WO2010054045A1 - Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors - Google Patents
Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors Download PDFInfo
- Publication number
- WO2010054045A1 WO2010054045A1 PCT/US2009/063349 US2009063349W WO2010054045A1 WO 2010054045 A1 WO2010054045 A1 WO 2010054045A1 US 2009063349 W US2009063349 W US 2009063349W WO 2010054045 A1 WO2010054045 A1 WO 2010054045A1
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- WIPO (PCT)
- Prior art keywords
- shp1
- cml
- shp2
- imatinib
- treatment
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57426—Specifically defined cancers leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
- C12Q1/42—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving phosphatase
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/916—Hydrolases (3) acting on ester bonds (3.1), e.g. phosphatases (3.1.3), phospholipases C or phospholipases D (3.1.4)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Definitions
- the present invention reiates to a method of treating chronic myeloid Seukemia (CML) in a human patient population.
- CML chronic myeloid Seukemia
- SHP-1 and SHP-2 are two Src homology 2 (SH2) domain-containing tyrosine phosphatases with seversl pathological implications on cell growth regulating signalling. They share significant overall sequence identity. Their biological functions are not well elucidated. SHP-1 is generally considered as a negative signal transducer and SHP-2 as a positive one. SHP-2 has been found widely expressed, while SHP-1 is highly expressed in hematopoietic ceils and, at a iower ievei, in some nonhematopoietic cells.
- SH2 Src homology 2
- SHP-1 and SHP-2 are thought to have important pathologicai implications, Namely, SHP-1 dephosphoryiates receptors of growth factors, cytokines, and antigens, and tyrosine- phosphoryiated proteins associated with these receptors. Therefore, it is often defined as a negative signal transducer.
- SHP-1 dephosphoryiates receptors of growth factors, cytokines, and antigens, and tyrosine- phosphoryiated proteins associated with these receptors. Therefore, it is often defined as a negative signal transducer.
- SHP-1 gene expression is observed in natural killer cell lymphomas as we!! as other types of lymphomas/leukemias.
- Methylation of the SHP-1 promoter causes loss of SHP-1 expression in malignant T-lymphoma cells. Decreased expression level of SHP-1 has been found associated with progression of chronic myeloid leukaemia (CML).
- CML chronic myeloid leukaemia
- Shp1 was shown to be physically associated with
- SHP-2 causes Noonan syndrome, an alsosomai dominant disorder characterized by dysmorphic facial features, proportionate short stature, and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy).
- This gain-of-function mutation of SHP-2 is aiso associated with sporadic juveniie myeiomonocytic leukemia, myeiodyspiasic syndrome, acute iymph ⁇ bSastic leukemia, and acute myelogenous ieukemia.
- SHP-2 has been described as an intracellular target of Helicobacter pylori CagA protein which is associated with gastritis and gastric cancer.
- MMR major molecular response
- the present invention pertains to the use of SHP1 and/or SHP2 as a biomarker for CML patients.
- the invention relates to the use of SHP1 as a bio- marker for CML patients.
- the ieve! of SHP1 and/or SHP2 is indicative for the therapeutic efficacy of imatinib or a pharmaceutically acceptable salt thereof.
- SHP 1 level is defined as relative to the Sevei of AbS.
- SHP2 leveP is defined as relative to the ievel of AbI. Meant is the mRNA leveis of SHP1 and SHP2, respectively, assayed by Q-PCR and expressed as ratio to ABL.
- St may be stated that measurement of SHP1 ievei and SHP2 level, respectively, can for instance be carried out on samples taken from bone marrow or biood, preferably of peripheral blood.
- SHP1 level and SHP2 level, respectively are preferably measured from samples of peripheral biood. The method of determine the level is described below,
- sample means biood or bone marrow sample, preferably peripheral blood sarnpie.
- warm-blooded animal preferably means a human or human patient.
- Patient preferably relates to a human patient.
- imatinib or a pharmaceutically acceptable salt thereof, preferably the mesylate salt.
