US 2016.0002733A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0002733 A1 Chu (43) Pub. Date: Jan. 7, 2016 (54) ASSESSING RISK FORENCEPHALOPATHY Related U.S. Application Data INDUCED BYS-FLUOROURACL, OR (60) Provisional application No. 61/772,949, filed on Mar. CAPECTABINE 5, 2013. Publication Classification (71) Applicant: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNOR (51) Int. C. UNIVERSITY, Palo Alto, CA (US) CI2O I/68 (2006.01) (52) U.S. C. (72) Inventor: Gilbert Chu, Stanford, CA (US) CPC ........ CI2O I/6886 (2013.01); C12O 2600/156 (2013.01); C12O 2600/106 (2013.01); C12O (21) Appl. No.: 14/769,961 2600/142 (2013.01) (22) PCT Fled: Feb. 26, 2014 (57) ABSTRACT Methods and systems are provided for determining Suscepti (86) PCT NO.: PCT/US14/18739 bility to 5-fluorouracil (5-FU) or capecitabine toxicity. Meth ods are provided for treating a human Subject based on a S371 (c)(1), determined susceptibility to 5-fluorouracil (5-FU) or capecit (2) Date: Aug. 24, 2015 abine toxicity. Patent Application Publication Jan. 7, 2016 Sheet 1 of 17 US 2016/0002733 A1 Figure 1A urea cycle pyrimidine synthesis -- - - - - - - - - - - - Glin / WPA H al-NAGS NH 3. NH3CPSIDcarbamoyl-P Glu->NAG->|CPS Ca rbamyl-Asp: carbamoyl-P OHO : P. Orotate ornithine citruline s --AlORNT - Y - - - OMPwY Ornithine citruline UDP am UMP as UTP RR urea { UDP in OSuccinat A. 5-FUTP arginine 8 gypsuccina e CUMP i. cycleRECTS-5-FdUMP4-5-FU dTMP Figure IB /a-ketoglutarate pyruvate Asp PD PC 4-acetyl-CoA Glu oxaloacetate malate isocitrate Krebs cycle NH3 fumarate a-ketoglutarate Glu succinate succinyl-CoA methylmalonyl-CoA r a fatty acid proponyi-UOE. X--fattyfatty acid acyl-CoA oxidation ---fatty acyl-CoA4ACAS acetyl-CoAACAD caritine - - - - - - - - - - - - - - - - - - - - - - - - - - - - - site Patent Application Publication Jan. 7, 2016 Sheet 2 of 17 US 2016/0002733 A1 Figure 2A Seen at local ER with delirium Admitted with Confusion, ataxia Capecitabine lactulose - S 160 O E S. N 120 O E 80 E s normal level fl O Days Figure 2B 2 O 1 5 10 5 O O 6 12 18 24 Time (hrs) Patent Application Publication Jan. 7, 2016 Sheet 3 of 17 US 2016/0002733 A1 Figure2C 70 Baseline Midcycle O O O 1 2 3 4 5 -6 8 9 O 11 12 13 14 5 16 17 18 1920 2: 22 23 24 25 26 27 28 29 Patients Patent Application Publication Jan. 7, 2016 Sheet 4 of 17 US 2016/0002733 A1 FIGURE 3 &gge S 744 1083. 1245 500 1OOO 15OO 2000 SNP position Patent Application Publication Jan. 7, 2016 Sheet 5 of 17 US 2016/0002733 A1 FIGURE 4 y - 0.254.6x - 0.2526 R at O.3943 'O. O 2 3O 40 5 SO Mean baseline ammonia (mol/L) Patent Application Publication Jan. 7, 2016 Sheet 7 of 17 US 2016/0002733 A1 Figure 6 Plasma amino acids Plasma armonia was 81 pirging on day of test FaSia Jewef Ref. range Artific acid frong alarine 77-583 B-alanine 0-2 