Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors

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

doi:10.1093/neuonc/noaa046

Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors

Neuro Oncol. 2020 Jul 7;22(7):944-954. doi: 10.1093/neuonc/noaa046.

Authors

Lindsey M Hoffman¹, Elizabeth Anne Richardson^{2

3

4}, Ben Ho^{2

3

4}, Ashley Margol^{5

6}, Alyssa Reddy⁷, Lucie Lafay-Cousin^{8

9}, Susan Chi^{10

11

12}, Irene Slavc^{13

14}, Alexander Judkins^{15

16

17}, Martin Hasselblatt¹⁸, Franck Bourdeaut^{19

20

21}, Michael C Frühwald^{22

23

24}, Rajeev Vibhakar^{25

26

27}, Eric Bouffet^{28

29

30}, Annie Huang^{29

30

31}

Affiliations

¹ Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.
² Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
³ Department of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁵ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
⁶ Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
⁷ Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, California, USA.
⁸ Department of Pediatric Hematology Oncology and Blood and Marrow Transplantation, Alberta Children's Hospital, Calgary, Alberta, Canada.
⁹ Department of Paediatrics and Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁰ Pediatric Medical Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹¹ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
¹² Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
¹³ Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
¹⁴ Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
¹⁵ Center for Personalized Medicine, Children's Hospital of Los Angeles.
¹⁶ Pathology and Laboratory Medicine, Children's Hospital of Los Angeles.
¹⁷ Department of Pathology, Keck School of Medicine University of Southern California, Los Angeles, California, USA.
¹⁸ Institute of Neuropathology, University Hospital Münster, Münster, Germany.
¹⁹ Curie Institute, Integrated Cancer Research Site, Paris, France.
²⁰ Departments of Genetics and of Oncopediatry and Young Adults, Curie Institute, Paris, France.
²¹ INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO Pediatric Oncology Center, Curie Institute, Paris, France.
²² Swabian Children's Cancer Center, University Children's Hospital, University Hospital Augsburg, Augsburg, Germany.
²³ Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, University of Münster, Münster, Germany.
²⁴ EU-RHAB Registry Working Group, Augsburg, Germany.
²⁵ Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
²⁶ Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado, USA.
²⁷ Department of Neurosurgery, University of Colorado Denver, Aurora, Colorado, USA.
²⁸ Child Health Evaluative Sciences, SickKids Research Institute, Toronto, Ontario, Canada.
²⁹ Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
³⁰ Division of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.
³¹ Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Abstract

Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.

Keywords: ATRT; enhancer; epigenomics; rhabdoid tumors; subgroup-specific therapeutics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Epigenomics
Humans
Neoplasms, Neuroepithelial*
Rhabdoid Tumor* / drug therapy
Rhabdoid Tumor* / genetics
SMARCB1 Protein / genetics

Substances

SMARCB1 Protein