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• W2775354429 abstract "Abstract Background: Neoadjuvant trametinib treatment of patients with locally advanced oral cavity squamous cell carcinoma (OSCC) demonstrates metabolic- and biomarker-based responses (Uppaluri et al., Clin. Can. Res, 2016). Patient response, defined as both metabolic response and decreased ERK phosphorylation in trametinib-treated tumors in comparison to baseline biopsies, was seen in 4/20 patients. We hypothesized that genomic and transcriptomic analyses of the pre- and post-treatment samples would provide insight into biomarkers of response for stratification of patients in future clinical trials. Methods: Tumor biopsies were collected at baseline and post-treatment at surgical resection. To generate patient-derived xenografts (PDX), biopsies from both baseline and post-treatment were implanted into immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Whole exome and RNA sequencing (WES, RNAseq) were performed on baseline specimens and RNA-Seq was also performed on matched post-treatment tumor samples. Successful PDX models were also interrogated with whole exome and RNA-Seq. For PDX therapy, tumor bearing NSG mice were treated with trametinib (GSK1120212) via daily oral gavage (3 mg/kg/dose) or vehicle control and monitored for tumor growth. Results: WES—The mutational landscape of our cohort largely reflected the constellation of mutations present in the TCGA OSCC samples. Mutations in TP53 occurred in 15/20 (75%) of patients, CDKN2A in 8/20 (40%), NOTCH1 in 6/20 (30%), FAT1 in 5/20 (25%) and CASP8 in 5/20 (25%) of patients. Although gain of function mutations in RAS are associated with activation of the RAS/RAF/MEK/ERK pathway, no patients in our trial had RAS, RAF or ERK mutations. RNA-Seq—We identified crosstalk between the MEK/RAF/ERK pathway and the Hippo pathway. Responder patients had significantly higher YAP1 expression at baseline than the non-responders (p=0.0141). Furthermore, treatment with trametinib induced substantial reduction in Hippo pathway associated genes. Matched RNA-Seq analysis of two of three responder patients showed decreased expression of YAP1 and its downstream targets FOXM1 and BIRC5, known mediators of cell survival and metastasis. PDX—We successfully established PDXs in 22 of 39 tumor samples. Comparison of the WES in a subset of early passage PDXs to their matched primary tumors (n=9) demonstrated conservation with the primary tumor mutational content. To evaluate if treatment of the PDX model would reflect in vivo responsiveness of the primary tumor we treated the baseline biopsy PDX of a responder with daily trametinib or vehicle control (n=8 each). Consistent with findings in the patient, all PDXs treated with trametinib had significant decrease in tumor size after 14 days of daily treatment whereas the control treated tumors grew progressively (average tumor volume 52 mm3 and 714 mm3, respectively. p=0.013). As the 14-day short window phase did not allow full tumor responses to mature in patients, we modeled continuous treatment beyond 14 days in the PDX to evaluate for clinical response. Whereas 8/8 vehicle treated PDXs displayed progressive growth, 7/8 trametinib-treated PDXs were dramatically attenuated until eventual escape and outgrowth between days 40-60. Conclusion: In this genomic and functional analysis of samples from a trametinib window trial in OSCC, we identified YAP1 overexpression to be associated with clinical and biomarker response. Functional inhibition of this pathway with trametinib was identified in 2/3 patients with reductions in YAP1, FOXM1 and BIRC5 message. Finally, we demonstrated successful prospective establishment of PDX models that prove useful for confirming patient responses and for pathway specific molecular dissection. This abstract is also being presented as Poster 65. Citation Format: Paul A. Zolkind, Katie M. Campbell, Tianxiang Lin, Zach Skidmore, Ashley Winkler, Erica Barnell, Tusar Giri, Douglas R. Adkins, Malachi Griffith, Gavin P. Dunn, Obi L. Griffith, Ravindra Uppaluri. Genomic and functional correlates from a phase II clinical trial of trametinib in surgically resectable oral cavity squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr PR01." @default.
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• W2775354429 date "2017-11-30" @default.
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• W2775354429 title "Abstract PR01: Genomic and functional correlates from a phase II clinical trial of trametinib in surgically resectable oral cavity squamous cell carcinoma" @default.
• W2775354429 doi "https://doi.org/10.1158/1557-3265.aacrahns17-pr01" @default.
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