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Updated: May 10, 2025
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Published on: June 19, 2021
Targeting FGFR Attenuates Tumor Growth in an Anal Squamous Cell Carcinoma Patient Derived Xenograft Model
Thuc Ly1, Athena E Golfinos-Owens2, Naren Raja3
1Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, Kansas City, Kansas, USA.
Abstract:
Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence and limited treatment options. To identify actionable therapeutic targets, we developed a patient-derived xenograft (PDX) model using a metastatic ASCC sample and performed single-cell RNA sequencing. Our analysis confirmed previously reported genetic mutations highly expressed in the sample, along with copy number alterations, and revealed epithelial cancer cell heterogeneity. Notably, epithelial cells exhibited a low hybrid epithelial-mesenchymal transition (hEMT) signature compared to stromal cells. Among epithelial subpopulations, the most abundant cluster displayed high expression of FGFR1-2 and FGF ligands. Treatment with AZD4547, an FGFR1-3 inhibitor, resulted in a significant reduction in tumor volume over time (p = 0.0036). Immunohistochemistry staining for proliferative Ki67 and cleaved caspase 3 suggested ongoing proliferation in residual cells. Fourier-transform infrared (FTIR) spectroscopy of post-treatment residual tumors revealed significant differences in the Amide I and Amide II regions between AZD4547-treated and control groups. These findings demonstrate that FGFR inhibition effectively attenuates ASCC tumor growth and highlights the promise of precision medicine in managing this rare cancer.
Insights
Fibroblast growth factor receptor (FGFR) inhibition significantly reduced anal squamous cell carcinoma (ASCC) tumor growth in a patient-derived xenograft model. This study identifies FGFR as a promising therapeutic target for this rare cancer.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- Anal squamous cell carcinoma (ASCC) is a rare cancer with increasing incidence and few treatment options.
- Identifying novel therapeutic targets is crucial for managing ASCC.
- Patient-derived xenograft (PDX) models offer valuable platforms for preclinical cancer research.
Purpose of the Study:
- To develop a PDX model for metastatic ASCC to identify actionable therapeutic targets.
- To investigate the molecular characteristics and heterogeneity of ASCC using single-cell RNA sequencing.
- To evaluate the efficacy of FGFR inhibition as a treatment strategy for ASCC.
Main Methods:
- Development of an ASCC patient-derived xenograft (PDX) model.
- Single-cell RNA sequencing to analyze tumor cell heterogeneity and gene expression.
- Treatment of PDX models with AZD4547, a FGFR1-3 inhibitor.
- Immunohistochemistry and Fourier-transform infrared (FTIR) spectroscopy for post-treatment analysis.
Main Results:
- Single-cell RNA sequencing revealed genetic mutations, copy number alterations, and epithelial cancer cell heterogeneity.
- A prominent epithelial subpopulation showed high expression of FGFR1-2 and FGF ligands.
- Treatment with AZD4547 significantly reduced tumor volume (p=0.0036).
- FTIR spectroscopy showed distinct molecular changes in residual tumors post-treatment.
Conclusions:
- FGFR inhibition effectively attenuates ASCC tumor growth.
- Targeting FGFR represents a promising precision medicine strategy for ASCC.
- Further research into FGFR signaling pathways in ASCC is warranted.
