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(12) Patent Application Publication (10) Pub. No.: US 2016/0146783 A1 CHERESH Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0146783 A1 CHERESH Et Al US 2016O146783A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0146783 A1 CHERESH et al. (43) Pub. Date: May 26, 2016 (54) COMPOSITIONS AND METHODS FOR Publication Classification TREATING CANCER AND DISEASES AND CONDITIONS RESPONSIVE TO CELL (51) Int. C. GROWTH INHIBITION GOIN33/50 (2006.01) (52) U.S. C. (71) Applicant: THE REGENTS OF THE CPC. G0IN33/5011 (2013.01); G0IN 2333/4724 UNIVERSITY OF CALIFORNLA, (2013.01); G0IN 2333/70557 (2013.01) Oakland, CA (US) (57) ABSTRACT (72) Inventors: David CHERESH, Encinitas, CA (US); In alternative embodiments, the invention provides composi Laetitia SEGUIN, San Diego, CA (US); tions and methods for overcoming or diminishing or prevent Sudarshan ANAND, San Diego, CA ing Growth Factor Inhibitor resistance in a cell, or, a method (US) for increasing the growth-inhibiting effectiveness of a Growth Factor inhibitor on a cell, or, a method for re-sensi (21) Appl. No.: 14/883,398 tizing a cell to a Growth Factor Inhibitor, comprising for example, administration of a combination of a TBK1 inhibi tor and an RTK inhibitor. In alternative embodiments, the cell (22) Filed: Oct. 14, 2015 is a tumor cell, a cancer cell or a dysfunctional cell. In alter native embodiments, the invention provides compositions Related U.S. Application Data and methods for determining: whether an individual or a patient would benefit from or respond to administration of a (63) Continuation of application No. 14/325,288, filed on Growth Factor Inhibitor, or, which individuals or patients Jul. 7, 2014, which is a continuation-in-part of appli would benefit from a combinatorial approach comprising cation No. PCT/US2013/035492, filed on Apr. 5, administration of a combination of at least one growth factor 2013. and at least one compound, composition or formulation used (60) Provisional application No. 61/672.236, filed on Jul. to practice a method of the invention, such as an NFKB 16, 2012, provisional application No. 61/620,725, inhibitor, such as a lenalidomide or a REVLIMIDTM, or IKK filed on Apr. 5, 2012. inhibitor; or an inhibitor of Galectin-3. Patent Application Publication May 26, 2016 Sheet 2 of 41 US 2016/O146783 A1 FIG. 1D FIG. 1 E FIG. 1 F FIG. 1 G ************************************* Patent Application Publication May 26, 2016 Sheet 4 of 41 US 2016/O146783 A1 X883 s 8tegrin 3 : integrin 3 NR&S -83.3 88As. FIG. 2E 883 :-838 8K8: w i:egis; 3 KRAS Patent Application Publication May 26, 2016 Sheet 5 of 41 US 2016/O146783 A1 FIG. 3A FIG. 3B 33 gigs:ye ce: 83-33 & 883. : 2. 