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The Two Tort Dit U Nonton Un Mountin THETWO TORT DIT USU 20180010132A1NONTONUN MOUNTIN ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 / 0010132 A1 MAVRAKIS et al. ( 43 ) Pub . Date : Jan . 11 , 2018 ( 54 ) INHIBITION OF PRMT5 TO TREAT Publication Classification MTAP - DEFICIENCY- RELATED DISEASES (51 ) Int . CI. C12N 15 / 113 ( 2010 .01 ) (71 ) Applicant : NOVARTIS AG , Basel (CH ) A61K 45 / 06 ( 2006 . 01) ( 72 ) Inventors : Konstantinos John MAVRAKIS , A61K 31 / 7088 (2006 . 01 ) Boston , MA (US ) ; Earl Robert COZK 16 / 40 ( 2006 .01 ) MCDONALD , III , Wayland , MA (US ) ; A61K 39 /395 ( 2006 . 01 ) Frank Peter STEGMEIER , Acton , GOIN 33 /574 (2006 . 01 ) A61K 39 / 00 ( 2006 .01 ) MA (US ) (52 ) U . S . CI. CPC . .. C12N 15 / 1137 ( 2013 .01 ) ; A61K 39 /3955 ( 73 ) Assignee : Novartis AG , Basel (CH ) ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; GOIN 33 /574 ( 2013. 01 ) ; C12Y 201/ 01 (2013 .01 ) ; ( 21 ) Appl. No. : 15 /510 , 542 A61K 31 /7088 (2013 .01 ) ; CO7K 16 / 40 ( 2013 .01 ) ; A61K 2039 /505 (2013 . 01 ) ; C12N ( 22 ) PCT Filed : Sep . 9 , 2015 2310 / 14 (2013 . 01 ) ; C12N 2320 / 31 ( 2013 .01 ) ; ( 86 ) PCT No .: PCT/ IB2015 /056902 CO7K 2317/ 76 ( 2013 .01 ) $ 371 (c ) ( 1 ) , (57 ) ABSTRACT ( 2 ) Date : Mar. 10 , 2017 The invention provides novel personalized therapies , kits , transmittable forms of information and methods for use in treating patients having cancer , wherein the cancer is Related U . S . Application Data MTAP - deficient and / or MTA -accumulating and thus ame (60 ) Provisional application No . 62/ 131 ,437 , filed on Mar . nable to therapeutic treatment with a PRMT5 inhibitor. Kits , 11 , 2015 , provisional application No . 62 /049 , 004 , methods of screening for candidate PRMT5 inhibitors, and filed on Sep . 11 , 2014 . associated methods of treatment are also provided . Patent Application Publication Jan . 11, 2018 Sheet 1 of 6 US 2018 / 0010132 A1 FIG . 1 . MTAPexpression . WWW . C . .. .. .. .. .. .. .. .. .. .. .. .. .. ... .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. '. .. .' . .. .. .. .. .. .. .. .. .. PRMT5 insensitive PRMT5 sensitive Patent Application Publication Jan 11 , 2018 Sheet 2 of 6 US 2018/ 0010132 A1 { {} ?.Y483 ?.33 ?? *.#H| ¥ÀAxxxxx?. * *{} XXX Y?ws { ??… " * * * * * ? * * “? * * -titstits , ???? tre * ????* * * ????? * ?? * ???? *#.* * ????? {} }} * - * * * # * * * * ; * * #Y * * * * w * * * {} { * ???????????????? * * * ? & * ## # ## * - FIG . 2 Patent Application Publication Jan . 11, 2018 Sheet 3 of 6 US 2018 / 0010132 A1 FIG . 3 OU 3902 dols-JoxeluUpsis Campoamud LOOK songsoon wwel ma MMMMMAMA ON tanpowoldfor 96LOH (+14AWW) me. OU Vzd-abu?qUessen SIWud WWW SCIO saga ???? OM wantino 4000ON BE fiffiffiffiffiffiffifin BOUQ10 ffffffffffffRRRRRRRRRRAAFFFFFFFFFFFF! Patent Application Publication Jan. 11, 2018 Sheet 4 of 6 US 2018 / 0010132 A1 FIG. 3 ? song a man ? ?? “ ?? ?,????????? ? ? ??“?????2013?????20% ???????????? AAAAAAAAAAAAAAyj- pMyAirity + Malving - MixRe : ????? * * ? ? ? ?«< ????????100% ????????2014 ???? ????????? ?????????? ????? ?????????? ????????? ????????????????????? «??&? ??? ? ??????? M ??4 ?? ??? 1988 ??? ?? ?? ???? ??“ ? ?? ???? ????????????????????????????????????????????????? ? Patent Application Publication Jan. 11, 2018 Sheet 5 of 6 US 2018 / 0010132 A1 FIG . 3 "-* .HI,"*| ? */ ": “ ? '" relliu *-;'/ … L | . 2012?0606010 yual. : *Wi' EFT":,tit ???? 2015 ; ,? 04/14 · |???-236 *" ? ?122018icial2012 "/ */ */ ; , ???????? ?? : finiiVillipFidtiidallilibi?? “” : " I " : w,, |??? " Irribe. 'le" ? : ??: i/ti ? " : : … … " “… ti/??i ????????? ??????????????? |?? : : * 2)-: ”? * /ite201227 / 2014-105/24·?, ?? ???????????????????????????????? ?????????? ?????????????? " ?? ??/filipid?????????ili“ ?“???13952? 2-212012 1993 Airiti/?? */ , ?2012 ???: ?????? /* SHI ? ? ??? ? ???????? ?? - - - tiriti |2012 ? 1"11. /di4f4iFi?? Lit: : ??,: ??, '* 2017 20 HET:wil“V" ::: 2011 )2 *: lulululiulinipinimultipliaWii :Stelease, "h ": : 017-12 , : : 365 i ?,2014? ? ?? : ? “??? 23:26)·???2012 iiiilibilibiliti , ??, "jiji/??????????????i????Lili??litidaltilitaid 2014?,“?”1989)2014 ? 9492016? ?: (2015-1226 #?, |???? “1996Livilibilibilituijill ????, ? ??????? ? : ; = = ? Patent Application Publication Jan . 11, 2018 Sheet 6 of 6 US 2018 / 0010132 A1 FIG . 3 PK1WT (MTAP + /* ") OMSO MTA 12 . 5 UM Hitttttt 50 PM PK1 (MTAP KO ) DMSO MTA 12 .5 PM9900 50 UM US 2018 / 0010132 A1 Jan . 