Caring for Carcinoid Foundation

"The overall goal of this proposal is to identify and validate molecular targets for therapy in a newly developed human midgut carcinoid tumor cell line."

Abstract (lay version)

"Utilizing a newly established cell line (there are only 2 in the world), we will determine proteins that mediate tumor growth by standard molecular biologic techniques. Once these targets are identified, we will use combinations of targeted therapies to inhibit growth in a novel model of liver metastasis in mice. We will also establish new cell lines, as we have a large clinical practice treating patients with carcinoid tumors. Identification of molecular targets will allow for the rapid development of new therapies to be tested in subsequent years in clinical trials by Dr. James Yao and colleagues."

Biography

Seung Kim, M.D., Ph.D. - Stanford University

Associate Professor in Developmental Biology at Stanford University

Amount

$250,000

Duration

2 years

Research Objectives

"We propose to generate mouse models of carcinoid using conditional genetics. These mouse lines will permit investigation of tumor pathogenesis and create tumor-derived cell lines. Collectively these novel reagents will facilitate genomic, physiologic, and pharmacologic studies of carcinoid."

Abstract (lay version)

"The study and treatment of human diseases has benefited enormously from the development of animal disease models, but such models are lacking for the classic form of human carcinoid. Thus, we are motivated to create new carcinoid models using the mouse, a laboratory animal for which powerful genetic tools have been developed. Carcinoid tumors are neuroendocrine (NE) tumors, and prior studies have revealed that the Tag oncogene is sufficient to produce NE tumors at multiple sites in mice. By activating the Tag oncogene only in neuroendocrine cells of the gastrointestinal and pulmonary tracts, we aim to direct tumor formation at specific locations where carcinoids are known to develop. Our strategies for producing carcinoid in mice would allow us to control the timing and location of tumor formation. Creation of these mice should be useful for isolating carcinoid cells, which will facilitate studies of tumor cell genetics and physiology. These cells and the mice should prove valuable for identifying signals that regulate carcinoid growth, and for testing candidate compounds for activity in arresting carcinoid tumors."

Biography

Andrew Leiter, M.D., Ph.D. - Tufts University

Professor of Medicine at Tufts University

Amount

$250,000

Duration

2 years

Research Objectives

"To identify and characterize precursor cells that differentiate into serotonin-expressing enteroendocrine cells and to identify a pathway controlling their differentiation that is distinct from other enteroendocrine cells."

Abstract (lay version)

"Gastrointestinal carcinoid tumors express serotonin and therefore are thought to arise from serotonin-expressing intestinal endocrine cells. At present, relatively little genetic information is available to support this theory. This proposal is based on two observations made by Dr. Leiter. First, some normal serotonin expressing cells develop differently than all other hormone-producing cells in the GI tract by a novel yet uncharacterized pathway. Second, Dr. Leiter has induced small intestinal tumors producing serotonin in genetically altered (transgenic) mice by putting a mutant gene into immature endocrine cells. The cancers in these mice arise from changes in a gene similar to mutations seen in some aggressive human carcinoids. This proposal aims to identify how serotonin cells become specialized to produce this hormone and to examine their potential to form carcinoid tumors in mice. Understanding how potentially normal cells give rise to carcinoids will be important for identifying new therapeutic targets for treating these tumors."

Biography

Matthew Meyerson, M.D., Ph.D. - Dana-Farber Cancer Institute

Associate Professor of Pathology at Dana-Farber Cancer Institute and Director of the Center for Cancer Genome Discovery

Amount

$250,000

Duration

2 years

Research Objectives

"1. To define the changes in histone H3 lysine 4 methylation that are dependent on menin function, first in model cellular systems and subsequently in carcinoid tumors. 2. To identify histone demethylase enzymes involved in the demethylation of histone H3 lysine 4."

Abstract (lay version)

"The most common known mutation in human carcinoid tumors is in the MEN1 gene. My laboratory has uncovered a biochemical function for the menin protein produced by this gene. Menin modifies the structure of histone proteins that are bound to DNA. The goal of this project is to map the specific modifications made to the histone proteins and also to look for enzymes whose action counteracts the activity of menin. Since menin function is absent in carcinoid tumors, inhibiting enzymes with opposite activity may be useful for carcinoid treatment."

Biography

2005 - $1 million awarded

Daniel Chung, M.D. - Massachusetts General Hospital

Director of the Gastrointestinal Cancer Genetics Clinic at Massachusetts General Hospital and Assistant Professor of Medicine at Harvard Medical School

Amount

$300,000

Duration

3 years

Research Objectives

Dr. Chung’s research focuses on determining whether there are unique protein expression patterns in gastrointestinal (GI) neuroendocrine tumors that can provide novel insights into disease pathogenesis. Unfortunately, the current understanding of the molecular pathogenesis of GI neuroendocrine tumors lags far behind that of most malignancies.

