Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma

  • Sci Transl Med. 2021 Jan 20;13(577):eaba7401. doi: 10.1126/scitranslmed.aba7401.
Raelene Endersby  1  2 ,  Jacqueline Whitehouse  3  2 ,  Allison Pribnow  4 ,  Mani Kuchibhotla  3 ,  Hilary Hii  3 ,  Brooke Carline  3 ,  Suresh Gande  3 ,  Jennifer Stripay  5 ,  Mathew Ancliffe  3 ,  Meegan Howlett  3  2 ,  Tobias Schoep  3 ,  Courtney George  3 ,  Clara Andradas  3  2 ,  Patrick Dyer  3  2 ,  Marjolein Schluck  3  6 ,  Brett Patterson  3 ,  Silvia K Tacheva-Gigorova  7 ,  Matthew N Cooper  8 ,  Giles Robinson  9 ,  Clinton Stewart  10 ,  Stefan M Pfister  11  12 ,  Marcel Kool  11  13 ,  Till Milde  11  12 ,  Amar Gajjar  9 ,  Terrance Johns  3  2 ,  Robert J Wechsler-Reya  7 ,  Martine F Roussel  5 ,  Nicholas G Gottardo  1  2  14
Affiliations
  • 1. Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA 6009, Australia. [email protected] [email protected].
  • 2. Division of Paediatrics/Centre for Child Health Research, Medical School, University of Western Australia, Crawley, WA 6009, Australia.
  • 3. Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA 6009, Australia.
  • 4. Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
  • 5. Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA.
  • 6. Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525 GA, Netherlands.
  • 7. Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 8. Biometrics, Telethon Kids Institute, University of Western Australia, Nedlands, WA 6009, Australia.
  • 9. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA.
  • 10. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38103, USA.
  • 11. Hopp Children's Cancer Center (KiTZ) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • 12. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany.
  • 13. Princess Máxima Center for Pediatric Oncology, Utrecht 3584 CS, Netherlands.
  • 14. Department of Pediatric and Adolescent Oncology/Hematology, Perth Children's Hospital, Nedlands, WA 6009, Australia.
PMID: 33472956 DOI: 10.1126/scitranslmed.aba7401
Abstract

Medulloblastoma (MB) consists of four core molecular subgroups with distinct clinical features and prognoses. Treatment consists of surgery, followed by radiotherapy and cytotoxic chemotherapy. Despite this intensive approach, outcome remains dismal for patients with certain subtypes of MB, namely, MYC-amplified Group 3 and TP53-mutated SHH. Using high-throughput assays, six human MB cell lines were screened against a library of 3208 unique compounds. We identified 45 effective compounds from the screen and found that cell cycle checkpoint kinase (Chk1/2) inhibition synergistically enhanced the cytotoxic activity of clinically used chemotherapeutics cyclophosphamide, cisplatin, and gemcitabine. To identify the best-in-class inhibitor, multiple Chk1/2 inhibitors were assessed in mice bearing intracranial MB. When combined with DNA-damaging chemotherapeutics, Chk1/2 inhibition reduced tumor burden and increased survival of Animals with high-risk MB, across multiple different models. In total, we tested 14 different models, representing distinct MB subgroups, and data were validated in three independent laboratories. Pharmacodynamics studies confirmed central nervous system penetration. In mice, combination treatment significantly increased DNA damage and Apoptosis compared to chemotherapy alone, and studies with cultured cells showed that CHK inhibition disrupted chemotherapy-induced cell cycle arrest. Our findings indicated Chk1/2 inhibition, specifically with LY2606368 (prexasertib), has strong chemosensitizing activity in MB that warrants further clinical investigation. Moreover, these data demonstrated that we developed a robust and collaborative preclinical assessment platform that can be used to identify potentially effective new therapies for clinical evaluation for pediatric MB.

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