11, 2018 INHIBITION OF PRMT5 TO TREAT 12 contiguous nucleotides (nt ) of the sequence of MTAP MTAP - DEFICIENCY - RELATED DISEASES provided in SEQ ID NO : 98 , wherein the primer is no longer than about 30 nt, about 50 nt, or about 100 nt in length . Cells TECHNICAL FIELD are determined to be MTA overproducing or MTA accumu [ 0001] The present invention provides novel composi lating by techniques known in the art; methods for detecting tions , as well as diagnostic and treatment methods for MTA include , as a non - limiting example , liquid chromatog diseases related to MTAP deficiency and / or MTA accumu raphy - electrospray ionization - tandem mass spectrometry ( LC - ESI -MS / MS ) . lation , including , but not limited to , types of cancer . [0009 ] In one embodiment, the invention provides use of a molecule that inhibits the cellular function of the PRMT5 BACKGROUND protein for the treatment of a disease associated with MTAP [ 0002 ] Many types of cancer are associated with a poor deficiency and /or MTA accumulation , including , but not prognosis . limited to , a cancer , including , for example , but not limited [ 0003 ] Pancreatic cancer is associated with a poor long to : glioblastoma , bladder cancer, pancreatic cancer , meso term survival rate of only 10 % to 15 % after resection . thelioma, melanoma, lung squamous, lung adenocarcinoma, Patients with positive microscopic resection margins have a diffuse large B -cell lymphoma, leukemia , head and neck worse survival. The median survival was 19 . 7 months with cancer, and cancers of the kidney, breast , endometrium , chemotherapy versus 14 . 0 months without. See , e . g ., Neop urinary tract, liver, soft tissue , pleura and large intestine . tolemos et al . 2001 Ann . Surg . 234 : 758 - 768 . [0010 ) Also provided is a use of a molecule that inhibits [0004 ] Mesothelioma is a rare form of cancer that devel the cellular function of the PRMT5 protein for the manu ops from cells of the mesothelium , the protective lining that facture of a medicament for treating a disease associated covers many of the internal organs of the body. Mesothe with MTAP deficiency and / or MTA accumulation , includ lioma is most commonly caused by exposure to asbestos . ing , but not limited to , a cancer, including , for example , but While mesothelioma is still relatively rare , rates have not limited to : glioblastoma , bladder cancer, pancreatic increased in the last twenty years . One study showed a cancer , mesothelioma , melanoma, lung squamous, lung survival rate of only 38 % at 2 years and 15 % at 5 years adenocarcinoma, diffuse large B - cell lymphoma , leukemia , (median 19 months ) . See , e . g ., Sugarbaker et al . 1999 J . head and neck cancer , and cancers of the kidney , breast , Thorac . Card . Surg. 117 : 54 -65 . endometrium , urinary tract, liver, soft tissue , pleura and [0005 ] Glioblastoma is the most common and most large intestine . aggressive malignant primary brain tumor in humans. It [ 0011 ] The PRMT5 inhibitor may be selected from the involves glial cells and accounts for half of all brain tumor group consisting of: a RNA inhibitor ( e . g ., a RNAi agent) , cases and a fifth of all intracranial tumors. Treatment can a CRISPR , a TALEN , a zinc finger nuclease , an mRNA , an involve surgery , radiation and chemotherapy . However , antibody or derivative thereof, a chimeric antigen receptor T median survival with treatment is only 15 months. cell (CART ) or a low molecular weight ( LMW ) compound . [0006 ] An unmet medical need exists for new treatments [0012 ] The PRMT5 inhibitor may be selected from the for these and other types of cancer . group consisting of: an antibody or derivative thereof, or a [0007 ] There is an increasing body of evidence that sug low molecular weight compound . In some embodiments , the gests a patient' s genetic profile can be determinative to a antibody or a derivative thereof binds to a HLA -peptide patient' s responsiveness to a therapeutic treatment. Given complex comprising a peptide having the sequence of any of the numerous therapies available to an individual having SEQ ID NOs : 101- 158 . cancer , a determination of the genetic factors that influence , [0013 ] According to an embodiment, the method accord for example , response to a particular drug , could be used to ing to the first aspect comprises administering to a subject in provide a patient with a personalized treatment regime. Such need thereof, a PRMT5 inhibitor in combination with a personalized treatment regimens offer the potential to maxi second therapeutic agent. mize therapeutic benefit to the patient while minimizing [ 0014 ] In an embodiment, the second therapeutic agent is related side effects that can be associated with alternative an anti - cancer agent, anti -allergic agent, anti - nausea agent and less effective treatment regimens . ( or anti - emetic ) , pain reliever , or cytoprotective agent. [00151 According to one embodiment, the second thera SUMMARY OF THE INVENTION peutic agent is an anti - cancer agent selected from the list [ 0008 ] According to a first aspect of the invention , meth consisting of: an HDAC
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