Virtual Library
Start Your Search
A.C. Roden
Author of
-
+
P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P1.04-086 - Dopamine D2 Receptor Agonists Inhibit Lung Cancer Progression by Reducing Angiogenesis and Tumor Infiltrating Myeloid Derived Suppressor Cells (ID 2922)
09:30 - 09:30 | Author(s): A.C. Roden
- Abstract
Background:
Lung cancer remains the leading cancer related cause of death in the United States and worldwide. Non-small cell lung cancer (NSCLC), the most common subtype (85%) of lung cancer, continues to be associated with a very poor 5-year survival rate of less than 15%. Despite the recent advances in systemic lung cancer treatment due to the introduction new therapies targeting angiogenesis, epidermal growth factor receptor (EGFR), and activin receptor-like kinase-1 (ALK1) in selected patient subgroups, the overall mortality of patients with advanced stage disease remains high. The development of new biomarkers and individualized therapies is needed to overcome these challenges and make significant strides towards improving the care of lung cancer patients. Dopamine (DA) has long been used in the treatment of Parkinson's disease and acute cardiac dysfunction. Given that DA is produced by the sympathetic nerves ending in blood vessels, we originally postulated and later revealed that DA and its dopamine D2 receptor (D~2~R) agonists inhibit VEGF-mediated angiogenesis and also completely block accumulation of tumor ascites and tumor growth in mice. Specifically, we demonstrated that DA stimulates endocytosis of VEGFR-2 via D~2~R thereby preventing angiogenesis by inhibiting VEGF binding, receptor phosphorylation and subsequent downstream signaling. These observations define a possible link between DA and vascular biology. Subsequent studies by numerous investigators clearly demonstrate that this strategy can be successfully applied to various diseases including cancer . Correspondingly, we observed significantly more angiogenesis, tumor growth, and VEGFR-2 phosphorylation in D~2~R knockout mice. We documented D~2~R colocalization with VEGFR-2 and described the molecular mechanism through which D~2~R/VEGFR-2 crosstalk can mediate the dephosphorylation of VEGFR-2. D~2~R agonists have been shown to increase the efficacy of anti-cancer drugs in preclinical models of breast and colon cancer. Here we show that D~2~R agonists inhibit tumor growth in orthotopic murine lung cancer models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells.
Methods:
We utilize syngeneic (LLC1) and human xenograft (A549) orthotopic murine lung cancer models as well as pathological examination of human lung cancer tissue to describe D~2~R agonist-mediated inhibition of lung tumor growth.
Results:
We sought to determine whether Dopamine D2 Receptor (D~2~R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D~2~R agonist therapy. We demonstrate D~2~R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D~2~R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D~2~R in lung endothelium.
Conclusion:
Our results suggest D~2~R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D~2~R expression and a smoking history.
