Caring for Carcinoid Foundation

"The development of more effective treatment regimens for patients with carcinoid metastasis and carcinoid syndrome has been hampered by the lack of effective in vivo models, which recapitulate the disease process in humans." - Dr. David Tuveson

Dr. Tuveson's laboratory will use their expertise in forward genetics and mouse cancer modeling to mutagenize enterochromaffin cells (ECCs), enteroendocrine cells found in the digestive and respiratory tracts, to both generate models of NET and simultaneously identify genes and pathways that promote NET formation.

Institution

Cancer Research UK, Cambridge Research Institute

Investigator

David Tuveson, MD, PhD

Amount

$300,000

Duration

2 years

Research Objectives

To generate the first accurate mouse models of neuroendocrine tumors
To establish enterochromaffic cell specific creERT2 alleles
To identify genes and pathways that cause NET formation following transposon-mediated mutagenesis in adult enterochromaffic cells

Abstract

Patients with neuroendocrine tumors (including carcinoid) have few therapeutics options besides surgery and investigational agents, and this is a frustrating reality in my clinical practice when I encounter such patients. Currently, there is no suitable animal model that recapitulates the human diseases to allow the development of new medical interventions for NETs. Also, the cause of NET has been difficult to establish from previous studies of clinical specimens. In this application, I proposed to develop animal (mouse) models of NET by taking advantage of a new method of generating tumor models with "jumping genes" that are called transposons. Any NET that develop in such mice will then be studied to quickly determine the genes that cause NET, and this information will both be useful way to determine the cause of NET and to establish reproducible models of NET for the field. This proposal will involve the training of a new physician scientist to facilitate the development of an independent NET cancer specialist.

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Pancreatic Neuroendocrine Tumor Genome Project

As with other cancers, the discovery of mutated genes is essential to understand pancreatic neuroendocrine cancer. Delayed diagnosis, and the lack of good prognostic markers and new treatments can be attributed to the fact that the pathogenesis of pancreatic neuroendocrine tumors is not understood.

Dr. Papadopoulos’ team of experts proposes to sequence all 21,000 protein-coding genes in a series of pancreatic neuroendocrine tumors. Investigators will first define the genes that are mutated in a sample of twelve tumors and then determine the prevalence of the most promising mutations by sequencing the relevant genes in additional tumors.

By identifying the genetic signature of pancreatic neuroendocrine tumors, Dr. Papadopoulos’ study will lead directly to new diagnostic tools and gene-specific therapies. Additionally, the discoveries made in this study will create opportunities for advancement in the field of pancreatic neuroendocrine tumor research.

Institution

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University

Investigator

Nickolas Papadopoulos, PhD

Amount

$500,000

Duration

2 years

Research Objectives

To identify the genetic changes underlying the development of human pancreatic neuroendocrine tumors
To use discoveries for the development of diagnostics and new targeted therapies

Abstract

Simply put, cancer is a genetic disease. Mutations in certain genes promote the growth of cancer cells. Discovery of the mutated genes is the critical step in understanding any form of cancer. Moreover, the mutations that are identified can be used to develop novel diagnostic tools and highly specific, targeted therapies. Despite their importance, little is known about the genetics of pancreatic endocrine neoplasms (pancreatic neuroendocrine tumors). The pancreatic research team at Johns Hopkins is proposing to identify the genes that are mutated in pancreatic endocrine neoplasms by sequencing all the genes that code for proteins using state-of-the-art technologies. It is our hope that this study will not only lead directly to new diagnostic tools and gene-specific therapies, but that it will also open the door to other investigators to follow-up on the discoveries we make.

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2009 - $1.5 million awarded

Carcinoid Cancer Genome Project

"Taking a closer look at these tumors allows us to learn critical information about the genetic landscape of this disease. Our study could achieve a real impact on the care of carcinoid patients." - Dr. Matthew Meyerson

CFCF will initiate a large-scale genomic survey of carcinoid tumors led by Matthew Meyerson, M.D., Ph.D., Director of the Center for Cancer Genome Discovery at the Dana-Farber Cancer Institute. The goal of this study is to find novel targets for carcinoid treatment and to facilitate the development of new targeted therapies and better diagnostics for patients. This is the first genomic study of this magnitude for carcinoid tumors.