- the ievei of SHP1 and/or SHP2 in a CML patient can be used for the assessment of the therapeutic amount of imatinib or pharmaceutically acceptable salt thereof, as well as for the additive or substitutive treatment of said patient with nilotinib and/or dasatinib or a pharmaceutically acceptable salt thereof, in particular, a level of SHP1 lower than 3 is indicative for raising the therapeutic amount of imatinib or a pharmaceutically acceptable salt thereof, pre- ferabiy to at least 150% of the standard dosage prescribed for CML patients. Treatment with nilotinib or dasatinib or a pharmaceutically acceptable salt thereof may occur additionally or in substitution of imatinib.
- the low SHP1 level is lower than 3. in further embodiments, the SHP1 level is from 0.01 to 3. In further embodiments, the upper limit of the SHP1 level is 3. 2.8, 2 6, 2.4, 2.2 and 2; and the lower limit of the SHP1 ievei is 0.01 or 0,1. It is understood that ail combinations of upper and Sower limit are comprised by present invention.
- the present invention pertains the use of SHP1 and/or SHP2 as a bio- marker for CML patients for determining the therapeutic efficacy of imatinib or a pharmaceutically acceptable salt thereof.
- present invention relates to an ex vivo method for determining the SHP1 and/or SHP2 level, comprising the steps of a) determining the mRNA level of SHP1 and/or SHP2 from a sample; b ⁇ determining the mRNA level of ABL; c ⁇ normalizing SHP1 and/or SHP2 mRNA to ABL.
- SHP1 level is determined with such ex vivo method. Determination and normalizing is preferably performed with the methods as described in the experimental section below.
- the blood sample is a peripheral blood sample.
- a further aspect of present invention relates to the use of the above ex vivo method for screening CML patients to determine appropriate treatment with imatinib, nilotinib, and/or dasatinib, or a pharmaceutically acceptable sait thereof.
- appropriate treatment in this context means to obtain more efficient treatment of CML, in particular in patients with lower response to imatinib. Lower response to imafinib or its pharmaceutically salts means a SHP1 level Sower than 3.
- “Appropriate treatment” includes increasing therapeutic amount of imatinib or a pharmaceutically acceptable sa!t thereof, additionsl treatment with nilotinib or dasatinib or a pharmaceutically acceptable sait thereof, or substituting imatinib treatment with treatment with nilotinib or dasatinib or a pharmaceutically acceptable sait thereof.
- a further aspect of present invention relates to a diagnostic kit comprising a) means for determining the mRNA ievei of SHP 1 and/or SHP2 from a sample; b) means for determining the mRNA ievei of ABL; c) means for normalizing SHP1 and/or SHP2 mRNA to ABL.
- SHP1 level is determined with such ex vivo method. Determination and normalizing is preferably performed with the methods as described in the experimental section beiow.
- the blood sampie is a peripheral blood sample.
- a further aspect of present invention relates to the use of imatinib, nilotinib, and/or dasatinib, or a pharmaceutically acceptable salt thereof, for the treatment of a CML patient with a SHP1 ievei Sower than about 3.
- a further aspect of present invention relates to the use of imatinib, nilotinib, and/or dasatinib, or a pharmaceutically acceptable sait thereof, for the manufacture of a medicament for the treatment of CML, wherein the SHP1 level of the patient is Sower than about 3,
- a further aspect of present invention relates to a method of treating CiVSL in a warm-bSooded animal comprising the steps of
- Step b) hence comprises either increasing the therapeutic amount of imatinib or a pharmaceutically acceptable sait thereof, additional treatment with niSotinib or dasatinib or a phar- maceutically acceptable salt thereof, or substituting imatinib treatment with treatment with nilotinib or dasatinib or a pharmaceutical Iy acceptable salt thereof.
