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WO 2018/234778 Al 27 December 2018 (27.12.2018) W !P O PCT

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WO 2018/234778 Al 27 December 2018 (27.12.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/234778 Al 27 December 2018 (27.12.2018) W !P O PCT (51) International Patent Classification: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, A61K 31/138 (2006.01) A61K 31/5025 (2006.01) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, A61K 31/437 (2006.01) 67 57/506 (2006.01) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, A61K 31/4375 (2006.01) 67 57/57 7 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 31/472 {2006.01) 67 57/579 (2006.01) A61K 31/4725 (2006.01) A61K 31/52 (2006.01) Declarations under Rule 4.17: A61K 31/496 {2006.01) A61K 31/565 (2006.01) — of inventorship (Rule 4.1 7(iv)) A61K 31/4985 (2006.01) A61P 35/00 (2006.01) Published: (21) International Application Number: — with international search report (Art. 21(3)) PCT/GB20 18/05 1694 — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (22) International Filing Date: amendments (Rule 48.2(h)) 19 June 2018 (19.06.2018) (25) Filing Language: English (26) Publication Langi English (30) Priority Data: 1709837.7 20 June 2017 (20.06.2017) GB 1806133.3 13 April 2018 (13.04.2018) GB (71) Applicants: THE INSTITUTE OF CANCER RESEARCH: ROYAL CANCER HOSPITAL [GB/GB]; 123 Old Brompton Road, London SW7 3RP (GB). BREAST CANCER NOW [GB/GB]; Ibex House, 42-47 Minories, London EC3N 1DY (GB). (72) Inventors: MARTIN, Lesley-Ann; The Institute of Can cer Research, 237 Fulham Road, London SW3 6JB (GB). NIKITOROWICZ-BUNIAK, Joanna; The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB (GB). (74) Agent: HGF LIMITED; 4th Floor, Merchant Exchange, 17-19 Whitworth Street West, Manchester M l 5WG (GB). (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, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 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, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 0 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, ∞ (54) Title: METHODS AND MEDICAL USES (57) Abstract: The invention described herein provides a method for the treatment of an oestrogen receptor positive breast cancer in a o subject in need thereof comprising administering to said subject a therapeutically effective amount of an MPS 1 inhibitor, wherein: (i) said subject has previously been treated with an endocrine therapy; and/or (ii) said breast cancer is resistant to endocrine therapy. o METHODS AND MEDICAL USES INTRODUCTION [001] The present invention provides new methods of treatment and medical uses relating to the treatment of endocrine resistant oestrogen receptor-positive breast cancer. Furthermore, the present invention provides combinations suitable for the treatment of oestrogen receptor-positive breast cancer. BACKGROUND OF THE INVENTION [002] It has long been recognised that many breast cancers are hormone dependent. Oestrogen (may be interchangeably referred to as estrogen), in particular, acts as an endocrine growth factor in a large proportion of breast cancers. Thus depriving these tumours of oestrogen is a major treatment modality in breast cancer. [003] The most commonly diagnosed breast cancer (BC) in the clinic is oestrogen receptor- (ER) positive and ER-positive BC accounts for over 80% of cases. [004] Oestrogen mediates its effects by binding to the ER. Oestrogen bound ER associates classically with oestrogen response elements (EREs) on target genes controlling proliferation and cell survival. ER has two distinct activation domains, AF-1 and AF-2. AF-2 is integral to the ligand-binding domain and is regulated by the binding of oestrogen. AF-1 activity is regulated by phosphorylation whilst AF-2 associates with coactivators of the p160 family, controlling the ER transcriptional complex. [005] Classically, patients with ER-positive BC are treated with endocrine agents such as tamoxifen or aromatase inhibitors (Al), which impede oestrogen signalling. [006] Although over 50% of patients show response to endocrine therapy, a large proportion relapse with de novo or acquired resistant disease, making it one of the greatest challenges for breast cancer research (reviewed by Ma et al. 2015). One striking feature of endocrine- resistant BC is the fact that the majority of patients continue to express ER. To date, multiple molecular mechanisms have been implicated in the resistant phenotype, all of which converge at the level of cyclin D, forcing cell cycle progression. This high degree of