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(12) Patent Application Publication (10) Pub. No.: US 2013/0149320 A1 Almouzni Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0149320 A1 Almouzni Et Al US 2013 O14932OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0149320 A1 Almouzni et al. (43) Pub. Date: Jun. 13, 2013 (54) ASF1B ASA PROGNOSS MARKER AND Publication Classification THERAPEUTIC TARGET INHUMAN CANCER (51) Int. C. GOIN33/68 (2006.01) A6II 45/06 (2006.01) A613 L/7088 (2006.01) (75) Inventors: Genevieve Almouzni, Neuilly Sur Seine A638/17 (2006.01) (FR); Armelle Corpet, Paris (FR) CI2O I/68 (2006.01) (73) Assignees: CENTRE NATIONAL DE LA A 6LX39/395 (2006.01) RECHERCHE SCIENTIFIOUE, (52) U.S. C. PARIS (FR), INSTITUTCURIE, CPC .......... G0IN33/6875 (2013.01); C12O 1/6886 PARIS (FR) (2013.01); A61K.39/39558 (2013.01); A61 K 31/7088 (2013.01); A61K 38/17 (2013.01); (21) Appl. No.: 13/700,792 A61K 45/06 (2013.01) USPC .......... 424/174.1; 435/7.92; 435/6.12:506/9; (22) PCT Filed: May 31, 2011 514/44 A: 514/44 R: 514/19.3: 436/501 (86) PCT NO.: PCT/EP2011/058939 (57) ABSTRACT S371 (c)(1), The present invention provides a prognostic marker in human (2), (4) Date: Feb. 5, 2013 cancer, ASflb, a high expression thereof being associated with a poor prognosis. The present invention also provides a (30) Foreign Application Priority Data method for selecting a subject affected with a cancer for an adjuvant therapy. Finally, the present invention provides a May 31, 2010 (EP) .................................. 1O164424.3 new therapeutic target for treating cancer. Patent Application Publication Jun. 13, 2013 Sheet 2 of 26 US 2013/014932.0 A1 FIG.2A O K4. AS 200 400 600 800 1000 Pl intensity AS G1 G1/S S S/G2 M ... m.a...wu wa-wrix wa-ana. "" " " -26 Cyclin A - - - - - usuruoup-assists --55 p60 - un pure us uruses --72 FIG.2C O,03 O,02 0.01 O Patent Application Publication Jun. 13, 2013 Sheet 3 of 26 US 2013/O14932O A1 Fig. 3A Celineis a : X "an PrimaryYoung fibroblastOld Senescent IMR90 or --- PO27 PD72 PD8O 1x2x 1X 2x 1x2x 1x2x -2BM (kDa) 1X 2X 4X X 2X 4X 1X 2X 4X MD Asf1 (a+b) is see s Asf1 (a+b) - sesse-res a -23 Cyclin A it is w -55 Cyclin A - m as - E. -35 CAF-1 p60 - as - - -72 CAF-1 p60 - - - - - -2 o-Tubulin up u us up us w ur-ss O-Tubulin to purveyenous uvue -ss Fig. 3B Fig. 3C P intensity Patent Application Publication Jun. 13, 2013 Sheet 4 of 26 US 2013/014932.0 A1 Fig. 4A Fig. 4B MCF7 120 MCF7 AS GO 2h 4h 8h 24h c X2X4XX2X4X1X2X4X 1X2X4X 1x2x4x 1x2x4x Moog As?1 (a+b)-is- a - - - - - a Cyclin A - - - - - - - - - - F - s - O CAF-1 peo - so ----- - - - - - - -2 PCNA woo as a s - m or sor or - - - we as - o-Tubulin ---------- two we - - - - - -ss Fig. 4C MCF7 Fig. 4D PI intensity