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Updated: Oct 16, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer
Yuqing Zhang1,2,3, Emily N Arner1,2,3, Ali Rizvi1
1Hamon Center for Therapeutic Oncology Research, Dallas, TX.
Abstract:
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States with a 5-year survival less than 5%. Resistance to standard therapy and limited response to immune checkpoint blockade due to the immunosuppressive and stroma-rich microenvironment remain major challenges in the treatment of pancreatic cancer. A key cellular program involved in therapy resistance is epithelial plasticity, which is also associated with invasion, metastasis, and evasion of immune surveillance. The receptor tyrosine kinase AXL is a key driver of tumor cell epithelial plasticity. High expression and activity of AXL is associated with poor prognosis, metastasis, and therapy resistance in multiple types of cancer including pancreatic. Here, we show that an AXL inhibitor (TP-0903), has antitumor and therapy sensitizing effects in preclinical models of pancreatic ductal adenocarcinoma (PDA). We demonstrate that TP-0903 as a single agent or in combination with gemcitabine and/or anti-programmed cell death protein 1 (PD1) antibody has anti-metastatic and anti-tumor effects in PDA tumor bearing mice, leading to increased survival. In addition, gene expression analysis of tumors demonstrated upregulation of pro-inflammatory and immune activation genes in tumors from TP-0903-treated animals compared with the vehicle, indicating pharmacologic inhibition of AXL activation leads to an immunostimulatory microenvironment. This effect was augmented when TP-0903 was combined with gemcitabine and anti-PD1 antibody. These results provide clear rationale for evaluating TP-0903 in the treatment of pancreatic cancer.
Insights
An AXL inhibitor, TP-0903, shows promise in treating pancreatic cancer by reducing metastasis and enhancing therapy response. This novel approach may overcome treatment resistance and improve survival rates in pancreatic ductal adenocarcinoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Pancreatic cancer has a poor prognosis, with limited treatment options due to therapy resistance and an immunosuppressive tumor microenvironment.
- Epithelial plasticity, driven by receptor tyrosine kinase AXL, contributes to pancreatic cancer's invasion, metastasis, and immune evasion.
- High AXL expression correlates with poor outcomes in various cancers, including pancreatic cancer.
Purpose of the Study:
- To investigate the therapeutic potential of the AXL inhibitor TP-0903 in preclinical models of pancreatic ductal adenocarcinoma (PDA).
- To evaluate the effects of TP-0903, alone and in combination with standard therapies, on tumor growth, metastasis, and survival.
- To assess the impact of AXL inhibition on the tumor microenvironment and immune activation.
Main Methods:
- Utilized preclinical mouse models of pancreatic ductal adenocarcinoma (PDA).
- Administered TP-0903 as a single agent or in combination with gemcitabine and/or anti-PD1 antibody.
- Assessed anti-tumor and anti-metastatic effects, survival rates, and analyzed gene expression in tumors.
Main Results:
- TP-0903 demonstrated significant anti-tumor and anti-metastatic effects in PDA models, improving survival.
- Combination therapy with TP-0903, gemcitabine, and anti-PD1 antibody showed augmented anti-tumor activity.
- TP-0903 treatment led to an upregulation of pro-inflammatory and immune activation genes, suggesting an immunostimulatory microenvironment.
Conclusions:
- Pharmacologic inhibition of AXL with TP-0903 exhibits antitumor and therapy-sensitizing effects in pancreatic cancer.
- TP-0903 holds potential for overcoming resistance to standard therapies and immune checkpoint blockade in pancreatic cancer.
- These findings provide a strong rationale for clinical evaluation of TP-0903 in pancreatic cancer treatment.
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