Brian J Druker

Publications (150)1637.58 Total impact

• Article: Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies.

  Joseph M Gozgit, Matthew J Wong, Scott Wardwell, Jeffrey W Tyner, Marc M Loriaux, Qurish K Mohemmad, Narayana I Narasimhan, William C Shakespeare, Frank Wang, Brian J Druker, Tim Clackson, Victor M Rivera
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  ABSTRACT: Ponatinib (AP24534) is a novel multitargeted kinase inhibitor that potently inhibits native and mutant BCR-ABL at clinically achievable drug levels. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). Here, using leukemic cell lines containing activated forms of each of these receptors, we show that ponatinib potently inhibits receptor phosphorylation and cellular proliferation with IC50 values comparable to those required for inhibition of BCR-ABL (0.3 to 20 nmol/L). The activity of ponatinib against the FLT3-ITD mutant, found in up to 30% of acute myeloid leukemia (AML) patients, was particularly notable. In MV4-11 (FLT3-ITD(+/+)) but not RS4;11 (FLT3-ITD(-/-)) AML cells, ponatinib inhibited FLT3 signaling and induced apoptosis at concentrations of less than 10 nmol/L. In an MV4-11 mouse xenograft model, once daily oral dosing of ponatinib led to a dose-dependent inhibition of signaling and tumor regression. Ponatinib inhibited viability of primary leukemic blasts from a FLT3-ITD positive AML patient (IC50 4 nmol/L) but not those isolated from 3 patients with AML expressing native FLT3. Overall, these results support the investigation of ponatinib in patients with FLT3-ITD-driven AML and other hematologic malignancies driven by KIT, FGFR1, or PDGFRα.
  Molecular Cancer Therapeutics 06/2011; 10(6):1028-35. · 5.23 Impact Factor
• Article: The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile.

  Christopher A Eide, Lauren T Adrian, Jeffrey W Tyner, Mary Mac Partlin, David J Anderson, Scott C Wise, Bryan D Smith, Peter A Petillo, Daniel L Flynn, Michael W N Deininger, Thomas O'Hare, Brian J Druker
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  ABSTRACT: Acquired point mutations within the BCR-ABL kinase domain represent a common mechanism of resistance to ABL inhibitor therapy in patients with chronic myeloid leukemia (CML). The BCR-ABL(T315I) mutant is highly resistant to imatinib, nilotinib, and dasatinib, and is frequently detected in relapsed patients. This critical gap in resistance coverage drove development of DCC-2036, an ABL inhibitor that binds the switch control pocket involved in conformational regulation of the kinase domain. We evaluated the efficacy of DCC-2036 against BCR-ABL(T315I) and other mutants in cellular and biochemical assays and conducted cell-based mutagenesis screens. DCC-2036 inhibited autophosphorylation of ABL and ABL(T315I) enzymes, and this activity was consistent with selective efficacy against Ba/F3 cells expressing BCR-ABL (IC(50): 19 nmol/L), BCR-ABL(T315I) (IC(50): 63 nmol/L), and most kinase domain mutants. Ex vivo exposure of CML cells from patients harboring BCR-ABL or BCR-ABL(T315I) to DCC-2036 revealed marked inhibition of colony formation and reduced phosphorylation of the direct BCR-ABL target CrkL. Cell-based mutagenesis screens identified a resistance profile for DCC-2036 centered around select P-loop mutations (G250E, Q252H, Y253H, E255K/V), although a concentration of 750 nmol/L DCC-2036 suppressed the emergence of all resistant clones. A decreased concentration of DCC-2036 (160 nmol/L) in dual combination with either nilotinib or dasatinib achieved the same zero outgrowth result. Further screens for resistance due to BCR-ABL compound mutations (two mutations in the same clone) identified BCR-ABL(E255V / T315I) as the most resistant mutant. Taken together, these findings support continued evaluation of DCC-2036 as an important new agent for treatment-refractory CML.
  Cancer Research 05/2011; 71(9):3189-95. · 7.86 Impact Factor
• Source

  Available from: Sean A Beausoleil

  Article: Survey of activated FLT3 signaling in leukemia.

  Ting-lei Gu, Julie Nardone, Yi Wang, Marc Loriaux, Judit Villén, Sean Beausoleil, Meghan Tucker, Jon Kornhauser, Jianmin Ren, Joan MacNeill, Steven P Gygi, Brian J Druker, Michael C Heinrich, John Rush, Roberto D Polakiewicz
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  ABSTRACT: Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3) and B cell acute lymphoblastic leukemia (normal and amplification of FLT3) cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC), we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr) that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia.
  PLoS ONE 01/2011; 6(4):e19169. · 4.09 Impact Factor
• Article: Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia.

