Cynthia Wetmore1, James Boyett1, Shaoyu Li1, Tong Lin1, Anne Bendel1, Amar Gajjar1, Brent A Orr1. 1. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., A.G.); Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (J.B., S.L., T.L.); Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota (A.B.); Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
Abstract
BACKGROUND: Aurora Kinase A (AURKA) encodes a protein that regulates the formation and stability of the mitotic spindle and is highly active in atypical teratoid rhabdoid tumors (ATRT) through loss of the INI1 tumor suppressor gene. Alisertib (MLN8237) inhibits AURKA in vitro and in vivo. Given the strong preclinical data supporting the use of alisertib for ATRT patients, we sought and obtained permission to use alisertib in single patient treatment plans for 4 recurrent pediatric ATRT patients. METHODS: Patients with recurrent or progressive ATRT received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle. Disease evaluation (MRI of brain and spine and lumbar puncture) was done after 2 cycles of alisertib and every 2-3 cycles thereafter for as long as the patients remained free from tumor progression. RESULTS: Four patients with median age of 2.5 years (range, 1.39-4.87 y) at diagnosis received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle, and all 4 patients had disease stabilization and/or regression after 3 cycles of alisertib therapy. Two patients continued to have stable disease regression for 1 and 2 years, respectively, on therapy. CONCLUSIONS: Single-agent alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology. Alisertib has moderate but manageable toxicities, and its chronic administration appears feasible in this pediatric population. These novel data support the incorporation of alisertib in future therapeutic trials for children with ATRT.
BACKGROUND:Aurora Kinase A (AURKA) encodes a protein that regulates the formation and stability of the mitotic spindle and is highly active in atypical teratoid rhabdoid tumors (ATRT) through loss of the INI1tumor suppressor gene. Alisertib (MLN8237) inhibits AURKA in vitro and in vivo. Given the strong preclinical data supporting the use of alisertib for ATRT patients, we sought and obtained permission to use alisertib in single patient treatment plans for 4 recurrent pediatric ATRT patients. METHODS:Patients with recurrent or progressive ATRT received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle. Disease evaluation (MRI of brain and spine and lumbar puncture) was done after 2 cycles of alisertib and every 2-3 cycles thereafter for as long as the patients remained free from tumor progression. RESULTS: Four patients with median age of 2.5 years (range, 1.39-4.87 y) at diagnosis received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle, and all 4 patients had disease stabilization and/or regression after 3 cycles of alisertib therapy. Two patients continued to have stable disease regression for 1 and 2 years, respectively, on therapy. CONCLUSIONS: Single-agent alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology. Alisertib has moderate but manageable toxicities, and its chronic administration appears feasible in this pediatric population. These novel data support the incorporation of alisertib in future therapeutic trials for children with ATRT.
Authors: Amar Gajjar; Murali Chintagumpala; David Ashley; Stewart Kellie; Larry E Kun; Thomas E Merchant; Shaio Woo; Greg Wheeler; Valerie Ahern; Matthew J Krasin; Maryam Fouladi; Alberto Broniscer; Robert Krance; Gregory A Hale; Clinton F Stewart; Robert Dauser; Robert A Sanford; Christine Fuller; Ching Lau; James M Boyett; Dana Wallace; Richard J Gilbertson Journal: Lancet Oncol Date: 2006-10 Impact factor: 41.316
Authors: Tanya M Tekautz; Christine E Fuller; Susan Blaney; Maryam Fouladi; Alberto Broniscer; Thomas E Merchant; Matthew Krasin; James Dalton; Gregory Hale; Larry E Kun; Dana Wallace; Richard J Gilbertson; Amar Gajjar Journal: J Clin Oncol Date: 2005-03-01 Impact factor: 44.544
Authors: P C Burger; I T Yu; T Tihan; H S Friedman; D R Strother; J L Kepner; P K Duffner; L E Kun; E J Perlman Journal: Am J Surg Pathol Date: 1998-09 Impact factor: 6.394
Authors: Jaclyn A Biegel; Lu Tan; Fan Zhang; Luanne Wainwright; Pierre Russo; Lucy B Rorke Journal: Clin Cancer Res Date: 2002-11 Impact factor: 12.531
Authors: Joanne M Hilden; Sharon Meerbaum; Peter Burger; Jonathan Finlay; Anna Janss; Bernd W Scheithauer; Andrew W Walter; Lucy B Rorke; Jaclyn A Biegel Journal: J Clin Oncol Date: 2004-07-15 Impact factor: 44.544
Authors: K Sasai; J M Parant; M E Brandt; J Carter; H P Adams; S A Stass; A M Killary; H Katayama; S Sen Journal: Oncogene Date: 2008-03-17 Impact factor: 9.867
Authors: I Versteege; N Sévenet; J Lange; M F Rousseau-Merck; P Ambros; R Handgretinger; A Aurias; O Delattre Journal: Nature Date: 1998-07-09 Impact factor: 49.962
Authors: Michael C Frühwald; Jaclyn A Biegel; Franck Bourdeaut; Charles W M Roberts; Susan N Chi Journal: Neuro Oncol Date: 2016-01-10 Impact factor: 12.300
Authors: Pietro Spennato; Giancarlo Nicosia; Lucia Quaglietta; Vittoria Donofrio; Giuseppe Mirone; Giuliana Di Martino; Elia Guadagno; Maria Laura del Basso de Caro; Daniele Cascone; Giuseppe Cinalli Journal: Childs Nerv Syst Date: 2015-09-09 Impact factor: 1.475
Authors: Lindsey M Hoffman; Elizabeth Anne Richardson; Ben Ho; Ashley Margol; Alyssa Reddy; Lucie Lafay-Cousin; Susan Chi; Irene Slavc; Alexander Judkins; Martin Hasselblatt; Franck Bourdeaut; Michael C Frühwald; Rajeev Vibhakar; Eric Bouffet; Annie Huang Journal: Neuro Oncol Date: 2020-07-07 Impact factor: 12.300
Authors: Cory T Zumbar; Aisulu Usubalieva; Paul D King; Xiaohui Li; Caroline S Mifsud; Hailey M Dalton; Muge Sak; Sara Urio; William M Bryant; Joseph P McElroy; George Farmer; Norman L Lehman Journal: J Neurooncol Date: 2018-02-02 Impact factor: 4.130