Dr. Stabile is interested in the role of growth factors and hormones in the development of human lung cancer. The hepatocyte growth factor (HGF)/c-Met pathway and the estrogen pathway both play key roles in the development and progression of lung cancer and represent attractive targeted pathways for drug development. Lung cancer kills more Americans every year than any other type of cancer, and the 5-year survival rate is only 16% (Figure 1). Lung cancer patients are typically diagnosed at a late stage and have very few effective therapeutic options. Thus, new targeted strategies are essential to make an impact on this disease.
Figure 1: Top three estimated US cancer deaths for 2007
c-Met is a receptor tyrosine kinase whose activation by HGF can lead to transformation (conversion of a normal cell into a malignant cell) and tumorigenicity (growth of tumors) in a variety of human tissues. Since c-Met and HGF are frequently overexpressed in lung cancer and there is a strong correlation between overexpression and decreased patient survival, the HGF/c-Met signaling pathway is a potential target for tumor control. Primary projects in this area of interest include: 1) studying the development and inhibition of lung carcinogenesis in a novel transgenic mouse model that overexpresses HGF in the airways 2) preclinical development of therapeutic drugs that target this pathway using a variety of techniques such as neutralizing antibodies to HGF, c-Met small molecule inhibitors, c-Met guanidinium-peptide nucleic acid antisense technology and 3) understanding the mechanism of signaling interactions between c-Met and the epidermal growth factor receptor (EGFR) pathway.
Dr. Stabile has successfully developed a murine model that mimics the overproduction of HGF found in human lung tumors and have shown that a single human HGF neutralizing antibody, L2G7, has profound inhibitory effects on development of lung tumors in this transgenic mouse model. Furthermore, lung tumors with K-ras mutation are resistant to blockage of the HGF pathway using L2G7. In addition, we have recently demonstrated the importance of induction of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway and subsequent activation of EGFR by HGF in lung cancer cells. Figure 2 describes the signaling pathway of HGF that we are studying and areas of therapeutic intervention.Another aspect of research involves the estrogen pathway in lung cancer. Lung cancer is becoming increasingly common in women and in the U.S. accounts for more female deaths annually than breast cancer and all other gynecological cancers combined. Epidemiological studies show that male-female differences exist in the presentation of lung cancer. These observations suggest the role of estrogens in lung carcinogenesis. Primary projects in this area of interest include: 1) understanding both genomic and non-genomic effects of estrogen in the lung 2) elucidating cross-talk pathways between estrogen and the EGFR and VEGF pathways in the lung 3) understanding the differences in estrogen signaling in lung cancer patients who actively smoked versus those who never smoked and 4) preclinical development of therapeutic drugs that target this pathway such as estrogen antagonists and aromatase inhibitors.
Figure 2: HGF Signaling Pathway and Direct & Indirect Therapeutic Inhibitors
Dr. Stabile has demonstrated that estrogen receptors are expressed in both normal lung as well as lung tumor cells and that estrogen promotes the growth of lung tumor cells. The growth stimulation is significantly inhibited in vitro and in vivo with the pure estrogen receptor antagonist, ICI 182,780 (Faslodex, fulvestrant).
In addition, Dr. Stabile has demonstrated that the estrogen receptor pathway can cross-talk with the EGFR pathway and targeting both pathways simultaneously using clinically relevant agents show enhanced anti-tumor effects compared to targeting either pathway alone. This drug combination is currently being tested in clinical trials. Dr. Stabile is currently interested in elucidating the role of the newly discovered estrogen receptor, GPR30, which is thought to be responsible for some of the non-genomic actions of estrogen. Figure 3 describes the non-genomic estrogen signaling pathway in the lung that she is studying.
Figure 3: Non-Genomic Mechanism of Estrogen Action Through Rapid Activation of EGFR
The overall goal for both areas of interest are to test different mechanisms by which these pathways control other growth-promoting proteins in the lung and test both available and novel drugs as single agent or combination therapies using novel animal models of lung cancer to determine how to inhibit these pathways most effectively. Optimal preclinical drugs will ultimately be translated to patient clinical trials.
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