  Thomas O'Hare, Michael W N Deininger, Christopher A Eide, Tim Clackson, Brian J Druker
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  ABSTRACT: Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABL(T315I). A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABL(T315I). The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABL(T315I) mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABL(T315I) in the development pipeline.
  Clinical Cancer Research 01/2011; 17(2):212-21. · 7.74 Impact Factor
• Article: Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity.

  Amie S Corbin, Anupriya Agarwal, Marc Loriaux, Jorge Cortes, Michael W Deininger, Brian J Druker
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  ABSTRACT: Imatinib therapy, which targets the oncogene product BCR-ABL, has transformed chronic myeloid leukemia (CML) from a life-threatening disease into a chronic condition. Most patients, however, harbor residual leukemia cells, and disease recurrence usually occurs when imatinib is discontinued. Although various mechanisms to explain leukemia cell persistence have been proposed, the critical question from a therapeutic standpoint--whether disease persistence is BCR-ABL dependent or independent--has not been answered. Here, we report that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy. Imatinib inhibited BCR-ABL activity to the same degree in all stem (CD34+CD38-, CD133+) and progenitor (CD34+CD38+) cells and in quiescent and cycling progenitors from newly diagnosed CML patients. Although short-term in vitro imatinib treatment reduced the expansion of CML stem/progenitors, cytokine support permitted growth and survival in the absence of BCR-ABL activity that was comparable to that of normal stem/progenitor counterparts. Our findings suggest that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR-ABL will not eliminate CML stem cells.
  The Journal of clinical investigation 01/2011; 121(1):396-409. · 15.39 Impact Factor
• Article: Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS).

  Timothy P Hughes, Andreas Hochhaus, Susan Branford, Martin C Müller, Jaspal S Kaeda, Letizia Foroni, Brian J Druker, François Guilhot, Richard A Larson, Stephen G O'Brien, Marc S Rudoltz, Manisha Mone, Elisabeth Wehrle, Vijay Modur, John M Goldman, Jerald P Radich
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  ABSTRACT: This study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients enrolled in the International Randomized Study of Interferon and STI571 (IRIS). Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time. Analyses of event-free survival (EFS) and time to progression to accelerated phase/blast crisis (AP/BC) at 7 years were based on molecular responses using the international scale (IS) at 6-, 12-, and 18-month landmarks. Patients with BCR-ABL transcripts > 10% at 6 months and > 1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response [MMR: BCR-ABL (IS) ≤ 0.1%] by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years. The probability of loss of complete cytogenetic response by 7 years was only 3% for patients in MMR at 18 months versus 26% for patients with complete cytogenetic response but not MMR (P < .001). This study shows a strong association between the degree to which BCR-ABL transcript numbers are reduced by therapy and long-term clinical outcome, supporting the use of time-dependent molecular measures to determine optimal response to therapy. This study is registered at www.clinicaltrials.gov as NCT00006343.
  Blood 11/2010; 116(19):3758-65. · 9.90 Impact Factor
• Article: BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib.

  Daniel W Sherbenou, Oliver Hantschel, Ines Kaupe, Stephanie Willis, Thomas Bumm, Lalita P Turaga, Thoralf Lange, Kim-Hien Dao, Richard D Press, Brian J Druker, Giulio Superti-Furga, Michael W Deininger
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  ABSTRACT: Point mutations in the kinase domain of BCR-ABL are the most common mechanism of drug resistance in chronic myeloid leukemia (CML) patients treated with ABL kinase inhibitors, including imatinib. It has also been shown in vitro that mutations outside the kinase domain in the neighboring linker, SH2, SH3, and Cap domains can confer imatinib resistance. In the context of ABL, these domains have an autoinhibitory effect on kinase activity, and mutations in this region can activate the enzyme. To determine the frequency and relevance to resistance of regulatory domain mutations in CML patients on imatinib, we screened for such mutations in a cohort of consecutive CML patients with various levels of response. Regulatory domain mutations were detected in 7 of 98 patients, whereas kinase domain mutations were detected in 29. One mutation (T212R) conferred in vitro tyrosine kinase inhibitor resistance and was associated with relapse, whereas most other mutations did not affect drug sensitivity. Mechanistic studies showed that T212R increased the activity of ABL and BCR-ABL and that T212R-induced resistance may be partially the result of stabilization of an active kinase conformation. Regulatory domain mutations are uncommon but may explain resistance in some patients without mutations in the kinase domain.
  Blood 10/2010; 116(17):3278-85. · 9.90 Impact Factor
• Article: CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability.

