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(12) Patent Application Publication (10) Pub. No.: US 2010/0009364 A1 Fant Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0009364 A1 Fant Et Al US 2010.0009364A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0009364 A1 Fant et al. (43) Pub. Date: Jan. 14, 2010 (54) METHODS FOR DIAGNOSIS, PROGNOSIS filed on Aug. 1, 2008, provisional application No. AND METHODS OF TREATMENT 61/104,666, filed on Oct. 10, 2008, provisional appli cation No. 61/120,320, filed on Dec. 5, 2008. (75) Inventors: Wendy J. Fantl, San Francisco, CA (US); David B. Rosen, San Francisco, CA (US); Alessandra Cesano, Redwood City, CA (US); Publication Classification Santosh K. Putta, Foster City, CA (51) Int. Cl. (US); Garry Nolan, San Francisco, CI2O I/68 (2006.01) CA (US); Aileen Cohen, Palo Alto, CA (US); Erik Evensen, Foster City, CA (US) (52) U.S. Cl. ............................................................ 435/6 Correspondence Address: WILSON, SONSINI, GOODRICH & ROSATI / NODALITY, INC (57) ABSTRACT 650 Page Mill Road Palo Alto, CA 94304-1050 (US) The present invention provides an approach for the determi nation of the activation states of a plurality of proteins in (73) Assignee: Nodality, Inc., South San single cells. This approach permits the rapid detection of Francisco, CA (US) heterogeneity in a complex cell population based on activa tion states, expression markers and other criteria, and the (21) Appl. No.: 12/460,029 identification of cellular subsets that exhibit correlated changes in activation within the cell population. Moreover, (22) Filed: Jul. 10, 2009 this approach allows the correlation of cellular activities or properties. In addition, the use of modulators of cellular acti Related U.S. Application Data Vation allows for characterization of pathways and cell popu (60) Provisional application No. 61/079,766, filed on Jul. lations. Several exemplary diseases that can be analyzed 10, 2008, provisional application No. 61/085,789, using the invention include AML, MDS, and MPN. Receptors C-Kit Receptor ligands F3R Growth factors: Flt3, CXCR4 SCF, EPO-R Chernokines:SOF 10, G-CSFR Cytokines: M-CSF, G GM-CSFR CSF, GM-CSF Interleukins: IL-3, L-4, IL AraC, Dauno 6, IL-10, IL-27 Etoposide Interferons: IFNo, IFNy Other CD4OL, TNFo, Thapsigargin, Staurosporine LPS PMA 9 o 2. Survival DNA p-Stat1, 3, 5 PI3Kinase Pathway Darage NFKB Pathway Pete p-Creb w p-Akt p-P65/RelA p-S6 Apoptosis P-PRAS-40 p-p38 p-Plcg2 p-Erk Cell Cycle P-GSK-3 p-SLP76 p-Chk2 8. p-S6 p-Lok 52AX proliferation p-S6 Cytochrome C Psi, 5 SES i AEK Pathways (p-Erk, p-p38 p-Akt gifC-3SO2S Cyclin D p-Erk Survivin Cyclin B XAP p-Cdk-1 p-HistoneH3 p-CDC25 Patent Application Publication Jan. 14, 2010 Sheet 1 of 42 US 2010/0009364 A1 Wd sisoqdodyq?JO-d Patent Application Publication Jan. 14, 2010 Sheet 2 of 42 US 2010/0009364 A1 Áouanbauj?ueupeno (%8'99SA%96’9) duvd pemeelp AV peAee Patent Application Publication Jan. 14, 2010 Sheet 3 of 42 US 2010/0009364 A1 3.Aunosl??Jepuneeuw Patent Application Publication Jan. 14, 2010 Sheet 4 of 42 US 2010/0009364 A1 asedseo sa?eu?sqnS (dawd)` ÅÅÅÅÅÅiiiiiiiiti?titutim 6esedseO sÁewu?edsisoqdodv Patent Application Publication Jan. 14, 2010 Sheet 5 of 42 US 2010/0009364 A1 p-value= 0.02358 AUC 0.7792 (CR,NR)=(7, 22) CR NR H0pplCy2 p-value= 0.0974 AUCE O.7468 (CR, NR)=(7,22) Patent Application Publication Jan. 14, 2010 Sheet 6 of 42 US 2010/0009364 A1 AemsueS €. 