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  3. Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

  • Cancers (Basel). 2020 Aug 26;12(9):2426. doi: 10.3390/cancers12092426.
Pankita H Pandya 1 2,  Lijun Cheng 3,  M Reza Saadatzadeh 1 2,  Khadijeh Bijangi-Vishehsaraei 1 2,  Shan Tang 3,  Anthony L Sinn 4,  Melissa A Trowbridge 4,  Kathryn L Coy 4,  Barbara J Bailey 2,  Courtney N Young 2,  Jixin Ding 2,  Erika A Dobrota 2,  Savannah Dyer 4,  Adily Elmi 2,  Quinton Thompson 2,  Farinaz Barghi 2 5,  Jeremiah Shultz 2,  Eric A Albright 6,  Harlan E Shannon 2,  Mary E Murray 1,  Mark S Marshall 1,  Michael J Ferguson 1,  Todd E Bertrand 7,  L Daniel Wurtz 7,  Sandeep Batra 1,  Lang Li 3,  Jamie L Renbarger 1 2 6 8,  Karen E Pollok 1 2 4 5 9
Affiliations

Affiliations

  • 1 Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 2 Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 3 Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
  • 4 In Vivo Therapeutics Core, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 5 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 6 Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 7 Department of Orthopedics Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 8 Indiana Institute of Personalized Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 9 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
PMID: 32859084 DOI: 10.3390/cancers12092426
Abstract

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and Chk1, in order to test the hypothesis that the inhibition of BET + Chk1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and Chk1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

Keywords

BETs; CHK1; MYC; RAD21; biomarkers; molecular signature; osteosarcoma; precision genomics.

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