  Brian J Lannutti, Sarah A Meadows, Sarah E M Herman, Adam Kashishian, Bart Steiner, Amy J Johnson, John C Byrd, Jeffrey W Tyner, Marc M Loriaux, Mike Deininger, Brian J Druker, Kamal D Puri, Roger G Ulrich, Neill A Giese
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  ABSTRACT: Phosphatidylinositol-3-kinase p110δ serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ as a treatment approach for patients with B-cell malignancies. We thus identified 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one (CAL-101), a highly selective and potent p110δ small molecule inhibitor (half-maximal effective concentration [EC(50)] = 8nM). Using tumor cell lines and primary patient samples representing multiple B-cell malignancies, we have demonstrated that constitutive phosphatidylinositol-3-kinase pathway activation is p110δ-dependent. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies, thereby providing a rationale for the ongoing clinical evaluation of CAL-101.
  Blood 10/2010; 117(2):591-4. · 9.90 Impact Factor
• Article: A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors.

  Ji-Heui Seo, Lisa J Wood, Anupriya Agarwal, Thomas O'Hare, Collin R Elsea, Ian J Griswold, Michael W N Deininger, Akira Imamoto, Brian J Druker
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  ABSTRACT: CRKL (CRK-like) is an adapter protein predominantly phosphorylated in cells that express the tyrosine kinase p210(BCR-ABL), the fusion product of a (9;22) chromosomal translocation causative for chronic myeloid leukemia. It has been unclear, however, whether CRKL plays a functional role in p210(BCR-ABL) transformation. Here, we show that CRKL is required for p210(BCR-ABL) to support interleukin-3-independent growth of myeloid progenitor cells and long-term outgrowth of B-lymphoid cells from fetal liver-derived hematopoietic progenitor cells. Furthermore, a synthetic phosphotyrosyl peptide that binds to the CRKL SH2 domain with high affinity blocks association of endogenous CRKL with the p210(BCR-ABL) complex and reduces c-MYC levels in K562 human leukemic cells as well as in mouse hematopoietic cells transformed by p210(BCR-ABL) or the imatinib-resistant mutant T315I. These results indicate that the function of CRKL as an adapter protein is essential for p210(BCR-ABL)-induced transformation.
  Cancer Research 09/2010; 70(18):7325-35. · 7.86 Impact Factor
• Article: MET receptor sequence variants R970C and T992I lack transforming capacity.

  Jeffrey W Tyner, Luke B Fletcher, Ellen Q Wang, Wayne F Yang, Michael L Rutenberg-Schoenberg, Carol Beadling, Motomi Mori, Michael C Heinrich, Michael W Deininger, Brian J Druker, Marc M Loriaux
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  ABSTRACT: High-throughput sequencing promises to accelerate the discovery of sequence variants, but distinguishing oncogenic mutations from irrelevant "passenger" mutations remains a major challenge. Here we present an analysis of two sequence variants of the MET receptor (hepatocyte growth factor receptor) R970C and T992I (also designated R988C and T1010I). Previous reports indicated that these sequence variants are transforming and contribute to oncogenesis. We screened patients with chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, thyroid cancer, or melanoma, as well as individuals without cancer, and found these variants at low frequencies in most cohorts, including normal individuals. No evidence of increased phosphorylation or transformative capacity by either sequence variant was found. Because small-molecule inhibitors for MET are currently in development, it will be important to distinguish between oncogenic sequence variants and rare single-nucleotide polymorphisms to avoid the use of unnecessary, and potentially toxic, cancer therapy agents.
  Cancer Research 08/2010; 70(15):6233-7. · 7.86 Impact Factor
• Article: Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl.

  Mark A Gregory, Tzu L Phang, Paolo Neviani, Francesca Alvarez-Calderon, Christopher A Eide, Thomas O'Hare, Vadym Zaberezhnyy, Richard T Williams, Brian J Druker, Danilo Perrotti, James Degregori
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  ABSTRACT: Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to eradicate Bcr-Abl(+) leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl(+) leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib mesylate in CML cells. This screen identified numerous components of a Wnt/Ca(2+)/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production, and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl(+) acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl(+) leukemias.
  Cancer cell 07/2010; 18(1):74-87. · 25.29 Impact Factor
• Article: Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells.

