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J. Molina
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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)
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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): J. Molina
- 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.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-096 - Randomized, Double-Blind, Placebo-Controlled Trial of Evofosfamide (TH-302) in Combination with Pemetrexed in Advanced ns-NSCLC (ID 659)
09:30 - 09:30 | Author(s): J. Molina
- Abstract
Background:
Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (previously known as TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea.
Methods:
An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential second-line treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measurable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if identified, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m[2]) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m[2]) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS with a one-sided alpha of 0.025. The first patient was enrolled in June 2014; recruitment is ongoing.
Results:
not applicable
Conclusion:
not applicable
