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(12) United States Patent (10) Patent No.: US 7,902,147 B2 Weinberg Et Al

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(12) United States Patent (10) Patent No.: US 7,902,147 B2 Weinberg Et Al US007902147B2 (12) United States Patent (10) Patent No.: US 7,902,147 B2 Weinberg et al. (45) Date of Patent: Mar. 8, 2011 (54) CHRONIC LYMPHOCYTICLEUKEMIA Dallongeville J et al. Modulation of plasma triglyceride levels by PROGNOSIS AND TREATMENT apoE phenotype: a meta-analysis. Journal of Lipid Research. 1992; 33: 447-454. Huang Pet al. Superoxide dismutase as a target for the selective (75) Inventors: J. Brice Weinberg, Durham, NC (US); killing of cancer cells. Nature. Sep. 21, 2000; 407: 390-395. Warren J. Strittmatter, Hillsborough, Gruber CJ et al. Production and actions of estrogens. The New NC (US) England Journal of Medicine. Jan. 31, 2002: 346(5): 340-352. Raber J et al. Androgens protects against apolipoprotein E4-induced (73) Assignee: Duke University, Durham, NC (US) cognitive deficits. The Journal of Neuroscience. Jun. 15, 2002; 22(12): 5204-5209. Dekroon RM et al. ApoE genotype-specific inhibition of apoptosis. (*) Notice: Subject to any disclaimer, the term of this Journal of Lipid Research. 2003:44: 1566-1573. patent is extended or adjusted under 35 Cuni Setal. A sustained activation of P13K/NF-\B pathway is critical U.S.C. 154(b) by 14 days. for the survival of chronic lymphocytic leukemia B cells. Leukemia. 2004; 18: 1391-1400. (21) Appl. No.: 12/265,079 Robak T. Monoclonal antibodies in the treatment of chronic lymphoid leukemias. Leukemia & Lymphoma. Feb. 2004; 45(2): (22) Filed: Nov. 5, 2008 205-219. Chiorazzi Netal. Chronic lymphocytic leukemia. The New England Journal of Medicine. Feb. 24, 2005; 352(8): 804-815. (65) Prior Publication Data Gao N et al. 2-methoxyestradiol-induced apoptosis in human leuke US 2009/O136496 A1 May 28, 2009 mia cells proceeds through a reactive oxygen species and Akt-depen dent process. Oncogene. 2005; 24: 3797-3809. Danilov AV et al. Molecular pathogenesis of chronic lymphocytic Related U.S. Application Data leukemia. Current Molecular Medicine. 2006; 6(6): 665-675. Dekroon R et al. APOE-4-VLDL inhibits the HDL-activated (60) Provisional application No. 60/985,365, filed on Nov. phosphatidylinositol 3-kinase/akt pathway via the phosphoinositol 5, 2007. phosphatase SHIP2. Circulation Research. Oct. 13, 2006; 829-836. Wang JM et al. Activation of estrogen receptor O, increases and (51) Int. Cl. estrogen receptor f3 decreases apoliprotein E expression in hip AOIN37/18 (2006.01) pocampus in vitro and in vivo. PNAS. Nov. 7, 2006; 103(45): (52) U.S. Cl. ....................................... 514/2; 514/4 169984-169988. Weinberg. JB et al. Apollipoprotein E (APOE) genotype as a determi (58) Field of Classification Search ........................ None nant of survival in women with chronic lymphocytic leukemia. Blood See application file for complete search history. (American Society of Hematology Annual Meeting Abstracts). 2007; 110: Abstract 3081. (56) References Cited Weinberg. JB et al. Clinical and molecular predictors of disease sever ity and Survival in chronic lymphocytic leukemia. American Journal U.S. PATENT DOCUMENTS of Hematology. 2007: 1063-1070. 5,288,717 A 2, 1994 Raveendranath et al. Weinberg. JB et al. Apollipoprotein E genotype as a determinant of 5,422,119 A 6/1995 Casper Survival in chronic lymphocytic leukemia. Leukemia. Leukemia. 5,508,167 A 4, 1996 Roses et al. 2008: 1-9. 5,716,828 A 2f1998 Roses et al. 5,723.455 A 3, 1998 Tanabe et al. * cited by examiner 5,767,248 A 6, 1998 Roses et al. 6,027,896 A 2/2000 Roses et al. Primary Examiner — Misook Yu 6,251,587 B1 6/2001 Sévigney et al. Assistant Examiner — Mark Halvorson 6.432,643 B1 8, 2002 Einstein et al. (74) Attorney, Agent, or Firm — Myers Bigel Sibley & 6,828,103 B2 12/2004 Herrington et al. 6,896,885 B2 5, 2005 Hanna Sajovec, P.A. 7,049,078 B2 5, 2006 Poirier 7,138.426 B2 11/2006 DiNinno et al. (57) ABSTRACT RE39,419 E 12/2006 Day et al. Provided herein are methods for identifying a subject afflicted 7,208.481 B2 4/2007 Phan et al. with chronic lymphocytic leukemia who is responsive to 7,220,833 B2 5, 2007 Nelson et al. treatment with a chemotherapeutic agent by detecting the OTHER PUBLICATIONS presence or absence of at least one APOE4 allele in the DeKroon et al., J. Lipid Res, 2003, 44:1566-1573.* subject, the presence of an APOE4 allele identifying the Freshney, Culture of Animal Cells, A Manual of Basic Technique, Subject as responsive to the treatment. Also provided are Alan R. Liss, Inc., 1983, New York, p4.* methods of treating a subject afflicted with chronic lympho Dermer, Bio/Technology, 1994, 12:320.* cytic leukemia, including administering an estrogenic agent, Gura (Science, 1997, 278: 1041-1042.* an androgen withdrawal agent, an apoE4 peptide or mimetic Johnson and Tracey, Peptide and Protein Drug Delivery. In: Ency thereof, and/or a chemotherapeutic agent in an amount effec clopedia of Controlled Drug Delivery, vol. 2, 1999, pp. 816-833.* tive to treat said chronic lymphocytic leukemia. Methods of Narasimhan P and Amaral L. Lymphopenic response of patients determining a prognosis for a patient diagnosed with chronic presenting with chronic lymphocytic leukemia associated with car lymphocytic leukemia are also provided. In addition, meth cinoma of the prostate to diethylstilbestrol: correlation of response to ods for stratifying a subject into a Subgroup of a clinical trial the in vitro synthesis of rnaby patientlymphocytes and its relation and methods for identifying a patient in a clinical trial of a ship to transcortin. American Journal of Hematology. 