38.88:23:8 88:8 ; :::::::::::: s a. t : x &: 888 Y a 88: 83.842 8: N FIG. 3C 33.88:38x8 ce:s vehicie &:38 : 3: 3. : 8:38-3: 8: 838 888 &:::::::::: 8888. s s: ::::: Ys . Patent Application Publication May 26, 2016 Sheet 6 of 41 US 2016/O146783 A1 FIG. 4B 33 egative cesis {3} w: w88:8 Eric:8 8:3 8:3 8-33K: 18:k: 8 3 : -88.88-x8 38888.x8 8-8-88 a: cassifies FIG. 4C 33 x3six8 x:is 83-33 3i:38: 323. : 3. ::::::::::8 88: 3.s 83. s : : s 8. : .8 : 388xitx38 kg is: FIG. 4E :::::::::: :::::: x: ::::::::: :::::::::: x:::::::: &:::::::::: Patent Application Publication May 26, 2016 Sheet 7 of 41 US 2016/O146783 A1 FIG. 5 (xxiopic ig carice: xerogats liki Patent Application Publication May 26, 2016 Sheet 8 of 41 US 2016/O146783 A1 FIG. 6A s FIG. 8 3.& 8 s & 3 |- s Patent Application Publication May 26, 2016 Sheet 9 of 41 US 2016/O146783 A1 Patent Application Publication May 26, 2016 Sheet 10 of 41 US 2016/O146783 A1 FIG. 9A 33 negative ceilis FG) 'fessie: Eriotii 33 positive ceis (-3-33 o W w 8xxix. 8 xxx xxx x33. FIG. 10A FIG. 1 OB :33:38:32:38:883: 3:33 a&s. $333s. 33.338g: x- &Y&::::::3& x-six 8: 838. :::::::::::::::: YX-. 8. sis:::::::3: *1--aww.s.l. & &ra 33S --. \s s $-Ss. ---------------------------------...-, -2. 8. Patent Application Publication May 26, 2016 Sheet 11 of 41 US 2016/O146783 A1 FIG 10C FIG. 1 1A 38: {:33:8:8 88: 8::::::::::::: 388 FIG. 11B Patent Application Publication May 26, 2016 Sheet 12 of 41 US 2016/O146783 A1 FIG. 12A FIG. 12B FIG. 12C 3 3.3383 88.S38 - 3. 88883 s 3. 8:3: : :38:3: 2. FIG. 12D i- : FIG. 12F FIG. 12G i::::::::::::::::::::::: witic: ::::::::::::::::::::::::::::::::: &: ::::::: . 3 3. : &------. s : 38 3888:::::::::::8: Patent Application Publication May 26, 2016 Sheet 13 of 41 US 2016/O146783 A1 FIG. 13A FIG. 13B FIG. 13C FIG. 13 FIG. 13F XXY $883 3:3 : 3. 39. s FIG. 13H 3. :w x.s 8: Patent Application Publication May 26, 2016 Sheet 14 of 41 US 2016/O146783 A1 FIG. 14A FIG. 14B FIG. 14C 8 y: is: 8. y:icie :::::::: s: 8:38 Sixx::::::s -- : s £3. 3 3$8 3: & FIG. 14) :: FIG. 14F Patent Application Publication May 26, 2016 Sheet 15 of 41 US 2016/O146783 A1 FIG. 14G FIG. 14H FIG. 14 8::::::38. Patent Application Publication May 26, 2016 Sheet 16 of 41 US 2016/O146783 A1 FIG. 15C FIG. 16A FIG. 16B FIG. 16C & : Patent Application Publication May 26, 2016 Sheet 17 of 41 US 2016/O146783 A1 FIG. 17A 83 FIG. 17B 8 : FIG. 18A FIG. 18B FIG. 18C ... -----------------------------------------, FIG. 18) aS Patent Application Publication May 26, 2016 Sheet 18 of 41 US 2016/O146783 A1 FIG. 18E FIG. 18F FIG. 19B Patent Application Publication May 26, 2016 Sheet 19 of 41 US 2016/O146783 A1 FIG. 20A FIG. 20B FIG.20C Patent Application Publication May 26, 2016 Sheet 20 of 41 US 2016/0146783 A1 FIG. 21A FIG 21B FIG. 21C Patent Application Publication May 26, 2016 Sheet 21 of 41 US 2016/O146783 A1 Patent Application Publication May 26, 2016 Sheet 22 of 41 US 2016/O146783 A1 FIG. 23A FIG. 23C Patent Application Publication May 26, 2016 Sheet 23 of 41 US 2016/O146783 A1 FG 24B FIG . 24A *****************************************************...; Patent Application Publication May 26, 2016 Sheet 24 of 41 US 2016/O146783 A1 FIG. 25A FIG. 25B FIG. 25C FIG.25D .. Ex Patent Application Publication May 26, 2016 Sheet 25 of 41 US 2016/O146783 A1 Patent Application Publication May 26, 2016 Sheet 26 of 41 US 2016/O146783 A1 Patent Application Publication May 26, 2016 Sheet 27 of 41 US 2016/O146783 A1 FIG. 28 Patent Application Publication May 26, 2016 Sheet 28 of 41 US 2016/O146783 A1 *::... 