Patent Application Publication Jun. 13, 2013 Sheet 5 of 26 US 2013/O14932O A1 Fig. 5A Fig. 5B ASf1 2 3 CAF-1 s p150 200 40 PI intensity Merge DAP Patent Application Publication Jun. 13, 2013 Sheet 6 of 26 US 2013/014932.0 A1 Fig. 6A Fig. 6B Mammary cells 3. - f T BSt E 1X 2X 4X 1X 2X 4X MoDa & . -, -26 Asfi (a+b) - : R. '' CAF-1 peo - or . -72 O-Tubulin - - us - or up - % S phase 25% 13% Fig. 6C ASf1 CAF-1 p150 DAP Fig. 6D Asfa ASffb T Bst Bst Asf1 a-p150+ Asfib+ p150+ Asfia p150- E. Asf1 b-p150 Asfa-4-p150- Asf1 b+ p150 Patent Application Publication Jun. 13, 2013 Sheet 7 of 26 US 2013/O14932O A1 Fig. 7A siCon siAsfia siASf 1b siAsf1(a+b) g siaSf (a+b) 1x2x4x 1x2x 4x 1x2x4x 1x2x4x MoD 2's siAs?ib Asf1 (ab) - e - - - -2s (-, siAsfia. a --- mm YM - siCon. O-Tubulin - oup - upu - us use -55 Pinto: SO Fig. 7B Fig. 7C siAsfia siASfb siGFP siAsfia siAst 1b siAsf1(a+b) 8 y - 8 f siAsf1(a-b) Fig. 7D Jun. 13, 2013 Sheet 8 of 26 US 2013/014932.0 A1 Fig. 7F DAP LaminA DAP LaminA Fig. 7G SiCOn SiASfa SASfo SiAsf1(a+b) siCon. siAsfah2 siAsfib+2 siAsf1(a+b)+2 Patent Application Publication Jun. 13, 2013 Sheet 9 of 26 US 2013/O14932O A1 Fig. 8A Asfa Asfb - - 0 6- . g 2-2 2-3 -s - s 2S N Fig. 8B es - g g-2 is 54 s 3.g- Seasas m *::::::: 12 - - - S Fig. 8C EGFR Neurofigina s -- siAsfia siAst1b - - siAsfia--b - G-15 s e - -2 a - FC O-RT-PCR 03 -19 -1.6 '" -0.1 -13 -0.9 -2.2 -0.8 - 17 FC Affymetrix 0.2 -1.6 -2.2 -0.1 -0.5 -0.2 -0.6 -0.2 -O.7 Patent Application Publication Jun. 13, 2013 Sheet 10 of 26 US 2013/O14932O A1 Figure 9 siasfa GO term -log(p-value) 2.5 3. 3,5 4. 45 5 55 cytokinesis (6) organelle organization (26) Mphase of mitotic cell cycle (8) response to stress (34) anatorica structure in morphogeneSISIR YESS (9) protein complex localization (2) regulation of blood vessel size (5) regulation of systemic arterial blood pressure (4) Smooth muscle hyperplasia (2) GIS transition of mitotic cell cycle (5) endothelial cell migration (5) siasfib GO term -log(p-value) 2.5 3. 3,5 4. 4.5 5 55 DNA-dependent DNA replication (10) iron-sulfur cluster assembly (3) Y. G1 Stransition of mitotic cell cycle (8) siasfahb GO terra -log(p-value) 2.5 3. 3.5 4. 4.5 5. 5.5 regulation of cell shape (9) cellular macromolecule catabolic process (36) intracellular transport (58 cardiac muscle cell development (4) biopolymer catabolic process (31) negative regulation of DNA metabolic process (10) aminosugar metabolic process (8) coenzyme metabolic process (4) Ci Patent Application Publication Jun. 13, 2013 Sheet 11 of 26 US 2013/O14932O A1 Fig. 10A p60/p150 Asfa/ASfb -15 - -0.5 O 0.5 log(p60) log(Asfia) Asfia/p60 Asf1b/p60 r O - 9 sgo Sun g", cy t -1 O 1. 