g-amingadipig acid O-S g-amingbutyric acid S-41 3-aringisobutyric acid arginine 15-128 asparagine 35-4 aspartic acid C-53 citruline 12-55 gyStathignine -3 Systine 5-82 ethalarie -153 glutamic acid 1-13 glutamine 25-5S glycine 151-49 giggySSS. hydroxyproline 1-25 isoleucine 30-18 leucine 72-21 lysine 11S-23S histidine F2-124 ethicine 1-42 Ornithine 48-195 phenylalanine 35-85 proline 97-32S Saggsins Serine 58-18 taurine 54-21 threnie S0-225 tryptophan 1-14 tyrosine 34-12 Waline 19-3S Patent Application Publication Jan. 7, 2016 Sheet 8 of 17 US 2016/0002733 A1 Figure 7 Plasma urine organic acids in Patient 1 Urine organic acids Plasma ammonia was 83 microngll on day of test Purine/pyrimidine rifle eye Ref. range creatinine) creatinine) hypoxanthine 5. Crotic acid thymine normal uracil 4 uric acid not measured Xanthine S Patent Application Publication Jan. 7, 2016 Sheet 9 of 17 US 2016/0002733 A1 {}}}| \ffff s ) to e a Patent Application Publication Jan. 7, 2016 Sheet 10 of 17 US 2016/0002733 A1 Figure 9A Lifar phosphodiestsease PDE4DIP p.R785* 4D interacting ap's cAMPPDE4D to protein CN2 p.Q5G9" 12 {6i E. peptidase N CartOxypeptidase Na-dependent eitfala.a. Ygg" solute carrier family transpaste, ..Y: 6 mites 8 fole is irrinoglycinuria & Yewcilitia -. zinc firger protein possible transcriptional FSCN3 R423 fascis-3 p.S474 lipoprotei Eipase triglyceridig hydrolysis LESSR Wact a sitein WSSB. sortifg-assoc vesicle-fi ediated trains. Of Toti i38 interfeof psilon NE CSS interie? of C-termina-binding crepresses taigeting CBP2 p.Q445 Grotis 2 t3nSctitional registOS R p R192" | 20 (145) to recept. ofactory receptor ROX 47 i8 story recept of ofactory receptor factory recept ORSO s i actory Receptor story recept of factory receptor a. OR.EXE p.Y273" | 108 (71) x aiiatory seceptor (C3 toyeep offactory receptor 45 ifactory recepto: ofactory feceptor 2. 5. factory recepto: ORECS CES actory seceptor olfactory recepto: REAR SR isitory Captor story receptor aifactory feceptor S C2AO 22solute gig carrier fi family organic aris transporter Patent Application Publication Jan. 7, 2016 Sheet 11 of 17 US 2016/0002733 A1 Figure 9B Sara if digits Frg FFFF NKG2-type 1 R p. W74 integral riter fare receptos on MK cells fotai hase-binding for S fre H pG 4.7" roteis }of Wiscers acyl-CoA synthetase ACSR2A p. Rii.5" redi Ein chain family medium chain fatty fiber 2A acid:OA ligase tra Smalbraie 4. tetrasparini protein, call TSFS i.S.S." 5 family embles Rosiferatio dual specificity MAP corponent of the MAP kinase kinase 3 kinase CaScade tuitingti-aSSOC proteis isoform 3 asSociates with untingtin cell division cycle anaphase profiloting protein 27 Oriolog Carex corporteri Serpin peptidase SERENE ifti, clade E is St. inhibits lysine-specific f teases organization of actii RN rhopiin-2 wioskeleto Equitin