@article{3928f888be2c45b5a23e9867f86ed67e,
title = "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",
abstract = "Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-na{\"i}ve 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 = "BETs, CDK4/6, Wilms tumor, adolescents and young adults (AYA), multi-OMICS, osteosarcoma (OS), patient-derived xenografts (PDXs), pediatric, precision genomics, rhabdomyosarcoma (RMS)",
author = "Pandya, {Pankita H.} and Jannu, {Asha Jacob} and Khadijeh Bijangi-Vishehsaraei and Erika Dobrota and Bailey, {Barbara J.} and Farinaz Barghi and Shannon, {Harlan E.} and Niknam Riyahi and Damayanti, {Nur P.} and Courtney Young and Rada Malko and Ryli Justice and Eric Albright and Sandusky, {George E.} and Wurtz, {L. Daniel} and Collier, {Christopher D.} and Marshall, {Mark S.} and Gallagher, {Rosa I.} and Wulfkuhle, {Julia D.} and Petricoin, {Emanuel F.} and Kathy Coy and Melissa Trowbridge and Sinn, {Anthony L.} and Renbarger, {Jamie L.} and Ferguson, {Michael J.} and Kun Huang and Jie Zhang and Saadatzadeh, {M. Reza} and Pollok, {Karen E.}",
note = "Funding Information: This research was funded by NICHD/NIH Specialized Centers in Research in Pediatric Developmental Pharmacology [(P50HD090215); P.H.P., K.B.-V., E.D., B.J.B., F.B., N.R., C.Y., R.M., H.E.S., M.S.M., J.L.R., M.J.F., J.Z., K.H., M.R.S. and K.E.P.], DOD WS00780029: CA210123 (P.H.P., M.R.S., E.D., C.Y., B.J.B., N.R. and K.E.P.), NIH/NCI Cancer Center Support Grant [(P30CA082709); A.L.S., M.T., K.C., B.J.B. and K.E.P.]. The Tyler Trent Cancer Research Endowment for the Riley Hospital for Children IU-Health (P.H.P., M.R.S., J.L.R. and K.E.P.), The Indiana University Grand Challenge Precision Health Initiative-Pre-Sarcoma/Sarcoma Pillar (P.H.P., A.J.J., K.B.-V., E.D., F.B., N.R., C.Y., R.M., L.D.W., C.D.C., M.S.M., J.L.R., M.J.F., J.Z., K.H., M.R.S. and K.E.P.), the Riley Children{\textquoteright}s Foundation (P.H.P., M.S.M. and K.E.P.), Curing Kids Cancer (P.H.P., J.L.R. and K.E.P.), Morgan Adams Foundation (P.H.P. and K.E.P.), Sarcoma Foundation of America (K.E.P.), the Caroline Symmes Cancer Endowment (J.L.R., R.M. and M.R.S.), the Wells Center for Pediatric Research Support for Clinical/Translational Research (M.R.S.), the Indiana Clinical and Translational Sciences Institute (P.H.P., grant number: TL1TR001107), and the American Cancer Society Institutional Research Grant [ACS-IRG Grant Mechanism (P.H.P., Grant Number: 16-192-31)]. Funding Information: We acknowledge Khadijeh Bijangi-Vishehsaraei (co-first author equivalent) and Reza Saadatzadeh (co-corresponding author equivalent) for their substantial contributions to the development of the PDX pipeline including regulatory procedures, sample acquisition, processing, archiving, pathway integration studies, and in vivo efficacy studies. We also extend special gratitude to the Precision Genomics team at the Riley Hospital for Children for their support in obtaining pediatric solid-tumor patient samples as well as the patients and their families for their generous donation of tumor specimens for research. We send a special thanks to Brian Ashmore in the Indiana Pediatric Biobank for tissue processing and archiving. We thank Mary Murray for her discussions and input into clinical history annotations. We thank Bryan Helm for initial discussions and input on -OMICs analyses. We also thank Leila Fehme, Rebekah Addison, and Maggie Granatir for expert technical assistance with histology. WGS for Wilms tumor PDX HT98, HT120 and HT139 was conducted by the Center for Medical Genomics at IUSM. PDX generation and archiving was conducted in by the IUSCCC Preclinical Modeling and Therapeutics Core (PMTC), which are partially supported by the Indiana University Grand Challenges Precision Health Initiative. We also thank Matthew Essex and Art Baluyut for their support and insightful discussions. Publisher Copyright: {\textcopyright} 2022 by the authors.",
year = "2023",
month = jan,
doi = "10.3390/cancers15010259",
language = "English",
volume = "15",
journal = "Cancers",
issn = "2072-6694",
number = "1",
}