المؤلفون: Damayanti, Nur P., Saadatzadeh, M. Reza, Dobrota, Erika, Ordaz, Josue D., Bailey, Barbara J., Pandya, Pankita H., Bijangi-Vishehsaraei, Khadijeh, Shannon, Harlan E., Alfonso, Anthony, Coy, Kathy, Trowbridge, Melissa, Sinn, Anthony L., Zhang, Zhong-Yin, Gallagher, Rosa I., Wulfkuhle, Julia, Petricoin, Emanuel, Richardson, Angela M., Marshall, Mark S., Lion, Alex, Ferguson, Michael J.

المصدر: Scientific Reports; 6/6/2023, Vol. 13 Issue 1, p1-18, 18p

مصطلحات موضوعية: CELL fusion, PROGRESSION-free survival, PROTEIN microarrays, CHROMOSOMAL rearrangement, PI3K/AKT pathway

مستخلص: Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794–0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4–9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions. [ABSTRACT FROM AUTHOR]

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المؤلفون: Lehman, Christine E., Spencer, Adam, Hall, Sarah, Shaw, Jeremy J. P., Wulfkuhle, Julia, Petricoin, Emanuel F., Bekiranov, Stefan, Jameson, Mark J., Gioeli, Daniel

المصدر: Scientific Reports; 5/24/2021, Vol. 11 Issue 1, p1-14, 14p

مصطلحات موضوعية: SOMATOMEDIN C, PROTEIN-tyrosine kinase inhibitors, HEAD & neck cancer, CELLULAR signal transduction, PROTEOMICS

مستخلص: Head and neck cancer is the sixth most common cancer worldwide with a 5-year survival of only 65%. Targeting compensatory signaling pathways may improve therapeutic responses and combat resistance. Utilizing reverse phase protein arrays (RPPA) to assess the proteome and explore mechanisms of synergistic growth inhibition in HNSCC cell lines treated with IGF1R and Src inhibitors, BMS754807 and dasatinib, respectively, we identified focal adhesion signaling as a critical node. Focal Adhesion Kinase (FAK) and Paxillin phosphorylation were decreased as early as 15 min after treatment, and treatment with a FAK inhibitor, PF-562,271, was sufficient to decrease viability in vitro. Treatment of 3D spheroids demonstrated robust cytotoxicity suggesting that the combination of BMS754807 and dasatinib is effective in multiple experimental models. Furthermore, treatment with BMS754807 and dasatinib significantly decreased cell motility, migration, and invasion in multiple HNSCC cell lines. Most strikingly, treatment with BMS754807 and dasatinib, or a FAK inhibitor alone, significantly increased cleaved-PARP in human ex-vivo HNSCC patient tissues demonstrating a potential clinical utility for targeting FAK or the combined targeting of the IGF1R with Src. This ex-vivo result further confirms FAK as a vital signaling node of this combinatorial treatment and demonstrates therapeutic potential for targeting FAK in HNSCC patients. [ABSTRACT FROM AUTHOR]

: Copyright of Scientific Reports is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Roller, Devin G., Hoang, Stephen A., Rawls, Kristopher D., Owen, Katherine A., Simmers, Michael B., Figler, Robert A., Wulfkuhle, Julia D., Petricoin, Emanuel F., Wamhoff, Brian R., Gioeli, Daniel

المصدر: Scientific Reports; 3/10/2021, Vol. 11 Issue 1, p1-15, 15p

مصطلحات موضوعية: TUMOR microenvironment, NON-small-cell lung carcinoma, ENDOTHELIAL cells, HEMODYNAMICS, EPIDERMAL growth factor receptors

مستخلص: Lung cancer rates are rising globally and non-small cell lung cancer (NSCLC) has a five year survival rate of only 24%. Unfortunately, the development of drugs to treat cancer is severely hampered by the inefficiency of translating pre-clinical studies into clinical benefit. Thus, we sought to apply a tumor microenvironment system (TMES) to NSCLC. Using microvascular endothelial cells, lung cancer derived fibroblasts, and NSCLC tumor cells in the presence of in vivo tumor-derived hemodynamic flow and transport, we demonstrate that the TMES generates an in-vivo like biological state and predicts drug response to EGFR inhibitors. Transcriptomic and proteomic profiling indicate that the TMES recapitulates the in vivo and patient molecular biological state providing a mechanistic rationale for the predictive nature of the TMES. This work further validates the TMES for modeling patient tumor biology and drug response indicating utility of the TMES as a predictive tool for drug discovery and development and potential for use as a system for patient avatars. [ABSTRACT FROM AUTHOR]

: Copyright of Scientific Reports is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)