التفاصيل البيبلوغرافية
| العنوان: |
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. |
| المؤلفون: |
Pandya, Pankita H., Jannu, Asha Jacob, Bijangi-Vishehsaraei, Khadijeh, Dobrota, Erika, Bailey, Barbara J., Barghi, Farinaz, Shannon, Harlan E., Riyahi, Niknam, Damayanti, Nur P., Young, Courtney, Malko, Rada, Justice, Ryli, Albright, Eric, Sandusky, George E., Wurtz, L. Daniel, Collier, Christopher D., Marshall, Mark S., Gallagher, Rosa I., Wulfkuhle, Julia D., Petricoin, Emanuel F. |
| المصدر: |
Cancers; Jan2023, Vol. 15 Issue 1, p259, 42p |
| مصطلحات موضوعية: |
BIOMARKERS, GENOME editing, XENOGRAFTS, ANALYSIS of variance, ANIMAL experimentation, ONCOGENES, RHABDOMYOSARCOMA, OSTEOSARCOMA, METASTASIS, RNA, IMMUNOBLOTTING, NEPHROBLASTOMA, GENOMICS, MULTIOMICS, RESEARCH funding, EPIGENOMICS, MICE |
| مستخلص: |
Simple Summary: Solid tumors account for ~60% of pediatric, as well as adolescent and young adult (AYA), cancers, and outcomes for patients with these progressive diseases remain poor. This highlights the critical need to develop tumor models from patients with aggressive cancers so that oncogenic signatures can be identified for therapeutic testing. Thus, patient-derived xenografts (PDXs) were established from sarcoma and Wilms tumor patients at diagnosis or following treatment. Overall, the molecular landscape of serially passaged PDXs recapitulated the original tumor based on an integrated multi-OMICS pipeline that cross-validated cancer-associated pathways. Actionable mechanisms of tumor progression were identified. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response for in vivo validation. In osteosarcoma PDXs harboring pertinent molecular signatures, inhibition of CDK4/6 or BETs decreased growth. This systematic approach that links patient disease history to data generated from its corresponding PDX provides a foundation to discover improved therapies for patients with high-risk cancers. 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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