Browsing by Author "Barghi, Farinaz"

Now showing 1 - 4 of 4
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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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    Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma
    (MDPI, 2020-08-26) Pandya, Pankita H.; Cheng, Lijun; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Tang, Shan; Sinn, Anthony L.; Trowbridge, Melissa A.; Coy, Kathryn L.; Bailey, Barbara J.; Young, Courtney N.; Ding, Jixin; Dobrota, Erika A.; Dyer, Savannah; Elmi, Adily; Thompson, Quinton; Barghi, Farinaz; Shultz, Jeremiah; Albright, Eric A.; Shannon, Harlan E.; Murray, Mary E.; Marshall, Mark S.; Ferguson, Michael J.; Bertrand, Todd E.; Wurtz, L. Daniel; Batra, Sandeep; Li, Lang; Renbarger, Jamie L.; Pollok, Karen E.; Pediatrics, School of Medicine
    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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    Therapeutic Targeting of the Cell Cycle in Pediatric, Adolescent and Young Adult Osteosarcoma
    (2024-01) Barghi, Farinaz; Pollok, Karen E.; Liu, Yunlong; Pandya, Pankita H.; Sears, Catherin R.
    Treating pediatric, adolescent, and young adult (AYA) osteosarcoma (OS) is challenging due to its aggressiveness, genetic complexity, lack of standard therapies, and chemotherapy long term side effects. Genetically guided therapies could enhance outcomes. This study explores palbociclib, an inhibitor of Cyclin-Dependent Kinases 4/6 (CDK4/6), targeting the cell cycle based on genomic insights. CDK4/6 forms complexes with cyclin D, facilitating retinoblastoma1 (RB1) phosphorylation, leading to RB1 dissociation from E2F transcription factor and promoting cell cycle progression. CDK4/6 inhibitor (CDK4/6i) monotherapy shows limited efficacy due to cytostatic responses and resistance through compensatory pathways like PI3K/mTOR pathway, common in OS. Hence, dual inhibition of CDK4/6 and PI3K/mTOR could be effective for OS treatment. In this study, OS patient-derived xenografts (PDX) models RHT-96 (from a treatment-naïve patient) and TT2-77 (from a pretreated patient with metastatic disease) were used. Molecular signatures (CDKN2A deletion, CCND3 amplification, RB1 proficiency) indicating sensitivity to CDK4/6i , were verified in both PDX models. Short-term palbociclib treatment in pretreated TT2-77 PDX upregulated PI3K/mTOR pathway via upstream growth factor receptors, highlighting the necessity for combination therapy with CDK4/6i. Both PDXs were treated long-term with CDK4/6i (50 mg/kg palbociclib), PI3K/mTOR inhibitor (50 mg/kg voxtalisib) or combination treatment. In both PDXs, combination treatment was more efficacious than single-agent following prolonged treatment and well-tolerated based on body weight and histological analyses. The increased efficacy of the combination treatment in the naïve RHT-96 PDX was associated with decreased pathway activity of PI3K/mTOR, and autophagy induction. In RB1 proficient OS cells, the combination treatment led to additive-to-synergistic growth inhibition, G1 arrest, and induced senescence and autophagy, as shown by senescence biomarker (beta-galactosidase) and autophagy markers. In the human OS lung colonization 143B model, combination treatment improved survival and reduced metastatic burden compared to the vehicle group, as observed in body scoring, quantification of human tumor cells, and histological analyses. Our data provide evidence that combining palbociclib and voxtalisib is safe, efficacious, and enhances palbociclib efficiency in both naïve and pretreated PDXs, as well as humanized lung colonization models of pediatric and AYA OS. This provides the rationale for earlier therapeutic intervention in patients with CDK4/6 hyperactivation signatures.