1980; 8(4): treatment for chronic lymphocytic leukemia are herein pro 369-375. Abstract only. vided. Rosen St et al. Estrogen receptor analysis in chronic lymphocytic leukemia. Blood. Nov. 1983; 62(5): 996-999. 15 Claims, 8 Drawing Sheets U.S. Patent Mar. 8, 2011 Sheet 1 of 8 US 7,902,147 B2 10", Apo. 1.0" S0.9 it. s0.9 d 0.8 0.8 re. v D 0.7 s f O.7 Not APOE4 5 O6 5 O6 ess as Fira a a Isis a 0.5 "Not APOE4 0:5 O4 i. 0.4 g 50.3 g0.3 20.1-APOE40.2- 12120 30.220.1-APOEA 41356 Cl Not APOE4 3829 9 ?h Combined 50 41 9 O 5 10 15 20 25 O 5 10 15 20 25 TIME FROM DIAGNOSIS (YEARS) TIME FROM DIAGNOSIS (YEARS) FIG. 1A FIG. 1B Median APOE4 Not APOE4 92 42 50 4.6 . Combined 133 60 73 T. "Not APOE4 0.1 0.1 Not APOE4 =0.42 O.O O.O- OFU. O 5 10 15 20 O 5 10 15 20 25 TIME FROM DIAGNOSIS (YEARS) TIME FROM DIAGNOSIS (YEARS) FIG. 1C FIG. 1D U.S. Patent Mar. 8, 2011 Sheet 2 of 8 US 7,902,147 B2 8O 3353 CONTROL 70 %CLL 1416 6 O LNEO`HEc §1),„ ?L3N £). ë?:1, CN O ???????????????????????????????????? n CC ? APOE GENOTYPE POE ALLELES FIG. 2 U.S. Patent Mar. 8, 2011 Sheet 3 of 8 US 7,902,147 B2 LOW LPL LOW LPL High LPL 12 8 4 High LPL 3529 6 O 5 10 15 20 25 O 5 10 15 20 25 TIME FROMDIAGNOSIS (YEARS) TIME FROM DAGNOSIS (YEARS) FIG. 3A FIG. 3B Low LPL High LPL 12 3 9 18 or 0.7 H50.6 X 0.4 High LPL . O 5 10 15 2O O 5 10 15 20 25 TIME FROM DAGNOSIS (YEARS) TIME FROM DIAGNOSIS (YEARS) FIG. 3C FIG. 3D U.S. Patent Mar. 8, 2011 Sheet 4 of 8 US 7,902,147 B2 1.O OC) CD OO 1.O - D. L.III APOE4/High LPL APOE4/High LPL s O.9 APOE4/Low LPL s O.9 APOE4/LOW PL > 0.8 D.O.O.D.I.D. 0.8 f Not APOE4/ : Not APOE41 Not APOE4/ OU),0.7 OW LPL : D O.7U. AEE :LOWLPL 506 506 05O4 wn 050.4 nO3- PU ?m 0.3 High LPL/E4 990-0 - On O2 – 90.2 - E. 20.1-Lowa LPLE422totala 1 220a r "O... inYO. 1-LowLow LPLE4990LP not E4. 17 13 4 "O..... 0.0 0.0-Combined 38 308 O 5 10 15 20 25 O 5 10 15 20 25 TIME FROM DIAGNOSIS (YEARS) TIME FROM DIAGNOSIS (YEARS) - 1.0 APOE4/High LP s0.9 APOE4/LOW LPL > 0.8 Not APOE4/ Low LPL O O.7 ... 5 0.6 NotHigh APOE41 LPL 05 r..... - o3-p=0.003O.4 S0.2High3 High LPL/E4Pinot E4.27880-0 21 6 - 20.1 Low LPLE413LPL/not E4 24 2313 01 ....."O O.O O 5 10 15 20 25 TIME FROMDIAGNOSIS (YEARS) FIG. 4C U.S. Patent Mar. 8, 2011 Sheet 5 of 8 US 7,902,147 B2 APOE 7 RECEPTOR HEPARAN SULFATE f PLASMA PROTEOGLY O MEMBRANE g 88. 88: 59SS3 858.333. FIG. 5 U.S. Patent Mar. 8, 2011 Sheet 6 of 8 US 7,902,147 B2 Not APOE4 APOE4 5347 6 Not APOE4 O 5 10 15 20 25 O 5 1O 15 20 25 TIME FROM DAGNOSIS (YEARS) TIME FROM DIAGNOSIS (YEARS) FIG. 6A FIG. 6B Mediplan 1.0 "tes...as 1.0 Low LPL s0.9 LO.9- Combined 110 48 62 > 0.8 50.8 D 0.7 0.7 LL 0.6 50.6 S0.5 0.5 H. O.4 H. O.4 s - in 0.3 in 0.3 g 02. PU. TotalAlive dead 50.2 Y O. 1 20.1 n O.O innO.O- p=0.002p=0.0 O 5 10 15 20 25 O 5 10 15 20 25 TIME FROM DAGNOSIS (YEARS) TIME FROMDIAGNOSIS (YEARS) FIG.
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