Browsing by Author "Riyahi, Niknam"

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    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
    (MDPI, 2022-12-30) 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.; Coy, Kathy; Trowbridge, Melissa; Sinn, Anthony L.; Renbarger, Jamie L.; Ferguson, Michael J.; Huang, Kun; Zhang, Jie; Saadatzadeh, M. Reza; Pollok, Karen E.; Pediatrics, School of Medicine
    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.
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    Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas
    (MDPI, 2022-07-25) Barghi, Farinaz; Shannon, Harlan E.; Saadatzadeh, M. Reza; Bailey, Barbara J.; Riyahi, Niknam; Bijangi-Vishehsaraei, Khadijeh; Just, Marissa; Ferguson, Michael J.; Pandya, Pankita H.; Pollok, Karen E.; Medical and Molecular Genetics, School of Medicine
    Despite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.
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    Therapeutic Targeting of BET Proteins in Osteosarcoma
    (2025-03) Riyahi, Niknam; Pollok, Karen; Angus, Steve; Fehrenbacher, Jill; Jerde, Travis; Yeh, Elizabeth
    Osteosarcoma (OS) is an aggressive bone cancer in pediatric, adolescent, and young adult patients with an exceedingly poor prognosis. An area of therapeutic opportunity is that OS exhibits increased oncogenic replication stress (RS), augmenting genome instability and tumor progression. Exploiting RS provides a treatment intervention. Bromodomain and extra-terminal (BET) proteins regulate DNA transcription, replication, and repair. BET inhibitors create an imbalance between transcription and replication kinetics, exacerbating oncogenic RS and increasing cell death. We hypothesized that BET inhibition would decrease OS tumor growth via modulation of gene expression and increased RS. Bivalent BET inhibitor AZD5153 monotherapy significantly suppressed the growth of patient-derived xenografts (PDXs) established from treatment-naïve male and female OS patients. AZD5153-mediated anti-tumor effect correlated with increased γ-H2AX levels, indicative of elevated RS. RNA-sequencing and kinome profiling revealed intra- and inter-tumoral molecular response mechanisms attributable to therapeutic response and potential resistance in BET inhibitor-treated PDX and OS cell lines. Reprogramming of signaling networks involved in DNA damage response, apoptosis, invasion, and Wnt signaling were identified. Combining AZD5153 with salvage agents demonstrated additive-to-synergistic cell growth inhibition in vitro with drug combinations inducing apoptosis. AZD5153 increased DNA-strand breaks that was further enhanced by salvage therapy. In a PDX established from a metastatic lesion of a patient treated with frontline and salvage therapy, a combination of AZD5153 and topotecan was well tolerated and increased survival probability compared to each agent alone. These data suggest that AZD5153 alone or in combination with low-dose salvage therapy holds promise as an efficacious treatment strategy in OS.