heterogeneity in adaptive mechanisms during the course of ER-positive BC progression highlights the importance of finding common nodes attributed to therapeutic failure. [007] As uncontrolled proliferation is a hallmark of cancer (reviewed by Hanahan & Weinberg 201 1) direct targeting of cell cycle with CDK inhibitors has provided an attractive proposition but until recently few have shown specificity and associated clinical toxicities have been unacceptable (Asghar et al. 2015). The CDK4/6-RB axis is critical for cell cycle entry and, not surprisingly, most cancers subvert this axis to promote proliferation, for instance 19% of breast cancers show amplification of CDK4 whilst, CCND1 amplification is associated with endocrine resistance (reviewed Musgrove et al. 201 1). [008] Recently, the combination of CDK4/6 inhibitors with endocrine therapy has been shown to improve clinical outcome in ER+ breast cancer patients. However, not all patients will benefit from such combination therapy and many will eventually relapse with acquired resistance. [009] There is a need in the art for new treatment options in respect of ER+ breast cancer. In particular, there is a need in the art for new, effective therapies for treating endocrine- resistant ER+ breast cancer. SUMMARY OF THE INVENTION [0010] Herein, it is shown for the first time that MPS1 is surprisingly associated with resistance to endocrine therapy, and furthermore that MPS1 provides a rational target for the treatment of breast cancers which are resistant to endocrine therapy. [0011] In one aspect, the present invention relates to a method for the treatment of an oestrogen receptor-positive breast cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of an MPS1 inhibitor, wherein: (i) said subject has previously been treated with an endocrine therapy; and/or (ii) said breast cancer is resistant to endocrine therapy. [0012] In one aspect, the present invention relates to an MPS1 inhibitor for use in the treatment of an oestrogen receptor-positive breast cancer in a subject in need thereof, wherein: (i) the subject has previously been treated with an endocrine therapy; and/or (ii) said breast cancer is resistant to endocrine therapy. [0013] In one aspect, the present invention relates to a use of an MPS1 inhibitor in the manufacture of a medicament for the treatment of an oestrogen receptor positive breast cancer in a subject in need thereof, wherein: (i) the subject has been previously treated with an endocrine therapy; and/or (ii) said breast cancer is resistant to endocrine therapy. [0014] In one aspect, the present invention relates to a combination comprising an MPS1 inhibitor and an endocrine agent. [0015] In one aspect, the present invention relates to a pharmaceutical product comprising an MPS1 inhibitor and an endocrine agent. [0016] In one aspect, the present invention relates to a method for the treatment of oestrogen receptor positive breast cancer in a subject in need thereof comprising administering to said subject, either separately, sequentially or in combination, a therapeutically effective amount of an MPS1 inhibitor and a therapeutically effective amount of an endocrine agent. [0017] In one aspect, the present invention relates to a pharmaceutical product comprising an MPS1 inhibitor and an endocrine agent for use in the treatment of an oestrogen receptor positive breast cancer, wherein the compound capable of inhibiting MPS1 and the endocrine agent are for separate, sequential or combined administration. [0018] In one aspect, the present invention relates to the use of a pharmaceutical product comprising an MPS1 inhibitor and an endocrine agent in the manufacture of a medicament for the treatment of oestrogen receptor positive breast cancer, wherein the compound capable of inhibiting MPS1 and the endocrine agent are for separate, sequential or combined administration. [0019] In one aspect, the present invention relates to an MPS1 inhibitor and an endocrine agent for use in the treatment of estrogen receptor-positive breast cancer. [0020] In one aspect, the present invention relates to an MPS1 inhibitor for use in the treatment of estrogen receptor-positive breast cancer, wherein said MPS1 inhibitor is for separate, sequential or combined administration with an endocrine agent. [0021] In one aspect, the present invention relates to an endocrine agent for use in the treatment of estrogen receptor-positive breast cancer, wherein said endocrine agent is for separate, sequential or combined administration with an MPS1 inhibitor.
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