Anneke D van Dijk1, Fieke W Hoff1,2, Yihua Qiu3, Robert B Gerbing4, Alan S Gamis5, Richard Aplenc6, E Anders Kolb7, Todd A Alonzo8, Soheil Meshinchi9, Gaye N Jenkins10, Eveline S J M de Bont1, Steven M Kornblau3, Terzah M Horton10. 1. Department of Pediatrics, University Medical Center Groningen, University of Groningen, Divison of Pediatric Oncology/Hematology, Groningen, The Netherlands. 2. Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA. 3. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. 4. COG Statistics and Data Center, Monrovia, California, USA. 5. Department of Hematology-Oncology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA. 6. Division of Pediatric Oncology/Stem Cell Transplant, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 7. Nemours Center for Cancer and Blood Disorders, Alfred I. DuPont Hospital for Children, Wilmington, Delaware, USA. 8. Keck School of Medicine, University of Southern California, California, USA. 9. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 10. Department of Pediatrics, Baylor College of Medicine/Dan L. Duncan Cancer Center and Texas Children's Cancer Center, Houston, Texas, USA.
Abstract
PURPOSE: The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin, and etoposide) did not improve overall outcome of pediatric AML patients in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031) . Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status. EXPERIMENTAL DESIGN: RelA-total and phosphorylation at serine 536 (RelA-pSer536 ) were measured in 483 patient samples using reverse phase protein array technology. RESULTS: In ADEB-treated patients, low-RelA-pSer536 was favorably prognostic when compared to high-RelA-pSer536 (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). Among low-RelA-pSer536 patients, RR significantly decreased with ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer536 and 295 other assayed proteins identified a strong correlation with HSF1-pSer326 , another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer536 and low-HSF1-pSer326 was a significant predictor of ADEB response (3-yr OS: 86% vs. 67%, p = 0.013). CONCLUSION AND CLINICAL RELEVANCE: Bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer536 and low-HSF1-pSer326 .
PURPOSE: The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin, and etoposide) did not improve overall outcome of pediatric AML patients in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031) . Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status. EXPERIMENTAL DESIGN: RelA-total and phosphorylation at serine 536 (RelA-pSer536 ) were measured in 483 patient samples using reverse phase protein array technology. RESULTS: In ADEB-treated patients, low-RelA-pSer536 was favorably prognostic when compared to high-RelA-pSer536 (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). Among low-RelA-pSer536 patients, RR significantly decreased with ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer536 and 295 other assayed proteins identified a strong correlation with HSF1-pSer326 , another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer536 and low-HSF1-pSer326 was a significant predictor of ADEB response (3-yr OS: 86% vs. 67%, p = 0.013). CONCLUSION AND CLINICAL RELEVANCE: Bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer536 and low-HSF1-pSer326 .
Authors: Steven M Kornblau; Raoul Tibes; Yi Hua Qiu; Wenjing Chen; Hagop M Kantarjian; Michael Andreeff; Kevin R Coombes; Gordon B Mills Journal: Blood Date: 2008-10-07 Impact factor: 22.113
Authors: Teru Hideshima; Hiroshi Ikeda; Dharminder Chauhan; Yutaka Okawa; Noopur Raje; Klaus Podar; Constantine Mitsiades; Nikhil C Munshi; Paul G Richardson; Ruben D Carrasco; Kenneth C Anderson Journal: Blood Date: 2009-05-12 Impact factor: 22.113
Authors: Fieke W Hoff; Anneke D van Dijk; Yihua Qiu; Peter P Ruvolo; Robert B Gerbing; Amanda R Leonti; Gaye N Jenkins; Alan S Gamis; Richard Aplenc; E Anders Kolb; Todd A Alonzo; Soheil Meshinchi; Eveline S J M de Bont; Sophia W M Bruggeman; Steven M Kornblau; Terzah M Horton Journal: Blood Date: 2021-02-25 Impact factor: 22.113