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Dynamic Imaging of Sodium Channels in Metastatic Lung Cancer

Institution: Stanford University
Investigator(s): Justin Du Bois, Ph.D.
Award Cycle: 2010 (Cycle 19) Grant #: 19XT-0149 Award: $400,000
Subject Area: Cancer
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Lung cancer is the leading cause of cancer related mortality in the United States. Each year more patients die from lung cancer than from breast, colon, and prostate cancer combined. This alarming statistic is a result of both the frequency and poor prognosis of the disease, with roughly 237,000 new cases each year and only 14% survival of all patients five years after diagnosis. The invasiveness and rapid spread of cancerous cells, or metastasis, within the lung and to other organs is a primary factor linked to the high incidence of mortality. Patients diagnosed with non-metastatic stage IA and IB lung cancer have a five-year survival rate of 67% and 57%, respectively. In contrast, the survival rate for individuals with metastatic lung cancer, classified as stage IV, is only 1%. Our research aims to study a specific class of sodium ion channel proteins that is thought to facilitate metastasis in many cancer types, including small cell and non-small cell lung cancer. Very recent data demonstrates that sodium ion channels are present in certain cancerous cell lines, and that the concentration and cellular distribution of these proteins is linked to cell invasiveness. Efforts to reveal the specific roles of sodium ion channels in cell metastasis can guide the development of novel therapies that arrest the spread of lung cancer.

Voltage-gated sodium ion channels (NaVs) are a class of integral membrane proteins most commonly associated with action potential propagation in excitable cells. Recent studies have revealed that members of this class are expressed in invasive cell types, such as macrophages and neoplastic cells. In small cell and non-small cell lung cancer, experiments using immunohistology and patch clamp electrophysiology provide evidence for a remarkable relationship between NaV distribution and metastatic potential. Using small molecule fluorophores patterned after the potent NaV inhibitor (+)-saxitoxin, we aim to make possible dynamic imaging of NaV trafficking in live lung cancer cell lines. This strategy will allow us to correlate NaV localization with extracellular matrix degradation and with subcellular structures, such as invadopodia, that are associated with increased cancer cell invasiveness. Through the addition of exogenous modifiers prior to imaging, we will probe specific biochemical pathways that regulate NaV distribution. Insights gained from these experiments could make possible the design of molecular therapeutics that alter NaV trafficking and thereby prevent lung cancer metastasis in vivo.

Fluorescent Saxitoxins for Live Cell Imaging of Voltage-gated Sodium Ion Channels Beyond the Optical Diffractin Limit
Periodical: Chemistry and Biology Index Medicus:
Authors: Ondrus, A. E.; Lee, H.-I. D.; Iwanaga, S.; Parsons, W. H.; Andresen, B. M.; Moemer, W. E.; ART
Yr: 2012 Vol: Nbr: 19 Abs: Pg: 902-912