Cancers (Dec 2022)
Integrative Multi-OMICs Identifies Therapeutic Response Biomarkers and Confirms Fidelity of Clinically Annotated, Serially Passaged Patient-Derived Xenografts Established from Primary and Metastatic Pediatric and AYA Solid Tumors
- Pankita H. Pandya,
- Asha Jacob Jannu,
- Khadijeh Bijangi-Vishehsaraei,
- Erika Dobrota,
- Barbara J. Bailey,
- Farinaz Barghi,
- Harlan E. Shannon,
- Niknam Riyahi,
- Nur P. Damayanti,
- Courtney Young,
- Rada Malko,
- Ryli Justice,
- Eric Albright,
- George E. Sandusky,
- L. Daniel Wurtz,
- Christopher D. Collier,
- Mark S. Marshall,
- Rosa I. Gallagher,
- Julia D. Wulfkuhle,
- Emanuel F. Petricoin,
- Kathy Coy,
- Melissa Trowbridge,
- Anthony L. Sinn,
- Jamie L. Renbarger,
- Michael J. Ferguson,
- Kun Huang,
- Jie Zhang,
- M. Reza Saadatzadeh,
- Karen E. Pollok
Affiliations
- Pankita H. Pandya
- Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Asha Jacob Jannu
- Department of Biostatistics & Health Data Science Indiana, University School of Medicine, Indianapolis, IN 46202, USA
- Khadijeh Bijangi-Vishehsaraei
- Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Erika Dobrota
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Barbara J. Bailey
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Farinaz Barghi
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Harlan E. Shannon
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Niknam Riyahi
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Nur P. Damayanti
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Courtney Young
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Rada Malko
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Ryli Justice
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Eric Albright
- Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- George E. Sandusky
- Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- L. Daniel Wurtz
- Department of Orthopedics Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Christopher D. Collier
- Department of Orthopedics Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Mark S. Marshall
- Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Rosa I. Gallagher
- Center for Applied Proteomics and Molecular Medicine, Institute for Biomedical Innovation, George Mason University, Manassas, VA 20110, USA
- Julia D. Wulfkuhle
- Center for Applied Proteomics and Molecular Medicine, Institute for Biomedical Innovation, George Mason University, Manassas, VA 20110, USA
- Emanuel F. Petricoin
- Center for Applied Proteomics and Molecular Medicine, Institute for Biomedical Innovation, George Mason University, Manassas, VA 20110, USA
- Kathy Coy
- Preclinical Modeling and Therapeutics Core, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Melissa Trowbridge
- Preclinical Modeling and Therapeutics Core, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Anthony L. Sinn
- Preclinical Modeling and Therapeutics Core, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Jamie L. Renbarger
- Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Michael J. Ferguson
- Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Kun Huang
- Department of Biostatistics & Health Data Science Indiana, University School of Medicine, Indianapolis, IN 46202, USA
- Jie Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- M. Reza Saadatzadeh
- Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Karen E. Pollok
- Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- DOI
- https://doi.org/10.3390/cancers15010259
- Journal volume & issue
-
Vol. 15,
no. 1
p. 259
Abstract
Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug–gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy.
Keywords
- pediatric
- adolescents and young adults (AYA)
- patient-derived xenografts (PDXs)
- osteosarcoma (OS)
- rhabdomyosarcoma (RMS)
- Wilms tumor
