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(12) Patent Application Publication (10) Pub. No.: US 2009/0004173 A1 Evans Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0004173 A1 Evans Et Al US 200900.041.73A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0004173 A1 Evans et al. (43) Pub. Date: Jan. 1, 2009 (54) DIAGNOSIS AND TREATMENT OF DRUG Related U.S. Application Data RESISTANT LEUKEMA (60) Provisional application No. 60/575,762, filed on May 28, 2004. (75) Inventors: William E. Evans, Cordova, TN Publication Classification (US); Robert Pieters, Rotterdam (51) Int. Cl. (NL); Meyling H. Cheok, A638/50 (2006.01) Memphis, TN (US); Monique L. GOIN 33/50 (2006.01) den Boer, Rotterdam (NL); C40B 30/06 (2006.01) Wenjian Yang, Germantown, TN A63L/437 (2006.01) (US) C40B 40/00 (2006.01) A6IP35/02 (2006.01) A63L/35 (2006.01) Correspondence Address: A 6LX 3/573 (2006.01) ALSTON AND BIRD LLP C40B 30/00 (2006.01) ST. JUDE CHILDREN'S RESEARCH HOSP (52) U.S. Cl. ................ 424/94.6; 702/19; 506/10; 506/7; TAL 514/285; 514/459; 506/13 BANK OF AMERICA PLAZA, 101 SOUTH TRYON STREET, SUITE 4000 (57) ABSTRACT CHARLOTTE, NC 28280-4000 (US) The present invention encompasses methods and composi tions useful in the diagnosis and treatment of drug resistant (73) Assignee: St. Jude Children's Research leukemia. The invention provides a number of genes that are Hospital, Memphis, TN (US) differentially expressed between drug resistant and drug sen sitive acute lymphoblastic leukemia (ALL). These genes act as biomarkers for drug resistant leukemia, and further serve as (21) Appl. No.: 11/597,468 molecular targets for drugs useful in treating drug resistant leukemia. Accordingly, the invention provides methods of diagnosing drug resistant leukemia and methods of selecting (22) PCT Filed: May 18, 2005 a therapy for Subjects affected by drug-resistant leukemia. The invention also provides methods for Screening for com (86). PCT No.: PCT/US2OOS/O17424 pounds for treating drug-resistant leukemia, and improved methods for treating drug-resistant leukemia. Compositions S371 (c)(1), of the invention include arrays, computer readable media, and (2), (4) Date: Aug. 12, 2008 kits for use in the methods of the invention. 3 Š s a Sensitive - - - - - -H-H-H - - - - - - - - - - - - - - - - - - termediate s 8 Resistant 9 : s s d is s s0.001 - No. atris' 2 * Years 6 8 10 Sensitive 5 5s 52 46 4. s s 3. interediate s2 8 35 8 8 3. Resistant 52 42 29 2 s 3. 2 b St.o wawaii. wr w w w w w w w 48 x w w w w w w x w---- a r + · ·sis r- 4 4-war a s 3 T. Ti----------------HoSersitive s intermediate 8 Resistant i ro is N PO.003 - to a Risk" 2 4 Years 6 8 10 Sense 28 2 26 2. 2S 9 $3. 9 4 Interediate 4S 44 43 3s 2 23 i8 Resistant 7 18 15 s 2 f s s s3 Patent Application Publication Jan. 1, 2009 US 2009/0004173 A1 a 3 ... -----------H----------. ---- . .--...-H... Sensitive intermediate Resistant O No. at Risk 2 4. Years 6 8 10 Sensitive S9 5S 52 46 27 4. 5 5 3. lintermediate 52 46 35 28 9. S 4. 3. Resistant 52 42 29 20 18 12 5 3. 2 O we5 ...t------. 4. For - or ss a s r s a r as a a e a a a a a e --- a r s as a ---- - - - - - - - - - - - - - - s O !----------- Sensitive N- do ------H-H----------H--- g intermediate o o Resistant 8 C. b v i S. O C P=0.003 No. at Risk 2 4 Years 6 8 10 Sensive 28 2 25 26 2S 25 19 3. s 4 interediate 45 44 43 39 35 29 23 8 Resistant 17 16 15 ts 12 2 f 5 5. s 13 F.G. 1 US 2009/00041 73 A1 Jan. 1, 2009 DAGNOSIS AND TREATMENT OF DRUG 0007. The subject expression profile and the reference RESISTANT LEUKEMA expression profile comprise values representing the expres sion levels of genes that are differentially expressed in drug FEDERALLY SPONSORED RESEARCHOR resistant versus drug-sensitive leukemia. In particular DEVELOPMENT embodiments, the profiles comprise values representing the 0001. This invention was made in part with U.S. Govern expression levels of genes selected from the genes shown in ment Support under National Institutes of Health grant nos. Tables 6A, 6B, 6C, 6D, 7A, 7B, 7C, 7D, 8A, 8B, 8C, 8D,9A, R37 CA36401, R01 CA78224, RO1 CA51001, RO1 9B, 9C, 9D, 10A, 10B, 11A, 11B, 12A, 12B, 13A, and 13B. CA71907, UO1 GM61393, UO1 GM61394, and Cancer Cen 0008 Tables 6A, 6B, 6C, 6D, 10A, and 10B provide genes ter Support Grant CA21765. The U.S. Government may have that are differentially expressed in prednisolone-resistant certain rights in this invention. ALL. Tables 7A, 7B, 7C, 7D, 11A, and 11B provide genes that are differentially expressed in Vincristine-resistant ALL. FIELD OF THE INVENTION Tables 8A, 8B, 8C, 8D, 12A, and 12B provide genes that are 0002 The present invention relates generally to genes differentially expressed in L-asparaginase-resistant ALL. associated with resistance to drugs used to treat leukemia and Tables 9A, 9B, 9C, 9D, 13A, and 13B provide genes that are methods for using these genes to improve treatment of leu differentially expressed