New Cell Lines and Potential Therapy Targets

Lee Ellis, MD
MD Anderson Cancer Center
Houston, TX 77030

Although advances are being made in the therapy of metastatic carcinoid tumors, true responses to biologic or chemotherapy remains less than 20%. In order to develop new therapeutic approaches for patients with metastatic carcinoid tumors, it is essential to understand the molecular alterations that lead to metastatic disease. Unfortunately, there are very few cancer cell lines that have been developed from carcinoid tumors and the few cell lines that are available are not widely used.

The major objective of our research is to develop newly established carcinoid tumor cell lines and determine targets for potential therapy. Working at a cancer center with a large number of patients with carcinoid tumors who come to surgery has allowed us to develop new human cell lines. We can harvest tissues from patients whose tumor has been removed, process it rapidly, and go through an extended period of selection and validation of these newly developed carcinoid cell lines. To date, we have published the results on the establishment and characterization of the first midgut carcinoid cell line reported in many years (Van Buren et al Clinical Cancer Research 2007). At the present time we are establishing and validating other newly developed carcinoid cell lines that can be used in labs throughout the world. Our first cell line has been shared with over twenty different research groups on several continents.

In very preliminary experiments, we have determined that there are several activated signaling pathways that may be good targets for therapy. One such pathway that appears activated in carcinoid tumors in the mTOR pathway. This pathway is currently being targeted in clinical trials and thus we are not pursuing studies regarding inhibition of this pathway in preclinical models. However we have established that the Src tyrosine kinase signaling molecule is activated in nearly all of our carcinoid tumor cell lines. When we use a Src inhibitor in cell culture, we can inhibit proliferation of these cells. In very preliminary studies in mice, when we use a chemical inhibitor of Src activity we are able to markedly inhibit tumor growth. This work requires validation studies that are ongoing.

We are very excited about the above findings, and are now obtaining clinical specimens to determine the frequency of Src activation in liver metastases from carcinoid tumors. Of course a great deal of further study is necessary in order to understand the role of Src in regulating tumor growth and metastases. However, our preliminary results are exciting and we are pursuing this research with a great deal of enthusiasm.