2 -2 - O 2 log(p60) log(p60) Asfa/Ki67 Asfb/Ki67 s s ge Se.g -1.5 - -0.5log(Asfia) O O5 -2 log(Asf1b)- Fig. 10B OVeral Survival p=0.01 c ce s 2 cc s ce wit ed c cs o Aso as 0.7 . , AS O.7 O 24 48 72 96 20 144 Time (months) Nunbeat risk As K-7 57 53 49 46 44 42 3. Asby O.7 28 18 15 Patent Application Publication Jun. 13, 2013 Sheet 12 of 26 US 2013/0149320 A1 Fig. 11A Tumor size Asfia s r go ge g 3: g". cy t - TO/T T2 p=0.06 Mitotic index p w g se g 3. 33 g T cy t Grade goun a o 3. 3. g r y te p=0.06 Fig. 11B Disease free interval p=0.017 Metastasis free interval p=0.0002 2 s 8 O i. O 24 48 72 S6 120 44 0 24 48 72 96. 120 144 Time (months) - Time (months) Nui Title at risk Nutbeat risk Asif K07 57 53 46 40 37 33 19 Asfb as 0.7. 57 53 49 46 44 41 29 Asix O.7 28 23 19 15 4. 13 10 AS-07 28 24 22 17 16 15 12 Patent Application Publication Jun. 13, 2013 Sheet 13 of 26 US 2013/0149320 A1 Fig. 12A Tumor grade Distant metastasis at 5 years Disease Free survival 5 years p=3x10-5 p=1.7x10-5 p=5.9x10-5 1. 1.5 20 ge 1. se g o 51. 1.0 s S 30.5 2 a 0. Ot g 0. o 300 iosas s CA. 0.5 e 31. c 0. e -1. 1.5 -2. 3-0. s:-20 -2. -3.0 -3.0 -1.0. -3.5 no distant distant no disease relapse metastasis metastasis (n=9) (n=33) (n=33) (n=154) (n=35) (n=196) (n=79) Fig. 12B Skin Breast Liver p=1.5x10-14 p=2.6x10-5 1.0 p=1.1x10-8 1.5 0.5 2 2 s g s g 0. 51. 3 5-05 e e C 1. 0. So. 5-1.5 d e s c 3-2 2. 2 2-3. -3.5 -0.5 -0.5 -4. normal benign cutanenous normal breast non-tumor hepatocellular Skin nevus melanoma breast carcinoma liver carcinoma (n=7) (n=18) (n=45) (n=7) (n=40) (n=76) (n=104) Ovarian Lung p=6.7x10-5 p=1x10-7 1. 25" e.g.05 < 0. 3. Soo g s 0. 2-0. -0.5 -10 normal ovarian normal lung ovary SeOUS lung adenocarcinoma adenocarcinoma (n=4) (n=41) (n=31) (n=31) Patent Application Publication Jun. 13, 2013 Sheet 14 of 26 US 2013/0149320 A1 Fig. 13A Cox MODEL FOR METASTASIS FREE INTERVAL (n = 73) Variables included in the model: mitotic index (qualitative), tumor size (qualitative and quantitative), tumor grade, Asf1b, CAF-1 peo, CAF-1 p150, HP1, Ki67 Wariables RR 95% CI p-value Asf1b. ASF 1b a 0.70 1 ASF 1b > 0.70 71 2.0 - 26.0 8.66x10-4 cox MoDEL FOR DISEASE FREE INTERVAL (n = 73) Variables included in the model: mitotic index (qualitative), tumor size (qualitative and quantitative), tumor grade, Asf1b, CAF-1 peso, CAF-1 p150, HP1, Ki67 Variables RR 95% C. p-value CAF-1 p50 CAF-1 p60s 0.60 1 - - CAF-1 péO > 0.60 5.5 2.5 - 11.9 6.58x10-5 COX MODEL FOR OVERALL SURVIVAL (n = 73) Variables included in the model age, mitotic index (qualitative), tumor size (quantitative), hormonal receptor status (ERPR), Asf1b, CAF-1 peso, CAF-1 p150, HP1, Ki67 Watiables RR 95% Ci p-value CAF-1 peo CAF-1 p50s 0.60 1 CAF-1 péO > 0.60 12.9 2.6 - 64.2 5.95x10-4 Fig.
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