in daunorubicin-resistant ALL. The kemia. invention also provides a method of determining the progno sis for a patient with leukemia or predicting whethera Subject BACKGROUND OF THE INVENTION affected by leukemia has an increased risk of relapse. The 0003. The treatment of pediatric acute lymphoblastic leu method comprises the steps of providing a Subject expression kemia has improved remarkably over the past four decades, profile of a sample from the subject affected by leukemia, resulting in long-term disease-free Survival of approximately providing a reference expression profile associated with 80 percent (Pui and Evans (1998) N. Engl. J. Med. 339:605 resistance to an antileukemic agent, and determining whether 615 and Pui et al. (2001) Lancet Oncol. 2:597-607. Despite the subject expression profile shares sufficient similarity to this progress, the number of patients with acute lymphoblas the reference expression profile associated with resistance to tic leukemia who are not cured with contemporary therapy the antileukemic agent. The subject affected by leukemia is exceeds the total number of children with newly diagnosed predicted to have an increased risk of relapse if the subject acute myeloid leukemia and most other childhood cancers. expression profile shares sufficient similarity to the reference Patients whose leukemia cells exhibit in vitro resistance to expression profile associated with resistance to the antileuke antileukemic agents have a significantly worse prognosis than mic agent. patients whose acute lymphoblastic leukemia cells are drug 0009. In another embodiment, the invention provides a sensitive (den Boer et al. (2003).J. Clin. Oncol. 21:3262-68; method of selecting a therapy for a subject affected by leuke Kaspers et al. (1997) Blood 90:2723-29; et al. Pieters R. mia. The method comprises the steps of providing a subject (1991) Lancet 338:399-403). expression profile of a sample from the subject affected by 0004 Little is known about the genomic determinants of leukemia, providing a reference expression profile associated leukemia cell resistance to chemotherapy. Such knowledge with resistance to at least one antileukemic agent selected would provide important new insights for overcoming drug from prednisolone, Vincristine, L-asparaginase, and dauno resistance in acute lymphoblastic leukemia. Accordingly, rubicin, and determining whether the Subject expression pro there remains a need for the identification of genes whose file shares sufficient similarity to the reference expression expression is associated with drug resistance in leukemia. profile associated with resistance to the antileukemic agent; where the therapy selected for the subject does not comprise SUMMARY OF THE INVENTION the antileukemic agent if the Subject expression profile shares 0005. The present invention encompasses methods and sufficient similarity to the reference expression profile asso compositions useful in the diagnosis and treatment of drug ciated with resistance to the antileukemic agent. resistant leukemia. The invention provides a number of genes 0010. In a further aspect, the invention provides a method that are differentially expressed between drug resistant and for screening a library of compounds to identify a compound drug sensitive acute lymphoblastic leukemia (ALL). These to improve treatment of drug resistant leukemia. The method genes act as biomarkers for drug resistant leukemia, and comprises the steps of providing a reference expression pro further serve as molecular targets for drugs useful in treating file comprising one or more values representing the expres drug resistant leukemia. sion level of a gene selected from the genes shown in Tables 0006. Accordingly, in one embodiment the invention pro 6A, 6B, 6C, 6D, 7A, 7B, 7C, 7D, 8A, 8B, 8C, 8D,9A,9B, 9C, vides a method of diagnosing drug resistant leukemia in a 9D, 10A, 10B, 11A, 11B, 12A, 12B, 13A, and 13B, providing subject affected by leukemia. The method comprises the steps a cell that is resistant to an antileukemic agent; contacting the of providing a Subject expression profile of a sample from a cell with one or more compounds from the library of com Subject affected by leukemia, providing a reference expres pounds; creating a test expression profile by determining a sion profile associated with resistance to at least one antileu value representing the expression level in the cell of one or kemic agent selected from prednisolone, Vincristine, L-as more of the genes whose expression level is represented in the paraginase, and daunorubicin, and determining whether the reference expression profile, and determining whether the test subject expression profile shares sufficient similarity to the expression profile is distinguishable the reference expression reference expression profile, where the Subject is diagnosed profile.
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