To read more on this ground-breaking project, click here & here.

Institution

Dana-Farber Cancer Institute

Investigator

Matthew Meyereson, MD, PhD

Amount

$1.5 million

Duration

3 years

Research Objectives

To discover candidate oncogenes in carcinoid.
To determine which candidate genes have oncogenic activity.
Long-term objectives: To indentify novel targets for carcinoid treatment and to facilitate the development of new targeted therapies

Abstract

DNA alterations in key genes cause cancer. This fact is more than academic, because targeted therapies that block the action of these altered genes can treat cancer. The first goal of this project is to indentify which genes are altered in carcinoid, by studying carcinoid DNA with the most powerful new methods available, and comparing these genes sequences to genes from normal tissue. The second goal is to decipher which of these genes can promote tumor growth. The long-term goal is to find new drugs that block the effects of carcinoid-causing genes and thereby kill carcinoid cells.

Biography

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Mary Terese Hartzheim Award for Neuroendocrine Tumor Research

CFCF is funding a Young Investigator Award for NET research through the American Gastroenterological Association (AGA). This Award is made possible by a partnership with the MTH Foundation. The “Mary Terese Hartzheim Award for Neuroendocrine Tumor Research” is the first of its kind to attract young investigators to research the biology of NETs and the development of novel therapeutics for NETs.

To learn more about Mary Terese Hartzheim and the MTH Foundation please click here

Institution

Massachusetts General Hospital

Investigator

Michael Choi, MD

Amount

$150,000

Duration

2 years

Research Project

Molecular mechanisms involved in enteroendocrine cell differentiation and neuroendocrine tumorigenesis

Abstract

The technology of cellular reprogramming from the stem cell field offers us a novel method to investigate the neuroendocrine tumor (NET) biology. We hypothesize that new insights will be gained by reprogramming cellular identity of both normal and tumor cells by forcibly expressing a correct set of transcription factors, genes that turn on or off other genes. Such change in cellular identity could result in transdifferentiation where one cell lineage type changes to another or in dedifferentiation where cells acquire potential to become many different cell types, similar to stem cells. Broadly, we propose to investigate the biology of endocrine cells and their counterpart NET cells by inducing transdifferentiation or dedifferentiation

This research plan will not only enhance molecular understanding of enteroendocrine cell and NET biology, but will also serve as a vehicle for me to successfully enter the field of NET research as an independent physician-scientist. The Mary Terese Hartzheim Award will provide the means necessary for this critical transition in my research career.

Biography

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2008 - $400,000 awarded

Caring for Carcinoid Foundation Neuroendocrine Tumor Bioconsortium

CFCF will collaborate with leading cancer research centers to launch the CFCF Neuroendocrine Tumor Bioconsortium. This Bioconsortium will link the biobanks at five centers, which specialize in carcinoid and related NETs. A biobank is a collection of stored tissue specimens linked to a database of anonymous patient information. Because of this collaboration, researchers will be able to identify connections between the molecular characteristics of tissue samples and the patient data associated with individual disease progression, and to test and validate hypotheses that arise from these correlations. This exciting collaboration will enable scientists to characterize specific disease pathways, uncover genetic and environmental indicators of disease, identify novel drug targets, and tailor treatment programs to the needs of patients.

