He Biao Ph.D.

Lay Description

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.

Scientific Abstract

Bronchioalveolar carcinoma (BAC) is a distinct subtype of non-small cell lung cancer (NSCLC), the latter the most common form of lung cancer. Its incidence has been the subject of much debate with some studies arguing BAC is the rise and may now comprise up to 20% of all lung cancers. This controversy may reflect the decision by the WHO in 1999 to restrict the diagnosis of BAC to non invasive lung cancers growing along the alveolar walls of the lung in a lepidic growth pattern. Pure BAC is rare, comprising 3 4% of lung cancers, as contrasted with the vast majority of BACs seen in the clinic, which are mixed tumors exhibiting varying degrees of invasiveness.

While BAC is primarily a tobacco-related disease, it occurs disproportionately in non smokers and women, raising intriguing questions about its tumor biology. Tumors of non smokers lack the genetic mutations induced by tobacco carcinogens, and therefore make for a more simplified model for studying BAC. BAC is typically diagnosed at an advanced stage when surgery is not an option and also appears chemo-insensitive. This underscores the urgent need to elucidate its tumor biology and to develop novel targeted therapies against the disease.

Wnt proteins comprise a family of highly conserved secreted signaling molecules regulating cell to-cell interactions. Wnt expression initiates pathways leading to transcription of cell proliferation signals through cytosolic pooling of ß-catenin and inhibition of apoptosis. Our group has previously demonstrated that Wnt 1, Wnt-2, and Wnt 16 genes are overexpressed in lung adenocarcinoma and that Wnt signaling is overactivated downstream in the pathway. Our preliminary data showed marked overexpression, compared with normal lung, of Wnt-1 and Wnt-2 genes in a set of BAC tumor specimens. When treated with Wnt-1 and Wnt-2 monoclonal antibodies, and RNAi, we observed decreased cell proliferation and induction of apoptosis in both lung cancer and BAC cell lines.

We propose to analyze expression patterns of Wnt signaling in human BAC tumor specimens and to identify candidate genes as putative therapeutic targets. We will isolate tumor RNA through laser capture microdissection from more than 100 snap frozen samples of surgically-resected BAC currently stored in the Thoracic Oncology Tumor Bank at UCSF. We will then amplify RNA from tumor and matched normal lung using sense RNA amplification technology, and perform an analysis with Wnt microarrays consisting of Wnt 1-19 isoforms, and downstream signals including Wif, Dvl, ß-catenin, and Survivin. We expect to confirm the presence of aberrant Wnt signaling in BAC. We anticipate that a subset of Wnt pathway genes, most notably Wnt-1, Wnt-2 will be abnormally expressed, confirming our preliminary data. We propose to identify genes that are consistently overexpressed in BAC and validate them using RT-PCR and Western blotting techniques. We will then develop monoclonal antibodies and siRNA, testing them for efficacy in vitro in BAC cell lines. Finally, we will develop expression profiles correlated with BAC histology and match them to our clinical database based on patient characteristics and clinical course.