- the therapeutic amount of dasatinib is in genera! 100 mg/day, that of ⁇ iiotinib is 800 mg/day,
- a further aspect of present invention relates to a method of treating chronic myeloid ie ⁇ ke- mia (CML) in a human patient comprising the steps of
- the present invention pertains to a method of treating GML in a warm ⁇ blooded animal comprising the steps of increasing the daily dose of Imatinib mesylate, nilotinib, or dasatinib to the patient suffering from CML showing a lower SHP2,
- said daily dose of Imatinib mesylate, nilotinib or dasatinib is 150%, 200%, 250% or 300% of the standard dosage prescribed for CML patients.
- the daily dose to be administered to patients having lower SHP1 is between about 800 and 1200 mg of lmatinib mesylate, e.g. 600 mg/day, 800 mg/day, 1000 mg/day or 1200 mg/day.
- Preferred amounts of imatinib mesylate in case of a SHP1 level lower than 3 are 600 mg/day to 1200 mg/day. Further preferred iower limits are 650 mg/day, 700 mg/day, 750 mg/day, 800 mg/day and 850 mg/day, Further preferred upper limits are 1150 mg/day, 1100 mg/day, 1050 mg/day > 1000 mg/day, 950 mg/day and 900 mg/day. It is to be understood that each combination of upper and lower limits are comprised in present invention. in an embodiment, in step (b) a daily dose of lmatinib mesylate is administered orally,
- lmatinib is generically and specifically disclosed in the patent applications US 5,521 ,184. in particular in Example 21, the subject-matter of which is hereby incorporated into the present application by reference, lmatinib can also be prepared in accordance with the processes disclosed in WO03/066613.
- lmatinib is preferably applied in the form of its mono-mesylate salt
- imatinib mono-mesylate can be prepared in accordance with the processes disclosed in US 6,894,051 the subject-matter of which is hereby incorporated into the present application by reference. Comprised are likewise the corresponding polymorphs, e.g. crystal modifications, which are disclosed therein.
- Niiotinib is for instance disclosed in WO2004005281 , example 92, the subject-matter of which is hereby incorporated into the present application by reference.
- Dasatinib is for instance disclosed in WO 00/62778,
- the collecting of a blood sample from CML patients can be accomplished by standard pro ⁇ cedures being state of the art.
- the Q-PCR is performed as below:
- RNAsin Pharmacia, Upsala, Swe ⁇ d ⁇ n
- 25 mM random examers Pharmacia
- 10 mM of DTT Pharmacia
- 100 U of MoMLV reverse transcriptase Invitr ⁇ gen Ltd ⁇ , PCR amplification of SHP- 1 and SHP-2 encoding cDNAs were separately carried out in a reaction mixture consisting of 1 x Master Mix (Applied BioSystem, Foster City, CA USA), 300 nM
- Gain-of-function mutations have been described in various hemopoietic neoplasias including Juvenile Chronic Myeio- monocytic Leukemia.
- oncogenic Bcr/Abl protein activates Shp2 through Gab2, an adaptor protein that, once phosphoryiated is abie to bind SH2 domain of Shp2.
- Shp2 is aiso a signal transducer of growth factor receptor.
- Shp1 through dephosphoryiation. might modulate the activity of Shp2 and constitute an important mechanism of Ima resistance.
