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Target therapy using a small molecule inhibitor against angiogenic receptors in pancreatic cancer
Peter Büchler1, Howard A Reber, Mendel M Roth
1Department of Surgery, UCLA School of Medicine, University of California, Los Angeles, CA 90095-6904, USA.
Purpose:
PD173074, a small molecule inhibitor of VEGF-RII and FGF-RI, targets neoangiogenesis and mitogenesis. This study aimed to analyze a single-compound-driven inhibition of FGF and VEGF receptors in pancreatic cancer.
Experimental Design:
RT-PCR and Western blots were performed to quantify protein expression and phosphorylation. Anchorage dependent and independent growth assays were used to study cell growth. With flow cytometry, cell cycle analysis and apoptosis were studied. In vivo HPAF-II and MIA PaCa-2 cells were xenografted. Animals were treated daily for 10 weeks. Immunohistochemistry was used to quantify microvessel density and apoptosis.
Results:
Highest levels of FGF-RI were detectable in MIA PaCa-2 cells, lowest in HPAF-II cells. PD173074 inhibited cell growth most prominently in cells expressing high levels of FGF-RI. Cell cycle progression was inhibited by blocking transition in the G(0)/G(1) phase, and consequently, apoptosis was increased. In vivo significant inhibition of orthotopic tumor growth was achieved by a combination effect of inhibition of mitogenesis, induction of apoptosis, and reduction of angiogenesis in PD173074-treated animals.
Conclusions:
These data highlight VEGF-RII and FGF-RI as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable pancreatic cancer patients.
Insights
PD173074, an inhibitor of fibroblast growth factor receptor-I (FGF-RI) and vascular endothelial growth factor receptor-II (VEGF-RII), effectively inhibited pancreatic cancer cell growth, apoptosis, and angiogenesis. This suggests potential for tyrosine kinase inhibitors in treating pancreatic cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Pancreatic cancer is a leading cause of cancer-related deaths.
- Neoangiogenesis and mitogenesis are critical processes in tumor growth.
- VEGF and FGF signaling pathways play significant roles in pancreatic cancer progression.
Purpose of the Study:
- To investigate the efficacy of PD173074, a dual inhibitor of VEGF-RII and FGF-RI, in targeting pancreatic cancer.
- To analyze the effects of single-compound inhibition on FGF and VEGF receptors in pancreatic cancer models.
Main Methods:
- Quantitative RT-PCR and Western blotting for protein expression and phosphorylation analysis.
- Cell proliferation assays (anchorage-dependent and -independent) to assess growth inhibition.
- Flow cytometry for cell cycle and apoptosis analysis.
- In vivo xenograft models (HPAF-II and MIA PaCa-2) with daily treatment for 10 weeks.
- Immunohistochemistry to evaluate microvessel density and apoptosis in tumors.
Main Results:
- PD173074 demonstrated potent inhibition of cell growth, particularly in cells with high FGF-RI expression.
- The drug induced cell cycle arrest at the G(0)/G(1) phase and increased apoptosis.
- In vivo studies showed significant inhibition of orthotopic tumor growth.
- Tumor growth inhibition was attributed to reduced mitogenesis, increased apoptosis, and decreased angiogenesis.
Conclusions:
- VEGF-RII and FGF-RI are validated as crucial therapeutic targets in pancreatic cancer.
- PD173074 shows promise as a single-agent therapy or in combination treatments.
- Tyrosine kinase inhibitors represent a potential therapeutic strategy for managing inoperable pancreatic cancer.
