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R. Ikemori
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-023 - Nintedanib Selectively Inhibits the Activation and Tumor-Promoting Effects of Fibroblasts from Lung Adenocarcinoma Patients (ID 9981)
09:30 - 09:30 | Author(s): R. Ikemori
- Abstract
Background:
There is growing awareness that tumor-associated fibroblasts (TAFs) play critical roles in both tumor progression and response to therapies in solid tumors including non-small cell lung cancer (NSCLC). Nintedanib (NTD) is a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients in combination with docetaxel. The main goal of this study was to assess how TAFs contribute to the selective therapeutic effects of NTD in lung ADC.
Method:
Because TAFs are largely activated in vivo, patient derived lung TAFs from ADC and squamous cell carcinoma (SCC) patients as well as paired control fibroblasts from non-malignant pulmonary tissue were activated with TGF- β1 in the presence of increasing concentrations of NTD. Conditioned medium was also collected and used to stimulate the growth and invasion of several cancer cell lines. A panel of activation markers indicative of fibrosis were analyzed in TAFs, including alpha-smooth muscle actin, collagen-I/III and P4HA2.
Result:
Nintedanib dose-dependently inhibited the TGF-β1-induced expression of all activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibiton was very modest in SCC-TAFs, suggesting that TAF activation is regulated by different mechanisms in ADC and SCC. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by the conditioned medium from activated TAFs in ADC but not SCC. These results reveal that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD.
Conclusion:
These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumor-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumors.