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Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/126,683 US20110312968A1 (en) | 2008-11-07 | 2009-11-05 | Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors |
JP2011535659A JP2012508019A (en) | 2008-11-07 | 2009-11-05 | Method for optimizing treatment of chronic myeloid leukemia with AbI tyrosine kinase inhibitors |
CA2742512A CA2742512A1 (en) | 2008-11-07 | 2009-11-05 | Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors |
CN2009801436852A CN102203294A (en) | 2008-11-07 | 2009-11-05 | Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors |
BRPI0921276A BRPI0921276A2 (en) | 2008-11-07 | 2009-11-05 | method for optimizing treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors |
MX2011004858A MX2011004858A (en) | 2008-11-07 | 2009-11-05 | Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors. |
EP09756880A EP2356254A1 (en) | 2008-11-07 | 2009-11-05 | Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors |
RU2011122721/10A RU2011122721A (en) | 2008-11-07 | 2009-11-05 | METHOD FOR OPTIMIZING TREATMENT OF CHRONIC MYELOLEukOSIS BY ABL TYROSINKASE INHIBITORS |
AU2009313504A AU2009313504A1 (en) | 2008-11-07 | 2009-11-05 | Method for optimizing the treatment of chronic myeloid leukemia with ABL tyrosine kinase inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11222108P | 2008-11-07 | 2008-11-07 | |
US61/112,221 | 2008-11-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010054045A1 true WO2010054045A1 (en) | 2010-05-14 |
Family
ID=41723012
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2009/063349 WO2010054045A1 (en) | 2008-11-07 | 2009-11-05 | Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors |
Country Status (11)
Country | Link |
---|---|
US (1) | US20110312968A1 (en) |
EP (1) | EP2356254A1 (en) |
JP (1) | JP2012508019A (en) |
KR (1) | KR20110095878A (en) |
CN (1) | CN102203294A (en) |
AU (1) | AU2009313504A1 (en) |
BR (1) | BRPI0921276A2 (en) |
CA (1) | CA2742512A1 (en) |
MX (1) | MX2011004858A (en) |
RU (1) | RU2011122721A (en) |
WO (1) | WO2010054045A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103063850B (en) * | 2013-01-08 | 2014-12-31 | 中国人民解放军第二军医大学 | Application of Shp2 protein in preparation of liver cancer prognosis evaluation kit |
RU2693815C1 (en) * | 2018-07-04 | 2019-07-04 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Самарский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Method for managing patients with chronic myeloid leukemia in prescribing tyrosine kinase inhibitors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050164196A1 (en) * | 2002-04-17 | 2005-07-28 | Dressman Marlene M. | Methods to predict patient responsiveness to tyrosine kinase inhibitors |
-
2009
- 2009-11-05 JP JP2011535659A patent/JP2012508019A/en active Pending
- 2009-11-05 MX MX2011004858A patent/MX2011004858A/en not_active Application Discontinuation
- 2009-11-05 BR BRPI0921276A patent/BRPI0921276A2/en not_active IP Right Cessation
- 2009-11-05 WO PCT/US2009/063349 patent/WO2010054045A1/en active Application Filing
- 2009-11-05 CN CN2009801436852A patent/CN102203294A/en active Pending
- 2009-11-05 AU AU2009313504A patent/AU2009313504A1/en not_active Abandoned
- 2009-11-05 US US13/126,683 patent/US20110312968A1/en not_active Abandoned
- 2009-11-05 CA CA2742512A patent/CA2742512A1/en not_active Abandoned
- 2009-11-05 EP EP09756880A patent/EP2356254A1/en not_active Withdrawn
- 2009-11-05 KR KR1020117012760A patent/KR20110095878A/en not_active Application Discontinuation