36euepVNO Patent Application Publication Jan. 14, 2010 Sheet 7 of 42 US 2010/0009364 A1 Ungated (95% blasts) Total Cells Live Cells Unstim G-CSF P-Stats FIG. 6 Patent Application Publication Jan. 14, 2010 Sheet 8 of 42 US 2010/0009364 A1 -Iz=peelds z:0 Sued Patent Application Publication Jan. 14, 2010 Sheet 10 of 42 US 2010/0009364 A1 00000||000?, 00||0 |WillS WILSNT) adÅ?os,uouMelp?u||a??u80Jød%96. |Ou?uOO Patent Application Publication Jan. 14, 2010 Sheet 11 of 42 US 2010/0009364 A1 unstim 3.0 - R all = 0.14 p = 0.4170 2.5 oooo R CR = -0.08 p = 0.8393 oooo RNR = 0.19 p = 0.3505 2.0 15 O1 5O -0.2 O.O 0.2 O.4 0.6 O.8 1.O 1.2 log2 p-Stat1 Y701 FoldAF FIG. 10 Patent Application Publication Jan. 14, 2010 Sheet 12 of 42 US 2010/0009364 A1 HOOH -R all = 0.12 p = 0.5356 oooo RCR = 0.89 p = 0.0075* oooo RNR = 0.00 p = 0.9869 -0.2 O.O O.5 1.O 15 2.0 25 log2 p-Stat1 Y701 FoldAF FIG 11 Patent Application Publication Jan. 14, 2010 Sheet 13 of 42 US 2010/0009364 A1 unstim - Rall = 0.70 p = 0.0000" R CR = 0.51 p = O. 1637 Oooo RNR = 0.77 p = 0.0000" 2. 5 2 O O.5 1.0 15 2.0 2.5 3.0 log2 p-Erk (T202) FoldAF FIG. 12 Patent Application Publication Jan. 14, 2010 Sheet 14 of 42 US 2010/0009364 A1 L-3 -R all = 0.44 p = 0.007.1" 4.0 coee R CR = -0.10 p = 0.791 3. 5 3. O 22 O5 1 5 0.5 O.O 0.5 10 15 2.O 2.5 3.0 3.5 log2 p-Erk (T202) FoldAF FIG. 13 Patent Application Publication Jan. 14, 2010 Sheet 15 of 42 US 2010/0009364 A1 L-6 4.0 R all = 0.52 p = 0.0011* 3.5 oooo R CR = 0.03 p = 0.9304 g oooo RNR = 0.76 p = 0.0000" \o LL C 3.0 O O 32.5 o O 2.0 C O. g 1.5 1.0 a 0.5 10 -0.5 O.O O.5 1.0 15 2.O 2.5 3.0 3.5 log2 p-Erk (T202) FoldAF FIG. 14 Patent Application Publication Jan. 14, 2010 Sheet 16 of 42 US 2010/0009364 A1 -27 R all = 0.51 p = 0.0015 aboo R CR = -0.03 p = 0.9291 0.0 0.5 1.O 1.5 2.0 2.5 3.O 3.5 log2 p-Erk (T202) FoldAF F.G. 15 Patent Application Publication Jan. 14, 2010 Sheet 17 of 42 US 2010/0009364 A1 Use of Signaling Networks to Select Patients for Specific Targeted Therapies patient 1 HiG-CSF->p-Stat3/p-Stat5NR1 Subset 1 Potential InhibitOrS. JAK SrC New therapeutics ge" ; fi orios', is- ---xpe-2 s g s i S3: SS - s th-wes vs. s......&w a...- ... ss we w a '-w as is x- a : w Sik H. H. NR Subset 2: HiFLT3L->p-Akt/p-S6 ---w Potential inhibitors: FLT3R PI3K/mTor New therapeutics NR Subset 3 HiGCSF - Stat3/p-Stat5 HiFLT3L->p-Akt/p-S6 HiSCF ->p-Akt/p-S6 Potential Inhibitors: Jak. Src PI3K/mTOr Other RTK inhibitors New therapeutics Patent Application Publication Jan. 14, 2010 Sheet 18 of 42 US 2010/0009364 A1 8.00 8.00 7.50 7.50 7.00 7.00 6.50 6.50 6.00 6.00 5.50 5.50 3 33 46698 9 3.50 3.50 A 356 3.00 5 2.59 2.50 2.00 2.00 150 150 1.00 1.00 9.00 8.00 7.00 2 6.00 o fifttoo. 68% / 4.00 HIE | 3,00 | | 0 ||H of PE FIG. 17 olo ozo oso oo oso oso oro 0.10 0.20 O.30 0.40 0.50 0.60 0.70 Etoposide Treatment->Apoptosis Ability to isolate CRs is enhanced by examining multiple pathways Patent Application Publication Jan. 14, 2010 Sheet 19 of 42 US 2010/0009364 A1 o -0.5 O.O. O.5. 1.O 15 2.0 2.5 p Akt. FLT3L FIG. 18 Patent Application Publication Jan. 14, 2010 Sheet 20 of 42 US 2010/0009364 A1 Node p WalAge p Val Node AUCAge PMA->p-CREB OOO2 O.O42 O.69 IL27 ->p-Stat3 0.001 0.13 O.60 IL27 ->p-Stat1 OOO1 0.027 O60 PMA->p-CREB IL-27->p-Stat1 | | | | ||4 / 4 O | | | || 1 2 50. s O 4. L AUC = 0,906 4 AUC = 6.862 0. AUC = 0.828 1 (CRNR) (35.11) 0.4 CRNR)) is (14)44.14 . (CR, NR) = (44.14) 0.0 O2 0.4 0.6 O.8 OO O2 O.4 0.6 0.8 1.) O4 0.6 0.8 O Fraction CR Fraction CR Fraction CR FIG. 19 Patent Application Publication Jan. 14, 2010 Sheet 21 of 42 US 2010/0009364 A1 -O.2O O.OO O.2O O.40 0.6O O.80 100 120 140 16O 18O2.OO G-CSF->Stat1 (P1, Fold Change) -0.20 O.OO O.2O O.40 O.6O O.801.OO 1.2O 140 16O 18O2.OO G-CSF->Stat1 (P1, Fold Change) FIG. 20 Patent Application Publication Jan. 14, 2010 Sheet 22 of 42 US 2010/0009364 A1 No Etopo->PARP>T, L-27 /06'006'50'06'60'06700 -0.050.00050 100 150 2002.503.00 L-27->Stat1 FIG 21 Patent Application Publication Jan. 14, 2010 Sheet 23 of 42 US 2010/0009364 A1 6 | | | | | | | | 206H456 | H-E-| | | | | ...100-0,500.000501.OO 150 2.00 2.5O3,OO ... 100 -0.5O O.OO O.5O 1.OO 150 2.OO 2.50 3.00 L-27->Stat1 L-2->Stat1 Patent Application Publication Jan. 14, 2010 Sheet 24 of 42 US 2010/0009364 A1 PARP, D214. FTC.A.Ara.C.
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