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

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
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Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Department of Orthopedics Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Indiana Institute of Personalized Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
*
Authors to whom correspondence should be addressed.
Co-first authors with equal contributions.
Cancers 2020, 12(9), 2426; https://doi.org/10.3390/cancers12092426
Received: 24 May 2020 / Revised: 1 August 2020 / Accepted: 14 August 2020 / Published: 26 August 2020
(This article belongs to the Special Issue Sarcomas: New Biomarkers and Therapeutic Strategies)
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.
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Keywords: osteosarcoma; precision genomics; molecular signature; biomarkers; MYC; RAD21; CHK1; BETs osteosarcoma; precision genomics; molecular signature; biomarkers; MYC; RAD21; CHK1; BETs
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MDPI and ACS Style

Pandya, P.H.; Cheng, L.; Saadatzadeh, M.R.; Bijangi-Vishehsaraei, K.; Tang, S.; Sinn, A.L.; Trowbridge, M.A.; Coy, K.L.; Bailey, B.J.; Young, C.N.; Ding, J.; Dobrota, E.A.; Dyer, S.; Elmi, A.; Thompson, Q.; Barghi, F.; Shultz, J.; Albright, E.A.; Shannon, H.E.; Murray, M.E.; Marshall, M.S.; Ferguson, M.J.; Bertrand, T.E.; Wurtz, L.D.; Batra, S.; Li, L.; Renbarger, J.L.; Pollok, K.E. Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma. Cancers 2020, 12, 2426. https://doi.org/10.3390/cancers12092426

AMA Style

Pandya PH, Cheng L, Saadatzadeh MR, Bijangi-Vishehsaraei K, Tang S, Sinn AL, Trowbridge MA, Coy KL, Bailey BJ, Young CN, Ding J, Dobrota EA, Dyer S, Elmi A, Thompson Q, Barghi F, Shultz J, Albright EA, Shannon HE, Murray ME, Marshall MS, Ferguson MJ, Bertrand TE, Wurtz LD, Batra S, Li L, Renbarger JL, Pollok KE. Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma. Cancers. 2020; 12(9):2426. https://doi.org/10.3390/cancers12092426

Chicago/Turabian Style

Pandya, Pankita H., Lijun Cheng, M. R. Saadatzadeh, Khadijeh Bijangi-Vishehsaraei, Shan Tang, Anthony L. Sinn, Melissa A. Trowbridge, Kathryn L. Coy, Barbara J. Bailey, Courtney N. Young, Jixin Ding, Erika A. Dobrota, Savannah Dyer, Adily Elmi, Quinton Thompson, Farinaz Barghi, Jeremiah Shultz, Eric A. Albright, Harlan E. Shannon, Mary E. Murray, Mark S. Marshall, Michael J. Ferguson, Todd E. Bertrand, L. D. Wurtz, Sandeep Batra, Lang Li, Jamie L. Renbarger, and Karen E. Pollok 2020. "Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma" Cancers 12, no. 9: 2426. https://doi.org/10.3390/cancers12092426

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