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.
Wednesday, July 30, 2008
Wednesday, July 2, 2008
'Modeling' Carcinoid
Seung Kim, MD, PhD
Stanford University School of Medicine
Stanford, CA 94305
What is carcinoid? We know that it constitutes a rare, neuroendocrine tumor, but at the cellular and molecular level, we know very little about what carcinoid is. The past several decades of 'cancer research' has validated repeatedly that a detailed understanding of the basis for how cancers develop, where they come from, and how they progress can lead to development of effective treatments for specific cancers. Moreover, much of the most important work in these areas of cancer research comes from development of specific cancers in animal models, which provide powerful experimental tools for understanding the behavior and origins of cancer. Based on this successful precedent, the Caring for Carcinoid Foundation has made investments in a number of research projects that aim to use experimental animals like mice to investigate the cellular and molecular basis of 'what carcinoid is.'
In my group at Stanford University School of Medicine, we are using CFCF support in attempts to produce a mouse 'model' of carcinoid. This is a somewhat ambitious goal, since no genetic model of carcinoid yet exists. To accomplish this, we are using classical mouse genetic methods to perturb the 'growth control' of cells in the mouse intestine that are thought to be the origins of carcinoid tumors. (The origins and molecular defects leading to carcinoid tumor formation in mice are also being explored by the group led by Dr. Andrew Leiter, another recipient of CFCF support; see Wang et al 2007). In prior studies of endocrine tumors that form in organs like the prostate and pancreas, other groups have previously shown that tumor formation can be 'driven' by production of a foreign viral protein, called 'T-antigen' (Hanahan, 1985; Garabedian et al 1998). These studies led ultimately to new ways of thinking about neuroendocrine tumors in these organs (Hu et al 2004; Karnik et al 2005; Ippolito et al 2005, 2006). Our work in carcinoid, if successful, could lead to better understanding about the molecular and cellular changes that lead to formation of carcinoid tumors, and to better ways of testing and discovering new therapies for carcinoid.
Literature cited:
Garabedian, E.M., et al 1998. A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells. Proc Natl Acad Sci USA 95:15382-7
Hanahan, D. 1985. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115-22.
Hu, Y. et al 2004. RNA interference of achaete-scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites. Proc Natl Acad Sci USA 101:5559-64.
Ippolito, J.E., et al 2006. Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers. Proc Natl Acad Sci USA 103:12505-10.
Ippolito, J.E., et al 2005. An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers. Proc Natl Acad Sci USA 102:9901-6.
Karnik, S.K. et al 2005. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci USA 102:14659-64.
Wang, Y. et al 2007. Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active beta-catenin. Proc Natl Acad Sci USA 104:11328-33.
Stanford University School of Medicine
Stanford, CA 94305
What is carcinoid? We know that it constitutes a rare, neuroendocrine tumor, but at the cellular and molecular level, we know very little about what carcinoid is. The past several decades of 'cancer research' has validated repeatedly that a detailed understanding of the basis for how cancers develop, where they come from, and how they progress can lead to development of effective treatments for specific cancers. Moreover, much of the most important work in these areas of cancer research comes from development of specific cancers in animal models, which provide powerful experimental tools for understanding the behavior and origins of cancer. Based on this successful precedent, the Caring for Carcinoid Foundation has made investments in a number of research projects that aim to use experimental animals like mice to investigate the cellular and molecular basis of 'what carcinoid is.'
In my group at Stanford University School of Medicine, we are using CFCF support in attempts to produce a mouse 'model' of carcinoid. This is a somewhat ambitious goal, since no genetic model of carcinoid yet exists. To accomplish this, we are using classical mouse genetic methods to perturb the 'growth control' of cells in the mouse intestine that are thought to be the origins of carcinoid tumors. (The origins and molecular defects leading to carcinoid tumor formation in mice are also being explored by the group led by Dr. Andrew Leiter, another recipient of CFCF support; see Wang et al 2007). In prior studies of endocrine tumors that form in organs like the prostate and pancreas, other groups have previously shown that tumor formation can be 'driven' by production of a foreign viral protein, called 'T-antigen' (Hanahan, 1985; Garabedian et al 1998). These studies led ultimately to new ways of thinking about neuroendocrine tumors in these organs (Hu et al 2004; Karnik et al 2005; Ippolito et al 2005, 2006). Our work in carcinoid, if successful, could lead to better understanding about the molecular and cellular changes that lead to formation of carcinoid tumors, and to better ways of testing and discovering new therapies for carcinoid.
Literature cited:
Garabedian, E.M., et al 1998. A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells. Proc Natl Acad Sci USA 95:15382-7
Hanahan, D. 1985. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115-22.
Hu, Y. et al 2004. RNA interference of achaete-scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites. Proc Natl Acad Sci USA 101:5559-64.
Ippolito, J.E., et al 2006. Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers. Proc Natl Acad Sci USA 103:12505-10.
Ippolito, J.E., et al 2005. An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers. Proc Natl Acad Sci USA 102:9901-6.
Karnik, S.K. et al 2005. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci USA 102:14659-64.
Wang, Y. et al 2007. Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active beta-catenin. Proc Natl Acad Sci USA 104:11328-33.
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