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WO 2014/153118 Al 25 September 2014 (25.09.2014) P O P C T

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WO 2014/153118 Al 25 September 2014 (25.09.2014) 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 2014/153118 Al 25 September 2014 (25.09.2014) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/7088 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, PCT/US20 14/029 164 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 14 March 2014 (14.03.2014) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/785,747 14 March 2013 (14.03.2013) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (71) Applicant: THE BOARD OF TRUSTEES OF THE LE- TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, LAND STANFORD JUNIOR UNIVERSITY [US/US]; EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, Office of Technology Licensing, 1705 El Camino Real, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Palo Alto, CA 94306 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: GAN, Lin; 2177 Williams Street, Palo Alto, CA 94306 (US). MEYER, Tobias; 570 Laurel Street, Published: Menlo Park, CA 94025 (US). — with international search report (Art. 21(3)) (74) Agent: BUCHBINDER, Jenny; 29 Clinton Street #201, — before the expiration of the time limit for amending the Redwood City, CA 94062 (US). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, — with sequence listing part of description (Rule 5.2(a)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: TREATMENT OF DISEASES AND CONDITIONS ASSOCIATED WITH DYSREGULATION OF MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1 (MTORC1) Figure 7 F (57) Abstract: Compositions and methods for treating diseases and conditions associated with dysregulation of mammalian target of rapamycin complex 1 (mTORCl) are disclosed. The invention is based in part on the discovery that protein mediator of amino acid signaling to mTOR (MORTOR) is involved in amino acid- induced translocation of mTORCl to lysosomes where MORTOR forms a signaling complex with mTORCl, Ragulator, and Rag GTPases, which controls protein synthesis. In particular, the invention relates to the use of antagonists of MORTOR for treating diseases and conditions associated with dysregulation of mTORC 1. Down - regulation of expression of MORTOR by RNA interference has been shown to reduce cell proliferation of cancerous cells and may be useful for treating cancer. TREATMENT OF DISEASES AND CONDITIONS ASSOCIATED WITH DYSREGULATION OF MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1 (MTORC1) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under contract CA1 20732 awarded by the National Institutes of Health. The Government has certain rights in this invention. TECHNICAL FIELD The present invention pertains generally to compositions and methods for treating diseases and conditions associated with dysregulation of mammalian target of rapamycin complex 1 (mTORCl). In particular, the invention relates to the use of antagonists of the protein mediator of amino acid signaling to mTOR (MORTOR) for treating diseases and conditions associated with dysregulation of mTORCl. BACKGROUND Mammalian cells control their size, proliferation activity, and autophagy rates by monitoring the concentration of amino acids. Amino acids can be sensed in lysosomes by a poorly understood signaling pathway involving mTORCl, an evolutionarily conserved signaling complex that includes the protein kinase mTOR and an adaptor protein raptor. Mammalian TORC1 controls cell growth by integrating multiple upstream signals including nutrients, growth factors, oxygen, and stress (Inoki et al. (2002) Nat. Cell Biol. 4:648-657; Ma et al. (2005) Cell 121:179- 193; Roux et al. (2004) Proc. Natl. Acad. Sci. USA 101:13489-13494; Inoki et al. (2003) Cell 115:577-590; Gwinn et al. (2008) Mol. Cell 30:214-226; Liu et al. (2006) Mol. Cell 21:521-531; Brugarolas et al. (2004) Genes Dev. 18:2893-2904; Feng et al. (2005) Proc. Natl. Acad. Sci. USA 102:8204-8209; and Lee et al. (2007) Cell 130:440-455). The complex is often described as a master regulator of cell growth because it induces important anabolic processes such as ribosome biogenesis, translation, lipid biosynthesis and transcription (Ma et al. (2009) Nat. Rev. Mol. Cell Biol. 10:307-318; Porstmann et al. (2008) Cell Metab. 