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

Wetmore, Cynthia; Boyett, James M.; Li, Shaoyu; Lin, Tong; Bendel, Anne; Gajjar, Amar; Orr, Brent A.

doi:10.1093/neuonc/nov017

Cited by 67 publications

(48 citation statements)

References 34 publications

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“…Among the 33 evaluable patients receiving alisertib in this study, a partial response (n=1) and prolonged stable disease (n=6) were observed. In another trial (45), single-agent alisertib once daily for 7 days of a 21-day treatment cycle administered to four pediatric patients with recurrent atypical teratoid rhabdoid tumors (ATRT), resulted in stable disease and/or durable regression for all patients. Further clinical development of alisertib focused on incorporation with mechanism-based combinations could achieve additive benefits in this patient population.…”

Section: Aurora Kinase Inhibitionmentioning

confidence: 99%

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

2017

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This review describes the pivotal roles of cell cycle and checkpoint regulators and discusses development of specific cell cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib) and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the crosstalk of signals activated by cell cycle arrest, as well as pediatric-focused drug development are critical for the advancement of drugs for rare childhood diseases.

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Section: Aurora Kinase Inhibitionmentioning

confidence: 99%

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

2017

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“…19 AURKA inhibitors such as alisertib have been used to target INI1-deficient tumors, such as AT/RT. 13 A recent case series documented disease stabilization in four patients with recurrent AT/RT using alisertib as mono-therapy. 13 It has been demonstrated that SMARCB1 regulates CDKN1C through LIN28B, a protein involved in early embryogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…13 A recent case series documented disease stabilization in four patients with recurrent AT/RT using alisertib as mono-therapy. 13 It has been demonstrated that SMARCB1 regulates CDKN1C through LIN28B, a protein involved in early embryogenesis. 14 Interestingly, LIN28B has also been shown to upregulate AURKA, thus possibly tying these pathways together (see schematic, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Results of her tumor sequencing were discussed in a CNS precision medicine tumor board teleconferenced with clinicians at multiple children’s hospitals, members of which made recommendation to consider adjuvant therapy with an aurora kinase A inhibitor, based on recent reports of efficacy in children with recurrent AT/RT. 13 …”

Section: Integrative Clinical Sequencingmentioning

confidence: 99%

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Loss of CDKN1C in a Recurrent Atypical Teratoid/Rhabdoid Tumor

Tran

Camelo-Piragua²,

Gupta³

et al. 2017

Journal of Pediatric Hematology/Oncology

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Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that is commonly associated with biallelic alterations of SMARCB1. Recurrent or refractory AT/RT has not been molecularly characterized as well. We present the case of a child with recurrent AT/RT who underwent clinically integrated molecular profiling (germline DNA and tumor DNA/RNA sequencing). This demonstrated a somatic lesion in CDKN1C alongside hallmark loss of SMARCB1. This data allowed us to explore potential personalized therapies for this patient and expose a molecular driver that may be involved in similar cases.

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“…Alisertib is a novel AurkA inhibitor, having been evaluated in early‐phase clinical trials for nongenomically selected malignancies such as sarcomas . Wetmore et al reported the use of alisertib in four children with recurrent or progressive atypical teratoid/rhabdoid tumors with INI‐1 deficiency, demonstrating stable disease or disease regression in all four patients, with two patients having stable disease regression for 1 and 2 years on therapy . Based on these findings, the board recommended to use an AurkA inhibitor such as alisertib.…”

Section: Patient Storymentioning

confidence: 99%

Clinical Benefit to an Aurora A Kinase Inhibitor in a Patient with Metastatic Integrase Interactor 1-Deficient Carcinoma

et al. 2018

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Integrase interactor 1 (INI‐1)‐deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non‐Fermentable‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 gene (SMARCB1) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30‐year‐old woman with INI‐1‐deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor. Next‐generation‐sequencing‐based targeted cancer‐related gene assay confirmed SMARCB1 loss and revealed other mutations in breast cancer 1 gene and checkpoint kinase 2 gene, which may have impacted her clinical course. After discussion at the molecular tumor board, she was offered alisertib, an aurora A kinase inhibitor, on a single‐patient expanded‐use program and achieved prolonged disease stabilization. Aurora A kinase inhibition may have an important role in the management of patients with INI‐1‐deficient tumors, warranting further evaluation in clinical studies. Key Points Loss of the SWItch/Sucrose Non‐Fermentable‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 gene (SMARCB1), which encodes integrase interactor 1 (INI‐1), is associated with various mesenchymal malignancies, but a few carcinomas with rhabdoid features have been recently described as a distinct entity. INI‐1‐deficient carcinoma can be very aggressive, and there is no known treatment option available. There are encouraging preliminary data with an enhancer of zeste homolog 2 inhibitor, tazematostat, in INI‐1‐deficient malignancies, including INI‐1‐deficient carcinomas. Loss of INI‐1 can activate aurora A kinase (AurkA), and inhibition of AurkA by alisertib could be a viable option and warrants further investigation in this cancer. Clinical genomic profiling can confirm diagnosis of molecularly defined malignancy and provide insights on therapeutic options.

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

Cited by 67 publications

References 34 publications

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

Loss of CDKN1C in a Recurrent Atypical Teratoid/Rhabdoid Tumor

Clinical Benefit to an Aurora A Kinase Inhibitor in a Patient with Metastatic Integrase Interactor 1-Deficient Carcinoma

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