- 2009-11-05 RU RU2011122721/10A patent/RU2011122721A/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050164196A1 (en) * | 2002-04-17 | 2005-07-28 | Dressman Marlene M. | Methods to predict patient responsiveness to tyrosine kinase inhibitors |
Non-Patent Citations (11)
Title |
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"[HG-U133A] Affymetrix Human Genome U133A Array", GEO,, 11 March 2002 (2002-03-11), XP002527544 * |
AMIN H M ET AL: "Decreased expression level of SH2 domain-containing protein tyrosine phosphatase-I (ShpI) is associated with progression of chronic myeloid leukaemia", JOURNAL OF PATHOLOGY, vol. 212, no. 4, August 2007 (2007-08-01), pages 402 - 410, XP002572701, ISSN: 0022-3417 * |
ANONYMOUS: "SHC1", INTERNET ARTICLE, 11 January 2010 (2010-01-11), XP002572705, Retrieved from the Internet <URL:http://www.genecards.org/cgi-bin/carddisp.pl?gene=SHC1&search=shc1> [retrieved on 20100310] * |
ANONYMOUS: "SHC2", INTERNET ARTICLE, 11 January 2010 (2010-01-11), XP002572706, Retrieved from the Internet <URL:http://www.genecards.org/cgi-bin/carddisp.pl?gene=SHC2&search=shc2> [retrieved on 20100310] * |
DONATO NICHOLAS J ET AL: "Src kinases and tyrosine phosphatases as regulators of imatinib mesylate sensitivity in chronic melogenous leukemia.", BLOOD, vol. 102, no. 11, 16 November 2003 (2003-11-16), 45TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY; SAN DIEGO, CA, USA; DECEMBER 06-09, 2003, pages 598A, XP009130773, ISSN: 0006-4971 * |
ESPOSITO NICOLA ET AL: "A decreased Level of Shp1 provides an additive survival advantage to the Ph plus Cells of CML Patients and may account for Resistance to Imatinib Treatment", BLOOD, vol. 112, no. 11, 16 November 2008 (2008-11-16), 50TH ANNUAL MEETING OF THE AMERICAN- SOCIETY-OF-HEMATOLOGY; SAN FRANCISCO, CA, USA; DECEMBER 06 -09, 2008, pages 1093, XP002572703, ISSN: 0006-4971 * |
ESPOSITO NICOLA ET AL: "Down-modulation of shp1 and hsp70 provides a survival advantage to the ph plus cells of CML patients additive to that related to the oncogenic BCR/ABL protein and may account for resistance to Ima treatment", BLOOD, vol. 110, no. 11, Part 1, November 2007 (2007-11-01), 49TH ANNUAL MEETING OF THE AMERICAN-SOCIETY-OF-HEMATOLOGY; ATLANTA, GA, USA; DECEMBER 08 -11, 2007, pages 307A, XP002572700, ISSN: 0006-4971 * |
ESPOSITO NICOLA ET AL: "The Expression of shp-1 and SHP-2: A Novel Powerful Predictor of Major Molecular Response (MMR) Achievement in Chronic Myeloid Leukemia Gleevec-Treated Patients Enrolled into the TOPS Clinical Trial", BLOOD, vol. 112, no. 11, 16 November 2008 (2008-11-16), 50TH ANNUAL MEETING OF THE AMERICAN- SOCIETY-OF-HEMATOLOGY; SAN FRANCISCO, CA, USA; DECEMBER 06 -09, 2008, pages 404, XP002572704, ISSN: 0006-4971 * |
OKABE SEIICHI ET AL: "Mechanism of drug resistance to dasatinib (BMS-354825) and imatinib in chronic myelogenous leukemia cells.", BLOOD, vol. 108, no. 11, Part 1, November 2006 (2006-11-01), 48TH ANNUAL MEETING OF THE AMERICAN-SOCIETY-OF-HEMATOLOGY; ORLANDO, FL, USA; DECEMBER 09 -12, 2006, pages 404A, XP002572702, ISSN: 0006-4971 * |
RAMIREZ P ET AL: "Therapy options in imatinib failures", ONCOLOGIST, ALPHAMED PRESS, US, vol. 13, no. 4, 1 April 2008 (2008-04-01), pages 424 - 434, XP008097601, ISSN: 1083-7159 * |
See also references of EP2356254A1 * |
Also Published As
Publication number | Publication date |
---|---|
KR20110095878A (en) | 2011-08-25 |
JP2012508019A (en) | 2012-04-05 |
AU2009313504A1 (en) | 2010-05-14 |
EP2356254A1 (en) | 2011-08-17 |
MX2011004858A (en) | 2011-05-31 |
RU2011122721A (en) | 2012-12-20 |
US20110312968A1 (en) | 2011-12-22 |
CA2742512A1 (en) | 2010-05-14 |
CN102203294A (en) | 2011-09-28 |
BRPI0921276A2 (en) | 2016-03-08 |
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