Targeted Imaging and Therapy of Lung Cancer
Abstracts
Initial Award Abstract |
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Lung cancer is the predominant cancer in the developed world and its onset is strongly correlated with smoking habits. Tobacco smoke contains agents that cause cancer. Nicotine, the well-known addictive component of tobacco, itself isn't one of them. However, in recent past years, researchers found that nicotine can directly enhance lung cancer cell growth and promote tumor angiogenesis--tumor new blood vessels formation which can provide oxygen, nutrition for tumor cells. They also reported that these nicotine bioactivities are mediated by alpha7 nicotinic acetylcholine receptors (alpha7-nAChRs). So, alpha7-nAChR pathway became the potential targets for anti-lung cancer therapies.
The involvement of alpha7-nAChR in nicotine-induced lung cancer proliferation and tumor angiogenesis has been well documented. However, the use of molecular imaging to quantitatively measure alpha7-nAChR level change responding to anti-alpha7-nAChR therapy is not investigated.
In this proposal, we seek to image alpha7-nAChR and monitor anti-alpha7-nAChR treatment efficacy by multimodality molecular imaging techniques. Firstly, we verify the key role of nicotine and alpha7-nAChR in lung cancer progression in cell level. And by using alpha7-nAChR siRNA as the therapeutics, we will further elucidate the relationship between nicotine induced alpha7-nAChR expression and lung cancer progression. Secondly, in this study, it is of critical importance to be able to measure alpha7-nAChR level in vivo non-invasively and quantitatively. In this aim we will label an alpha7-nAChR antagonist α-Cobratoxin (α-CbTx) with positrion emitting radionulclide 18F. Quantitative PET imaging with 18F-α-CbTx will not only reflect α7-nAChR expression in vivo but also provide the tumor targeting efficacy and in vivo kinetics of this lung cancer therapeutics. Lastly, in order to fully evaluate and understand the anti-tumor effect of α7-nAChR siRNA, we will test this siRNA in both subcutaneous and orthotopic lung cancer models. Multimodality molecular imaging techniques will be applied to determine the tumor burden (bioluminescence imaging and microCT), tumor metabolism (18F-FDG/PET), tumor proliferation (18F-FLT/PET), and angiogenesis (64Cu-VEGF121). The in vivo results will also be validated by ex vivo histopathological findings.
If successful, we will better the understanding of the relationship between tobacco use and lung cancer as well as find a solution for smoking-related lung cancer treatment. Furthermore, we will establish ways of monitoring effective lung cancer treatment. It is our hope that the newly developed molecular imaging probes, new treatment strategy, and new imaging methods of therapy monitoring will all be translated into the clinic and benefit lung cancer patients and provide solid evidence for the elimination of the use of tobacco products. |
