Xiaoqi Liu Ph.D.

This grant is being fully funded by Elliot’s Legacy, through the Uniting Against Lung Cancer Grant Program.

Lay Description

As the leading cause of cancer deaths in western industrial countries, lung cancer can be grouped into small cell lung cancer and non-small cell lung cancer. Surgery is the most effective therapeutic modality for the cure, but the postoperative prognosis remains poor. To improve the prognosis, establishment of biological markers that determine prognosis and response to a particular treatment is essential. Polo-like kinase 1 (Plk1) expression correlates with cellular proliferation and prognosis of patients with various cancers. Furthermore, Plk1 is found to be overexpressed in many lung cancer cell lines and human lung tumors. Thus, it is proposed that Plk1 might be a valuable diagnostic marker and a potential therapeutic target for lung cancer. Aurora-A and Aurora-B are two members of a protein kinase family that controls several aspects of cell division in mammalian cells. Significantly, Aurora kinases were also found to be overexpressed in many lung cancer cell lines and tumor samples. The objective of this proposal is to validate Plk1 as a novel therapeutic target in small cell lung cancer and discern its role relative to other mitotic kinases such as Aurora B. For that purpose, two specific aims are proposed. First, we will analyze Plk1 loss-of-function phenotypes in various lung cancer and normal cells. Second, we will examine the effect of Plk1 depletion in small cell lung cancer cells expressing different levels of Aurora kinases. It is likely that the data obtained from this proposal will validate Plk1 as a useful therapeutic target in small cell lung cancer, and that possible new approaches based on results of this proposal are likely to be small cell lung cancer specific.

Scientific Abstract

Lung cancer is the leading cause of cancer deaths in the United States. Current therapeutic strategies have shown only moderate success in increasing patient survival. New treatments for lung cancer are greatly needed and our increased understanding of the molecular events will aid in the development of these therapies. Polo-like kinase 1 (Plk1) and Aurora kinases are critical regulators for mitosis. Significantly, both Plk1 and Aurora kinases are overexpressed in many lung cancer cell lines and tumor samples. The objective of this proposal is to validate Plk1 as a novel therapeutic target in small cell lung cancer and discern its role relative to other mitotic kinases such as Aurora B. Towards that end, we will first analyze Plk1 loss-of-function phenotypes in various lung cancer and normal cells. Second, we will examine the phenotype of Plk1 depletion in small cell lung cancer cells expressing different levels of Aurora kinases. Accordingly, we will deplete Plk1 in various lung cancer cells with different levels of Plk1 and normal lung cells and to compare the different phenotypes (Aim 1). To examine the phenotype of Plk1 depletion in lung cancer cells expressing different levels of Aurora kinases, we will deplete Plk1 in lung cells while either inhibiting or overexpressing Aurora kinases. We will also determine whether the various cellular functions of Plk1 are affected by the levels of Aurora kinases. Finally, we will analyze how Plk1 phosphorylation of AIF (apoptosis-inducing factor) controls apoptosis (Aim II). It is very likely that the data obtained from this proposal will validate Plk1 as a useful therapeutic target in small cell lung cancer, and increase our understanding of molecular mechanisms behind this disease. Possible new approaches based on results of this proposal are likely to be small cell lung cancer specific.