Research Objectives

Objectives: To build a Neuroendocrine Tumor Biospecimen Consortium (NTBC), thereby enabling investigations of:

Etiology and molecular epidemiology of neuroendocrine tumors
Early detection and diagnosis of neuroendocrine tumors
Predictors of patient outcome and treatment toxicity
Novel drug targets

Abstract

The National Cancer Institute has recently identified the lack of high quality, highly characterized biospecimens as the number one roadblock to translational research and the identification of better treatments for cancer. Generally, the term human biospecimen "bank" describes a collection of stored tissue specimens that have been surgically removed under uniform procedures, as well as a database of de-identified patient information that can be connected to each tissue sample. Access to even a fraction of a specimen enables researchers to draw connections between the state of the specimen on a molecular level and patient data associated with individual disease progression, and to test and validate hypotheses that arise from these observations. More specifically, well-designed tissue repositories are useful for characterizing specific disease pathways, uncovering genetic and environmental indicators of disease, and identifying drug targets; all of which are vital steps in understanding how to prevent and cure a disease. Such repositories are difficult to develop for rare diseases such as neuroendocrine tumors, since most cancer centers do not see enough patients to collect a critical mass of samples to conduct truly robust studies. Further, if tissue collection procedures or patient data content varies between institutional biospecimen banks, it is challenging to use pooled data in a scientifically meaningful way. The Neuroendocrine Tumor Biospecimen Consortium (NTBC) seeks to redress this imbalance through linking the carcinoid-tissue banking efforts of five separate institutions that are strongly invested in neuroendocrine tumor research: Dana-Farber Cancer Institute, MD Anderson Cancer Center, Massachusetts General Hospital, Stanford University Cancer Center, and Memorial Sloan Kettering Cancer Center.

This initial platform will be scalable, and should be easily replicated at additional institutions with an interest in pursuing neuroendocrine tumor research.

Institution

Dana-Farber Cancer Institute

Investigator

Matthew Kulke, MD

Amount

$80, 000

Duration

2 years

Personal Statement:

The systematic collection of tissue and associated clinical data within the CFCF neuroendocrine tumor bioconsortium will be an enormous advantage to neuroendocrine tumor research. The analysis of tissue and associated clinical information will allow us to discover the molecular and genetic changes in neuroendocrine tumors, identify novel drug targets, and tailor treatment programs to the needs of patients. We are delighted that the Caring for Carcinoid Foundation is supporting this effort, and are proud to be a part of the consortium.

Biography

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Institution

Massachusetts General Hospital

Investigator

Daniel Chung, MD

Amount

$80, 000

Duration

2 years

Personal Statement

I am thrilled to participate in the NTBC for several reasons. Advances in treatments for carcinoids and neuroendocrine tumors have been slow, and the identification of new therapies depends upon a better understanding of the tumors on a molecular level. The development of a tissue resource that maximizes the number of tumors available for analysis is an ideal way to reach this goal more quickly. Equally important is a careful clinical characterization of each tumor, because no two tumors are alike and research efforts are more productive when tumors that are the most similar can be analyzed together.

Biography

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Institution

MD Anderson Cancer Center

Investigator

James Yao, MD

Amount

$80, 000

Duration

2 years

Personal Statement

Biography

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Institution

Memorial Sloan Kettering Cancer Center

Investigator

Diane Reidy-Lagunes, MD

Amount

$80, 000

Duration

2 years

Personal Statement

I decided to join the NTBC because I believe collaboration is critical in allowing us to find better treatments for this disease. Neuroendocrine tumors pose a significant challenge because it is a rare tumor that can vary in its behavior and degree of aggressiveness. In addition, there is a lack of standard approaches for treatment. It is only through such teamwork that scientific advancement will proceed. A better understanding of NET biology is urgently needed, with emphasis on molecular genetics. Better symptom control and understanding of the hormone related symptoms are also vital in improving quality of life in our patients with NET.

Through the clinical history, pathology, and blood samples of NTBC, I believe we will be able to identify genes and molecular markers as well as possibly unravel the mechanisms that lead to the development of neuroendocrine tumors. It is my hope that this information will enable us to identify new and better treatments for our patients.

Biography

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Institution

Stanford Cancer Center

Investigator

Teri Longacre, MD

Amount

$80, 000

Duration

2 years

Personal Statement

Biography

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2006 - $1 million awarded

Lee Ellis, M.D. - M. D. Anderson Cancer Center

Professor of Surgery and Professor of Cancer Biology at M. D. Anderson Cancer Center

Amount

$250,000

Duration

2 years

Research Objectives

"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



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