8:224-236; Huffman et al. (2002) Proc. Natl. Acad. Sci. USA 99:1047-1052; Chen et al. (2008) J. Exp. Med. 205:2397-2408; and Cunningham et al. (2007) Nature 450:736-740). Mammalian TORC1 also suppresses autophagy, a process that breaks down and recycles cell mass when nutrients become limited (Chan (2009) Science Signaling, 2(84):pe51). A diverse number of proteins that control mTORCl are potential drug targets due to the central role mTOR plays not only in metabolic dysfunction but also in cancer, diabetes, aging, and neurodegenerative diseases (Zoncu et al. (201 1) Nat. Rev. Mol. Cell Biol. 12:21-35). SUMMARY The present invention is based, in part, on the discovery that MORTOR is involved in amino acid-induced translocation of mTORCl to lysosomes where MORTOR forms a signaling complex with mTORCl, Ragulator, and Rag GTPases, which controls protein synthesis. Antagonists of MORTOR can be used for treatment of diseases and conditions associated with dysregulation of mTORCl. In one aspect, the invention includes a method for treating a subject having a disease or condition associated with dysregulation of mammalian target of mTORCl, the method comprising administering a therapeutically effective amount of an antagonist of MORTOR to the subject. Diseases and conditions associated with dysregulation of mTORClthat can be treated by methods of the invention include, but are not limited to cancer, obesity, a metabolic disease or condition, a neurodegenerative disease or condition, or aging. Exemplary antagonists of MORTOR include antisense oligonucleotides or inhibitory RNA molecules, such as small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), and small nuclear RNAs (snRNAs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) interference (CRISPRi) systems comprising guide crRNAs and nuclease-deficient Cas (e.g., dCas9) protein that downregulate expression of MORTOR, antibodies that specifically bind to MORTOR that interfere with its interactions with other proteins (e.g., Raptor, mTOR, or Rag GTPases), and amino acid synthesis inhibitors. In one embodiment, the antagonist is an antibody that specifically binds to a MORTOR protein comprising a sequence selected from the group consisting of SEQ ID NOS:5-7 or a variant thereof displaying at least about 50- 99% sequence identity thereto, including any percent identity within this range, such as 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity thereto. In certain embodiments, the antagonist is an antagonist of GPR137A, GPR137B, or GPR137C, or any combination thereof. By "therapeutically effective dose or amount" of an antagonist of MORTOR is intended an amount that, when administered, as described herein, brings about a positive therapeutic response, such as improved recovery from a disease or condition associated with dysregulation of mTORCl . In one embodiment, the disease or condition associated with dysregulation of mTORCl is cancer and a "therapeutically effective dose or amount" of an antagonist of MORTOR is an amount that has anti tumor activity. In another aspect, the invention includes a method of inhibiting MORTOR in a subject, the method comprising administering an effective amount of an antagonist of MORTOR to the subject. In another aspect, the invention includes a method for inhibiting MORTOR in a cell by introducing an effective amount of an antagonist of MORTOR into the cell. In one embodiment, the cell is a cancerous cell, wherein inhibiting MORTOR decreases cell proliferation. In another aspect, the invention includes a method of decreasing translocation of mTORCl to lysosomes in a cell, the method comprising introducing an effective amount of an antagonist of MORTOR into the cell. In another aspect, the invention includes a method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising at least one antagonist of MORTOR. In certain embodiments, the antagonist downregulates expression of MORTOR through RNA interference (RNAi). In one embodiment, the antagonist is an antisense oligonucleotide or an inhibitory RNA molecule, such as a miRNA, siRNA, shRNA, piRNA, or snRNA comprising a nucleotide sequence sufficiently complementary to a MORTOR target mRNA sequence to bind to and downregulate expression of the MORTOR mRNA. In one embodiment, the antagonist is an antisense oligonucleotide or an inhibitory RNA molecule that binds to a target MORTOR mRNA comprising a sequence selected from the group consisting of SEQ ID NO:l and SEQ ID NO:2.
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