  Nathalie Carayol, Eliza Vakana, Antonella Sassano, Surinder Kaur, Dennis J Goussetis, Heather Glaser, Brian J Druker, Nicholas J Donato, Jessica K Altman, Sharon Barr, Leonidas C Platanias
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  ABSTRACT: mTOR-generated signals play critical roles in growth of leukemic cells by controlling mRNA translation of genes that promote mitogenic responses. Despite extensive work on the functional relevance of rapamycin-sensitive mTORC1 complexes, much less is known on the roles of rapamycin-insensitive (RI) complexes, including mTORC2 and RI-mTORC1, in BCR-ABL-leukemogenesis. We provide evidence for the presence of mTORC2 complexes in BCR-ABL-transformed cells and identify phosphorylation of 4E-BP1 on Thr37/46 and Ser65 as RI-mTORC1 signals in primary chronic myelogenous leukemia (CML) cells. Our studies establish that a unique dual mTORC2/mTORC1 inhibitor, OSI-027, induces potent suppressive effects on primitive leukemic progenitors from CML patients and generates antileukemic responses in cells expressing the T315I-BCR-ABL mutation, which is refractory to all BCR-ABL kinase inhibitors currently in clinical use. Induction of apoptosis by OSI-027 appears to negatively correlate with induction of autophagy in some types of BCR-ABL transformed cells, as shown by the induction of autophagy during OSI-027-treatment and the potentiation of apoptosis by concomitant inhibition of such autophagy. Altogether, our studies establish critical roles for mTORC2 and RI-mTORC1 complexes in survival and growth of BCR-ABL cells and suggest that dual therapeutic targeting of such complexes may provide an approach to overcome leukemic cell resistance in CML and Ph+ ALL.
  Proceedings of the National Academy of Sciences 07/2010; 107(28):12469-74. · 9.68 Impact Factor
• Article: Erratum: Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase.

  Hagop M Kantarjian, Richard A Larson, Francois Guilhot, Stephen G O'Brien, Manisha Mone, Marc Rudoltz, Tillmann Krahnke, Jorge Cortes, Brian J Druker
  Cancer 04/2010; · 4.77 Impact Factor
• Article: CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms.

  Jeffrey W Tyner, Thomas G Bumm, Jutta Deininger, Lisa Wood, Karl J Aichberger, Marc M Loriaux, Brian J Druker, Christopher J Burns, Emmanuelle Fantino, Michael W Deininger
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  ABSTRACT: Activating alleles of Janus kinase 2 (JAK2) such as JAK2(V617F) are central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5muM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2(V617F) allele burden, JAK2(V617F) cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2(V617F) cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells.
  Blood 04/2010; 115(25):5232-40. · 9.90 Impact Factor
• Article: Preliminary Evidence of Increased Pain and Elevated Cytokines in Fibromyalgia Patients with Defective Growth Hormone Response to Exercise.

  Rebecca L Ross, Kim D Jones, Robert M Bennett, Rachel L Ward, Brian J Druker, Lisa J Wood
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  ABSTRACT: Mounting evidence suggests fibromyalgia (FM) symptoms are influenced by dysfunction of the hypothalamic-pituitary-hormonal axes (HPHA) and the immune response system. The predominant FM symptoms of widespread pain, fatigue, sleep disturbance, depression, stiffness and exercise intolerance are related to abnormal levels of growth hormone (GH) and are reminiscent of "sickness behavior"; a syndrome initiated by the production of pro-inflammatory cytokines in response to various stressors. Cognizant of the reciprocal relationship between HPHA activity and the immune response system, we hypothesized that serum cytokine levels and FM symptom severity would be higher in FM patients with defective growth hormone response to exhaustive exercise compared to those without. Outpatients with FM (n = 165) underwent a Modified Balke Treadmill Protocol and GH response to exhaustive exercise was measured in peripheral blood samples. Levels of IL-1α, IL-1β, IL-1RA, IL-6, IL-8, IL-10, and TNF-α were measured from stored serum on a subset of 24 participants (12 with and 12 without normal GH response to exhaustive exercise). FM symptom severity was assessed using the Fibromyalgia Impact Questionnaire (FIQ), number of tender points and cumulative myalgic scores. GH dysfunction was associated with increased pain scores on the FIQ (p = 0.024), a greater number of tender points (p = 0.014), higher myalgic scores (p = 0.001) and higher pre-exercise levels of inflammatory cytokines IL-1α (p = 0.021), IL-6 (p = 0.012), and IL-8 (p = 0.004). These results suggest that a defective growth hormone response to exercise may be associated with increased levels of blood cytokines and pain severity in FM patients.
  The Open Immunology Journal 01/2010; 3:9-18.
• Article: Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study.