With a research grant from the Caring for Carcinoid Foundation, Dr. Chung is performing proteomic analysis of carcinoid to address this critical gap in scientific knowledge. Analysis of the proteome is inherently more challenging than that of the genome, but the potential insights that can be gained are unobtainable through a gene-based approach. Proteomic technologies have also matured so that comprehensive and meaningful analyses of tumor samples are now realistic. GI neuroendocrine tumors lend themselves to this type of proteomic analysis because they are rather homogeneous in terms of their cellular composition.

Dr. Chung’s research will define the proteomic profile of neuroendocrine tumors relative to normal tissue. Dr. Chung will also address several other questions, such as whether there may be protein markers that can distinguish benign versus malignant disease, predict natural history, or serve as novel therapeutic targets.

Dr. Chung is in a unique position to perform his proteomic study of carcinoid because of the extensive tumor bank that he and Dr. Kulke created. Dr. Chung is also undertaking a gene array expression strategy. The combination of complementary data sets from Dr. Chung’s DNA microarray and proteomic approaches will be a powerful one.

Biography

Ramesh Shivdasani, M.D., Ph.D. - Dana-Farber Cancer Institute

Physician and Researcher in the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School

Amount

$500,000

Duration

5 years

Research Objectives

Dr. Shivdasani’s research focuses on the mechanisms of cell differentiation for carcinoid and other cancers. Dr. Shivdasani runs a molecular biology laboratory at Dana-Farber Cancer Institute and recently spearheaded the creation of the Translational Research Laboratory in the Gastrointestinal Cancer Center.

With a research grant from the Caring for Carcinoid Foundation, Dr. Shivdasani is focusing on understanding carcinoid at the level of the target cell. Dr. Shivdasani is determining, for example, what makes gastrointestinal cells in the first place and what drives their specific differentiation toward enteroendocrine cells, the type present in carcinoid tumors. Specifically, Dr. Shivdasani is pursuing four lines of carcinoid research:

Investigating the biology of the gastrointestinal cell type that dominates in carcinoid tumors
Mapping all chromosomal abnormalities that characterize gastrointestinal neuroendocrine malignances and integrating that information with genes that are significantly dysregulated in this class of tumors
Analyzing the results within the larger context of interrelated cell activity to create a conceptual framework that integrates genetics with tumor and normal cell biology
Evaluating specific hypotheses in rigorous and physiologically relevant experimental models

This research will help Dr. Shivdasani decode the rules that govern the fates of different categories of gastrointestinal cells, specifically neuroendocrine cells. Dr. Shivdasani’s goal is to discover the key pathways of carcinoid cells. This missing piece of the carcinoid puzzle should unlock a new platform from which to launch an investigation into new therapeutic targets and test selected targeted therapies.

Biography

Matthew Kulke, M.D. - Dana-Farber Cancer Institute

Physician and Researcher in the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School

Amount

$250,000

Duration

5 years

Research Objectives

Dr. Kulke’s research focuses on discovering new treatments for carcinoid and pancreatic endocrine tumors. Over the past two years, Dr. Kulke has created one of the country’s largest tumor databases for carcinoid and pancreatic endocrine cancer. Specifically, he has facilitated the collection of tumor specimens, blood and urine samples, and clinical data of carcinoid and pancreatic endocrine patients from all over the world.

With a research grant from the Caring for Carcinoid Foundation, Dr. Kulke is now leveraging this tumor database to undertake unprecedented research. Dr. Kulke is analyzing the genes and biologic substances, such as hormones and cell proteins, in carcinoid patients and linking this information to disease occurrence and progression. Specifically, Dr. Kulke is pursuing four lines of carcinoid research:

Identifying carcinoid risk factors
Evaluating prognostic indicators
Specifying therapeutic targets
Performing clinical trials

Dr. Kulke is taking many actions to complete these four lines of research. For example, he is working with scientists and technologies located at the Belfer Center for Cancer Genomics to clarify the genetic particularities of carcinoid tumors. To analyze the complex series of events that occur when a cell turns malignant, Dr. Kulke is using gene profiling technologies that perform this analysis not “one gene at a time”, but thousands of genes at a time. Dr. Kulke’s goal is to lead comprehensive, systematic, and ongoing genetic analyses of carcinoid tumors that will identify the specific genetic expressions associated with the various stages of tumor growth and generate the information required to develop novel, targeted therapies specifically for carcinoid patients.

Biography