ORCID Profile
0000-0001-8331-8206
Current Organisations
Oregon Health & Science University
,
University of California, San Diego
,
OHSU Knight Cancer Institute
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Publisher: Proceedings of the National Academy of Sciences
Date: 16-10-2017
Abstract: Many therapeutic strategies are h ered by the development of drug resistance. High-throughput random mutagenesis screens represent a promising approach for identifying mutations that lead to drug resistance, but have often identified more resistant mutations than are observed in patients, raising questions of their clinical significance. We developed an improved high-throughput mutagenesis screening approach that uses CRISPR-Cas9–based genome editing to generate comprehensive libraries of point mutations at a defined genomic location and systematically study their effect on cell growth. As proof-of-concept, we show our approach accurately predicts the clinical prevalence of drug-resistant mutations in the oncogene BCR-ABL . Our approach can be broadly applied to a variety of oncogenes and represents a new strategy for evaluating resistance susceptibility during drug development.
Publisher: Springer Science and Business Media LLC
Date: 23-03-2014
DOI: 10.1007/S12185-014-1566-2
Abstract: The TOPS trial evaluated high- (800 mg/day n = 319) versus standard-dose (400 mg/day n = 157) imatinib in patients newly diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. Patients had a minimum follow-up of 42 months or discontinued early. Major molecular response (MMR) rates were similar between arms at (51.6 vs 50.2 % for 400 and 800 mg/day, respectively P = 0.77) and by (75.8 vs 79.0 % P = 0.4807) 42 months. There were no differences in event-free survival (EFS), progression-free survival(PFS), or overall survival (OS) between arms. The estimated rates of PFS on treatment and OS at 42 months were significantly higher in patients with MMR at 6, 12, and 18 months compared with those without MMR.Adverse events were more frequent with high-dose imatinib. Patients with B1 treatment interruption (vs [1) and those able to maintain imatinib C600 mg/day (vs\\600 mg/day) in the first year of treatment had faster and higher response rates, but no improvement in EFS or PFS. Adherence to prescribed dose without interruption may be more important than initiation of therapy with higher doses of imatinib. Achievement of MMR correlated with longterm clinical outcomes.
Publisher: American Society of Hematology
Date: 15-01-2015
DOI: 10.1182/BLOOD-2014-06-581173
Abstract: CML patients with advanced-phase myeloid disease frequently show decreased IKAROS protein in primitive cells. Expression of a dominant-negative IKAROS isoform expands primitive human CML cells and enhances their differentiation into basophils.
Publisher: American Society of Hematology
Date: 24-06-2010
DOI: 10.1182/BLOOD-2009-05-223727
Abstract: Activating alleles of Janus kinase 2 (JAK2) such as JAK2V617F 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 1.5μM 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 JAK2V617F allele burden, JAK2V617F cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2V617F 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.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-01-2010
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.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 07-02-2012
Publisher: Proceedings of the National Academy of Sciences
Date: 31-10-2006
Publisher: Springer Science and Business Media LLC
Date: 22-04-2015
Publisher: Massachusetts Medical Society
Date: 09-03-2017
Publisher: Proceedings of the National Academy of Sciences
Date: 03-10-2006
Abstract: Cell killing is a critical pharmacological activity of imatinib to eradicate Bcr/Abl + leukemias. We found that imatinib kills Bcr/Abl + leukemic cells by triggering the Bcl-2-regulated apoptotic pathway. Imatinib activated several proapoptotic BH3-only proteins: bim and bmf transcription was increased, and both Bim and Bad were activated posttranslationally. Studies using RNAi and cells from gene-targeted mice revealed that Bim plays a major role in imatinib-induced apoptosis of Bcr/Abl + leukemic cells and that the combined loss of Bim and Bad abrogates this killing. Loss of Bmf or Puma had no effect. Resistance to imatinib caused by Bcl-2 overexpression or loss of Bim (plus Bad) could be overcome by cotreatment with the BH3 mimetic ABT-737. These results demonstrate that Bim and Bad account for most, perhaps all, imatinib-induced killing of Bcr/Abl + leukemic cells and suggest previously undescribed drug combination strategies for cancer therapy.
Publisher: American Society of Hematology
Date: 03-12-2009
DOI: 10.1182/BLOOD-2009-04-214221
Abstract: Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC50) greater than 3nM among patients with mutations with lower or unknown IC50, efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844.
Publisher: American Society of Hematology
Date: 11-11-2010
DOI: 10.1182/BLOOD-2010-03-273979
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.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2005
Publisher: Springer Science and Business Media LLC
Date: 05-2010
DOI: 10.1038/LEU.2010.71
Publisher: Elsevier BV
Date: 2000
Publisher: American Society of Hematology
Date: 30-05-2013
DOI: 10.1182/BLOOD-2013-03-490003
Abstract: As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing and their impact on in idual patients and health care policies, and argues for the need to (1) lower the prices of cancer drugs to allow more patients to afford them and (2) maintain sound long-term health care policies.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2019
Publisher: Springer Science and Business Media LLC
Date: 12-03-2009
DOI: 10.1038/LEU.2009.38
Abstract: Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82% 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
Publisher: Elsevier BV
Date: 12-1998
Location: United States of America
Location: United States of America
No related grants have been discovered for Brian Druker.