5'- AGCACCTTGTCTGATGGCC AAG-3' (shVcn2; SEQ ID NO:44); or a combination thereof. Compositions and methods described herein can include at least one versiean inhibitor} peptide, for example, a peptide with a sequence that has at least 90% sequence identity to a sequence selected from the group consisting of SEQ ID NO:4-41 and 42. Compositions that include versiean inhibitors can also include an antibody that specifically binds to CDllb, CD33, VEGF receptor, AFP, CEA, CA-125, UC- , ETA, tyrosinase, ras, p53 MAGEl, or combinations of antibodies that specifically bind to any of CD1 lb, CD33, VEGF receptor, AFP, CEA, CA-125, MUC-1, ETA, tyrosinase, ras, p53, and MAGEl. Compositions and methods described herein can include an additional therapeutic agent or anti-cancer agent, for example, an agent selected from the group consisting of a radioactive drug, topoisomerase inhibitor, DNA binding agent, anti-metabolite, cytoskeletal-interacting d g, ionizing radiation, or a combination thereof. Compositions that include versiean inhibitors can also include cholesterol, phospholipids, mannose, retinal, a fat soluble vitamin, polyethylene glycol, technetium- 99m ( Tc), hemoglobin, or a combination thereof. Compositions that include versiean inhibitors can be formulated as a liposomal formulation. For example, compositions formulated as a liposomal formulation can have liposomes that comprise non-polymer molecules embedded within the liposomal exterior or bound to the exterior of the liposome, wherein the non-polymer molecules bind to a receptor or cell-membrane protein on the surface of a bone marrow cell, a bone marrow- derived cell, a myeloid progenitor cell, or a metastatic tumor cell. In some embodiments, compositions formulated as a liposomal formulation can have liposomes that include non- polymer molecules embedded within the liposomal exterior or bound to the exterior of the liposome, wherein the non-polymer molecules are selected from the group consisting of haptens, enzymes, antibodies, antibody fragments, cytokines, hormones, peptides, polypeptides, proteins or a combination thereof. The treatment methods described herein can also include detecting whether the animal has a metastatic tumor. For example, detection that the animal has a metastatic tumor can include testing whether a test sample from the animal expresses at least two- fold higher levels of versiean than a negative control sample. For example, the negative control sample can be a non-metastatic sample of the same tissue-type or fluid type as the test sample. The test sample can be a tissue sample or a bodily fluid. Another aspect of the invention is a method of detecting whether an animal has at least one metastatic tumor that includes: (a) measuring versican expression levels in a test sample from the animal; and (b) detecting that the animai has at least one metastatic tumor when at least two-fold higher levels of versican are expressed in the test sample than in a negative control sample. For example, the negative control sample can be a non-metastatic sample of the same tissue-type or fluid type as the test sample.
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