Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children

Malignant rhabdoid tumors (MRTs) are rare, highly aggressive tumors that occur in young children, which were initially reported in association with the kidney but have also been found in liver, thymus, and other soft tissue sites as well as within the central nervous system (CNS).1,2 The most common location for nonrenal MRT is the CNS, and these tumors are referred to as atypical teratoid/rhabdoid tumors (ATRTs).3 ATRT, along with primitive neuroectodermal tumor, is the most common type of tumor arising in children younger than aged 1 year.4,5 While there is no standard or effective therapy for ATRT, a subset of patients may benefit from intensive multimodal therapy.6–8 For most patients, the median event-free survival with surgery, chemotherapy, and radiotherapy is less than one year.5,9 Early cytogenetic studies revealed that these tumor cells carried few or no detectable chromosomal rearrangements and that monosomy 22 was a nonrandom chromosomal abnormality in ATRT.2,10,11 Researchers found that disruption of the locus at 22q11.2 resulted in loss of function of the switch/sucrose nonfermentable (SWI/SNF)-related ATP-dependent chromatin-remodeling complex.12,13 This was one of the first chromatin remodeling complexes to be identified and comprises 12–15 protein subunits in mammalian cells.14 Inactivating mutations have been identified in all 9 exons of SMARCB1 (also known as INI1, hSNF5, and BAF47) gene products, which are pathognomonic for of ATRT.15–17 Rhabdoid tumors may be distinguished from other tumor entities by characteristic histopathological features and immunohistochemical analysis of INI1/Baf47. Aurora Kinase A (AURKA) is a gene that encodes cell cycle-associated serine/threonine kinase that regulates centrosome maturation and mitosis.18 Inhibition of AURKA leads to mitotic delays and severe chromosome alignment and segregation defects, followed by cell death.19 AURKA is highly expressed in malignant rhabdoid tumors through the characteristic loss of the INI1 tumor suppressor gene.20 INI1 directly represses AURKA in a cell-type specific manner, and knockdown of AURKA in MRT cells induces mitotic arrest and apoptosis in MRT but not normal diploid cells. Although INI1 represses AURKA in tumor and normal cells, its repression of AURKA in normal diploid cells does not induce cleavage of caspase 3 and does not lead to decreased survival.20 This is an extremely exciting result with important clinical implications, particularly for the treatment of ATRTs that arise within the developing nervous system of young children. Alisertib (MLN8237) is a selective, potent, and orally bioavailable small-molecule inhibitor of AURKA, which has shown antitumor activity in vitro and in vivo models through the Pediatric Preclinical Testing Program (PPTP) and provided the preclinical rationale for development of alisertib in childhood cancer.21 Alisertib has been evaluated in adults with recurrent solid tumors and has been found to be tolerable and to have some indication of activity with tumor stabilization and one partial response.22 Recently, alisertib was evaluated in 33 pediatric patients with recurrent/refractory solid tumors (excluding CNS tumors) in a phase 1 study through Children's Oncology Group (COG).23 The maximum tolerated dose (MTD) in this cohort was 80 mg/m2/day administered orally once daily for 7 days out of a cycle of 21 days. Due to the lack of any curative therapy for ATRT, the strong biological rationale for AURKA inhibition in ATRT, and the safety and tolerability profile of alisertib in the pediatric phase 1 study, we conducted single patient treatment plans for 4 patients with recurrent/refractory ATRT at St. Jude Children's Research Hospital between July 2012 and August 2014.