  Jorge E Cortes, Michele Baccarani, François Guilhot, Brian J Druker, Susan Branford, Dong-Wook Kim, Fabrizio Pane, Ricardo Pasquini, Stuart L Goldberg, Matt Kalaycio, Beatriz Moiraghi, Jacob M Rowe, Elena Tothova, Carmino De Souza, Marc Rudoltz, Richard Yu, Tillmann Krahnke, Hagop M Kantarjian, Jerald P Radich, Timothy P Hughes
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  ABSTRACT: To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.
  Journal of Clinical Oncology 12/2009; 28(3):424-30. · 18.37 Impact Factor
• Article: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.

  Thomas O'Hare, William C Shakespeare, Xiaotian Zhu, Christopher A Eide, Victor M Rivera, Frank Wang, Lauren T Adrian, Tianjun Zhou, Wei-Sheng Huang, Qihong Xu, [......], Raji Sundaramoorthi, Mathew Thomas, Dong Zhou, Joseph Snodgrass, Lois Commodore, Tomi K Sawyer, David C Dalgarno, Michael W N Deininger, Brian J Druker, Tim Clackson
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  ABSTRACT: Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL(T315I) mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL(T315I)-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.
  Cancer cell 11/2009; 16(5):401-12. · 25.29 Impact Factor
• Article: A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib.

  Shannon K McWeeney, Lucy C Pemberton, Marc M Loriaux, Kristina Vartanian, Stephanie G Willis, Gregory Yochum, Beth Wilmot, Yaron Turpaz, Raji Pillai, Brian J Druker, Jennifer L Snead, Mary MacPartlin, Stephen G O'Brien, Junia V Melo, Thoralf Lange, Christina A Harrington, Michael W N Deininger
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  ABSTRACT: In chronic-phase chronic myeloid leukemia (CML) patients, the lack of a major cytogenetic response (< 36% Ph(+) metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure, we performed gene expression array profiling of CD34(+) cells from 2 independent cohorts of imatinib-naive chronic-phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response or more than 65% Ph(+) metaphases within 12 months of imatinib therapy. Based on analysis of variance P less than .1 and fold difference 1.5 or more, we identified 885 probe sets with differential expression between responders and nonresponders, from which we extracted a 75-probe set minimal signature (classifier) that separated the 2 groups. On application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of nonresponders. Bioinformatics analysis and comparison with published studies revealed overlap of classifier genes with CML progression signatures and implicated beta-catenin in their regulation, suggesting that chronic-phase CML patients destined to fail imatinib have more advanced disease than evident by morphologic criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit while sparing good-risk patients from unnecessary toxicity.
  Blood 10/2009; 115(2):315-25. · 9.90 Impact Factor
• Source

  Available from: laskerfoundation.org

  Article: Perspectives on the development of imatinib and the future of cancer research.

  Brian J Druker
  Nature medicine 10/2009; 15(10):1149-52. · 27.14 Impact Factor
• Source

  Available from: hematologylibrary.org

  Article: Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis.

  Jennifer L Snead, Thomas O'Hare, Lauren T Adrian, Christopher A Eide, Thoralf Lange, Brian J Druker, Michael W Deininger
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  ABSTRACT: Pioneering work with the Bcr-Abl inhibitor, imatinib, demonstrated a requirement for constant Bcr-Abl inhibition to achieve maximal therapeutic benefit in treating chronic myeloid leukemia (CML), establishing a paradigm that has guided further drug development for this disease. Surprisingly, the second-generation Bcr-Abl inhibitor, dasatinib, was reported to be clinically effective with once-daily dosing, despite a short (3- to 5-hour) plasma half-life. Consistent with this observation, dasatinib treatment of progenitor cells from chronic-phase CML patients for 4 hours, followed by washout, or continuously for 72 hours both resulted in an induction of apoptosis and a reduction in the number of clonogenic cells. Such acute treatments with clinically achievable dasatinib concentrations also irreversibly committed Bcr-Abl+ CML cell lines to apoptotic cell death. Potent transient Bcr-Abl inhibition using the alternative inhibitor, nilotinib, also resulted in cell death. These findings demonstrate that in vitro assays designed to model in vivo pharmacokinetics can predict clinical efficacy. Furthermore, they challenge the widely held notion that continuous target inhibition is required for optimal efficacy of kinase inhibitors.
  Blood 09/2009; 114(16):3459-63. · 9.90 Impact Factor