Gabxy de-biqirating CJB) JSP p.Ygi 3" | 129 terminal hydrolase Elzy Rig A fif-distridg FC8 p.R5" Gare it protein 8 protease inhibito: putative big-COrjug 9% identical to JB2M, UBENE p. 89." enzyrie E2 N-like role E. DNA repair and it lease Wii NE p.R325* like DNA glycosylass in BER 2-activaigdigail d gated on chaire Zn finger CCCH FC33 S di-Containing protein 3 fielaii Offia SAGEE2 . associated aftiger 2 fielano Ta MAGEB 6 p. R272 3.SSOciated artiger BE CStag p.R72" hypothetical protein 32 Patent Application Publication Jan. 7, 2016 Sheet 12 of 17 US 2016/0002733 A1 Figure 9C Gare ific. F. FFR as Fir Fif proteinhomolog EC-93 A isoform 2 protein CC2D2E isofori, 2 PRAME family RAE is jet 2 rips bindefki, (EKLC activat-e 2 is for Spetmatogethesis SAA8 p.R84." asSociated fiti 8 putatively-proteir Tp p. R21 phosphatase TPTE hypothetical protein C2F p.R37 Ca98.3 W. Wigan: NASB factor A dail containing serine hydroiase-Sike SERH prote 2 ferritin: heavy - Lif .E148 Oystid-like F Patent Application Publication Jan. 7, 2016 Sheet 13 of 17 US 2016/0002733 A1 Patent Application Publication Jan. 7, 2016 Sheet 14 of 17 US 2016/0002733 A1 N N Patent Application Publication Jan. 7, 2016 Sheet 15 of 17 US 2016/0002733 A1 Patent Application Publication Jan. 7, 2016 Sheet 16 of 17 US 2016/0002733 A1 Figure 13 Gere Cf. SNP Position aaf aa2 allele freg fax affeig fre ACAW SE3968 s G . OC55 A BA SW 80 5. NA A 8A: FS874,828 56 G NA ARG 6 SE 488 F9 NA CPS FS795,254 SS C S NA X CPS S525 6. N NA CPS S59398 8. G C NA C2 SEES 85 C O. O. CP2 S88 588 S. C 0.002 DEY i FSSF38F98 s O3 DPYD SSS) 733 W NA DPYD S3883 53. NA DPY) S858 53. S. N DRY SE9595 SS O. O.S EFA S S8 SS T O.O. 46 EPE 9 S35908 S. O.O3 EFE S3338. P , OF HA)-A S. C3 S W O O.O AA FSF58 5S C G NA HAHB 2 S35F3BS O N OO13 O.3 NCCC 3. FSF135OO 59 C NA CCC S35683 48 A. G O. 5 WLYC S fS35.955 43 C O. O).3 AA 4. Sail S7 i O.O.3 O)3 AAE FSSC i. S. A. M 8 S288 9 Y C O.O. OO CC X SS BOOBS 27. R OF O. PC S2229.745 873 N E NA, PC SW63.5 99 A. A. PC SFOA55 FS NP, .33 C FS355S-89 84 W .5 5 SLCA s FS 583 355 R C O.O25 O) SLCFA SR552, 38. t O.O2 SCA S5.583 SS R C CECS SLCAS 5. S388 35 R O.S O.O.5. SLC22A5 S5585. 49 Y D O.S S C22A5 fSSO3FS824 46 S. C O3 FM S8483,928 3 G S O.O.S O5 Patent Application Publication Jan. 7, 2016 Sheet 17 of 17 US 2016/0002733 A1 Figure 14 Frequency of Deleterious SNPs in the Population Max allele Sun of naX P(O) fred, X allele freq P(>1) P(>2) P(>3) O.O. O.39 O.726 0.273 O.O4 O.O4 O.005 0.344 0.79 0.29 0.047 0.05 O.CO O.369 O.69 O.309 O.O54. OOO6 O.O20 O.49 O.657 0.343 OO67 O.OO9 US 2016/0002733 A1 Jan. 7, 2016 ASSESSING RISK FORENCEPHALOPATHY provides methods for treating a human Subject based on a INDUCED BYS-FLUOROURACL, OR predicted susceptibility to 5-fluorouracil (5-FU) or capecit CAPECITABINE abine toxicity.