388 :::::::::::::::: 888 xx Patent Application Publication May 26, 2016 Sheet 29 of 41 US 2016/O146783 A1 Patent Application Publication May 26, 2016 Sheet 30 of 41 US 2016/0146783 A1 FG 32A FIG. 32B FIG. 32C FIG. 32D Patent Application Publication May 26, 2016 Sheet 31 of 41 US 2016/O146783 A1 FIG. 33A FIG. 33B FIG. 33D -------------------------------- Patent Application Publication May 26, 2016 Sheet 32 of 41 US 2016/O146783 A1 FIG. 33H FIG. 33 FIG. 33J X FIG. 34A FIG. 34B Patent Application Publication May 26, 2016 Sheet 33 of 41 US 2016/O146783 A1 FIG. 34C FIG. 34D 8 FIG. 34E FIG. 34F FIG. 34G FIG. 34H FIG. 34 8: Patent Application Publication May 26, 2016 Sheet 34 of 41 US 2016/O146783 A1 FIG. 35F 8 s X-----, --'-' -----' ----'s www.www.www. FIG. 35G & Patent Application Publication May 26, 2016 Sheet 35 of 41 US 2016/O146783 A1 FG . 36A FG 36B FIG 36C FIG. 36E FG FIG. Patent Application Publication May 26, 2016 Sheet 36 of 41 US 2016/O146783 A1 FIG. 37A FIG. 37B FIG. 37C FIG. 37E FIG. 37F : & 8 Patent Application Publication May 26, 2016 Sheet 37 of 41 US 2016/O146783 A1 FIG. 38B XXXXX-XXX-XXX-XXX-XXX-XXX-XXXXX-XXX-XXX-XXX-XXX-XXXXX Patent Application Publication May 26, 2016 Sheet 38 of 41 US 2016/O146783 A1 FIG. 38G FIG. 38H FIG. 38 Patent Application Publication May 26, 2016 Sheet 39 of 41 US 2016/O146783 A1 FIG. 39B FIG. 39A x: & FIG. 39C 3: FIG. 39E FIG. 39D Patent Application Publication May 26, 2016 Sheet 40 of 41 US 2016/O146783 A1 & & 8& s 8. Patent Application Publication May 26, 2016 Sheet 41 of 41 US 2016/O146783 A1 s aaaaaaaaa s i& US 2016/0146783 A1 May 26, 2016 COMPOSITIONS AND METHODS FOR Mutation/amplification in tyrosine kinase receptors or their TREATING CANCER AND DISEASES AND downstream effectors account for the resistance of a broad CONDITIONS RESPONSIVE TO CELL range of tumors. In particular, oncogenic KRAS, the most GROWTH INHIBITION commonly mutated oncogene in human cancer, has been linked to EGFR inhibitor resistance. However, in lung and RELATED APPLICATIONS pancreatic carcinomas, recent studies suggest that oncogenic 0001. This application is a continuation of U.S. patent KRAS is not sufficient to account for EGFR inhibitor resis application Ser. No. 14/325,288, filed Jul. 7, 2014, now pend tance indicating that other factor(s) might control this pro ing, which is a continuation in part (CIP) of Patent Conven CCSS, tion Treaty (PCT) International Application Serial No: PCT/ US2013/035492, filed Apr. 5, 2013, which claims benefit of SUMMARY priority to International Application Serial No: PCT/US2012/ 0006. In alternative embodiments, the invention provides 040390, filed Jun. 2, 2012, and which also claims benefit of methods for: priority to U.S. Provisional Patent Application Ser. No. 0007 overcoming or diminishing or preventing a Growth (“USSN)61/672,236, filed Jul. 16, 2012, and U.S. Ser.
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