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F. Zhao
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.03 - New Monoclonal Antibody Targeting on Basic Fibroblast Growth Factor against Lung Cancer In Vitro and In Vivo (ID 3136)
10:55 - 11:00 | Author(s): F. Zhao
- Abstract
Background:
basic fibroblast growth factor (bFGF) is an important molecule that involved with proliferation, angiogenesis, invasion and metastasis in malignant tumors. bFGF in lung adenocarcinoma,squamous cell carcinoma, breast cancer, colon cancer, malignant melanoma cells was highly expressed in the cytoplasm and cytoplasm. bFGF expression was closely related with tumor poor prognosis. FGF pathway activation is a potent driver of lung cancer. Autocrine activation of FGF signaling in NSCLC may contribute to EGFR inhibitor insensitivity. We have developed new monoclonal antibody targeting bFGF (anti-bFGF mAb) which neutralizes bFGF, blocking its ability to activate FGFR1 in treating solid tumors. The antitumor, antiangiogenesis, antimetastatic and reversal multidrug resistance (MDR) activities of anti-bFGF mAb could be investigated.
Methods:
The effect of anti-bFGF mAb on the proliferation of cancer cells was detected by CCK-8 method. Cellular apoptosis, cell cycle distribution and the expression of associated protein were analyzed by flow cytometry. The expressions of associated protein with apoptosis, metastasis, multidrug resistance, anti-bFGF mAb in suppressing cancer cells growth through the PI3K/AKT/mTOR pathway were examined by real-time fluorescence quantitative PCR and Western blotting. Preclinical pharmacokinetics of anti-bFGF mAb was measured in mice.
Results:
Anti-bFGF mAb significantly could inhibit the proliferation and induce apoptosis of lung cancer and show obvious inhibitory effects on the migration of cancer cells and the tube formation of HUVECs in vitro. Treatment of transplanted cancer with anti-bFGF mAb in vivo resulted in significant reduction in tumor size and prolonged survival time of mice. The expression of caspase-3，caspase-9, PARP, and BAX in combination group was higher than those from either agent alone. Anti-bFGF mAb suppressed the PI3K/AKT/mTOR pathway. The radiotherapy sensitization enhancement ratio of the combined treatment group increased 2.37 times by anti-bFGF mAb. bFGF, VEGF expression and MVD were significantly decreased by anti-bFGF mAb. Anti-bFGF mAb could induce down-regulated P-glycoprotein and MDR1. The main pharmacokinetic parameters of anti-bFGF mab were as follows: T1/2α 0.2 h，T1/2β 1.84h and T1/2γ 90.3h. Lung tissue was major organ for deposition of anti-bFGF mAb.
Conclusion:
Anti-bFGF mAbs display remarkable antitumor and antiangiogenic effects in vitro and in vivo. Anti-bFGF mAb is potential therapeutic candidates for lung cancer by effectively suppressing the tumor growth through inhibition of angiogenesis, proliferation, induction of apoptosis and autophagy, reversal of MDR. Further preclinical and systematical investigation on anti-bFGF mAb may help to increase efficacy and safety of molecular target treatment in lung cancer.
