Bronchioalveolar carcinoma (BAC) is a subtype of non-small cell lung cancer (NSCLC), the most common form of lung cancer. The overall incidence of BAC has been controversial. Some see its incidence as on the rise, with data suggesting it may comprise up to 20% of all lung cancers. This controversy may reflect the decision in 1999 by the World Heath Organization (WHO) to restrict the definition of BAC to its classic or “pure” form, a non invasive lung cancer growing along the alveolar walls of the lung in a so called lepidic growth pattern. This pure form is relatively rare, comprising perhaps 3 4% of lung cancers. Yet, the vast majority of BACs in clinical practice are mixed tumors exhibiting varying degrees of invasiveness.

Wnt proteins are an important group of secreted signaling molecules regulating numerous interactions in the cell. Wnt genes and Wnt signaling are implicated in lung cancer. When overexpressed (overproduced or hyperactive), they appear to contribute to a cascade of cellular derangement that results in rampant cell proliferation and a failure of defective cells to commit suicide (programmed cell death or apoptosis). Our lab has intensely studied the Wnt signaling pathway and demonstrated that Wnt genes are abnormally expressed in lung cancer.

Our goal is to identify aberrant Wnt signaling active in BAC and to develop novel therapies against it. Our preliminary data show marked overexpression of Wnt-1 and Wnt-2 genes in BAC tumor samples compared with normal tissue. Here, we propose to isolate RNA from 100 surgically-resected BAC tumor specimens and matched normal lung tissue and to measure the expression of Wnt signaling pathway genes through microarray analysis. We expect several Wnt genes and signaling components will be overexpressed as in other chemo resistant cancers. We will then correlate Wnt expression with disease stage or severity, with patient characteristics such as gender and smoking status, and with clinical endpoints, including progression and survival. We will then test Wnt antibodies and RNA inhibitors in culture to determine their ability to kill BAC tumor cells and develop novel targeting agents based on the most responsive compounds.