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Current Research Grants
Identifying altered epigenetic states and drivers in intentinal carcinoid and pancreatic neuroendocrine tumors
To date, few recurrent mutations have been identified in intestinal carcinoid and pancreatic neuroendocrine tumors and of the few that have been identified the majority are in genes involved in epigenetic regulation. This suggests that epigenetic changes may be underpinning the development and maintenance of carcinoid and pancreatic neuroendocrine tumors. Therefore it is necessary to understand the epigenomes of carcinoid and pancreatic neuroendocrine tumors to identify the root causes of these cancers and to identify new therapeutic targets.
With this funding, Dr. Bernstein and his collaborators will identify epigenetic alterations in carcinoid and pancreatic neuroendocrine tumors to identify new treatment strategies for patients. In the process they will build a public resource of epigenetic states, circuits and molecular dependencies for carcinoid and pancreatic neuroendocrine tumors. They will also generate new carcinoid and pancreatic neuroendocrine tumor models to assess new biomarkers and facilitate future research.
Massachusetts General Hospital, Broad Institute of Harvard and MIT, Dana Farber Cancer Institute
Bradley Bernstein, Daniel Chunk, Matthew Kulke, Ramesh Shivdasani
- Deep characterization of genome-wide chromatin states in primary human carcinoid tumor and pancreatic neuroendocrine tumor samples, with the goal to determine the gene regulatory circuits and aberrant epigenetic states that sustain these tumors and may thus represent therapeutic opportunities.
- Generation of stable new carcinoid tumor and pancreatic neuroendocrine tumor models to assess new biomarkers in carcinoid tumors and their associated stroma and to determine the significance of particular histone modifications through future perturbation studies.
Peptide Receptor Radionuclide Therapy (PRRT) is a technique widely used in Europe for the management of patients with metastatic neuroendocrine tumors. There are currently clinical trials in the United States for PRRT with somatostatin agonists as described below.
PRRT delivers targeted radiation therapy by exploiting the physiology of neuroendocrine tumors. Most neuroendocrine tumors, including carcinoid, have specialized cellular receptors that bind to somatostatin, a hormone that exists naturally in the human body. Scientists have developed artificial “analogs” of somatostatin to attach to these receptors. These are called somatostatin agonists and they include agents like octreotide. Somatostatin agonists are able to target neuroendocrine tumors by binding to the somatostatin receptors present on tumor cells.
The PRRT currently in use typically combines a somatostatin agonist with a radioactive substance called a radionuclide to form highly specialized molecules called radiopeptides. These radiopeptides can bind receptors on tumor cells where they emit radiation that can either 1) be read for diagnostic imaging or 2) kill tumor cells.
Studies have suggested that PRRT with somatostatin agonists can lead to a decrease in tumor size and alleviation of symptoms in some patients. However, not all patients respond and there can be serious side effects including kidney failure. To date, randomized prospective clinical trials, of the nature typically required by the FDA for regulatory approval have not yet been completed. However, there is currently a prospective randomized clinical trial of PRRT with somatostatin agonists in the United States enrolling patients at multiple centers.
The Memorial Sloan-Kettering Clinical Trial
To improve effectiveness while reducing side effects, Dr. Weber and his collaborators have developed a technique for “next generation” PRRT. Instead of somatostatin agonists, this next generation PRRT will employ somatostatin antagonists. Based on preclinical data, Dr. Weber believes that somatostatin receptor antagonists can be more effective and generate fewer side effects than the substances that are currently being used to treat patients.
Specifically, this trial will assess the potential viability of 68 Ga-DOTA-JR11 and 177 Lu-DOTA-JR11 as a pair of diagnostic and therapeutic radiopeptides for neuroendocrine tumor patients. Gallium 68 is a radionuclide that can be used in diagnostic PET scans. Lutetium 177 is a radionuclide often used with somatostatin analogs to form therapeutic radiopeptides. This study will assess the sensitivity of gallium 68 and the safety of lutetium 177 when combined with the somatostatin antagonist, DOTA-JR11 developed by the researchers. Eight patients with progressive, metastatic and inoperable tumors will participate in a clinical trial of peptide receptor radionuclide therapy with the somatostatin antagonist DOTA-JR11. Thanks to funding from another large Foundation these eight patients will enroll alongside an additional 12 patients for a total of 20 patients enrolled.
This trial may provide proof of concept data to assess the potential for peptide receptor radionuclide therapy with somatostatin antagonists as a new treatment for patients in the United States. Furthermore, strong data from this trial could enhance the commercial potential of these specific compounds. This could pave the way for development of a new treatment and diagnostic imaging strategy for patients with neuroendocrine tumors in the United States.
Wolfgang Weber, M.D. Ph.D.
Diane Reidy-Lagunes, M.D.
1. Assess biodistribution and tumor uptake of 68Ga-DOTA-JR11 and compare the sensitivity of 68Ga-DOTA-JR11 PET with conventional imaging
2. Determine tumor and normal organ doses after administration of 177Lu-DOTA-JR11; and
3. Obtain preliminary data on tumor response to 177LU-DOTA-JR11.
Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs has been developed in the 1990s, and is now frequently used in Europe for treatment of metastatic neuroendocrine tumors. However, not all patients respond well to PRRT; there are serious side effects, most notably chronic renal failure due to the renal excretion of the radiopeptides. Thus, there is a clear need to develop new ligands with higher tumor uptake and a more favorable tumor-to-kidney dose ratio.
To address this need, members of our group have developed radiolabeled somatostatin receptor type 2 antagonists. These are the first radiolabeled somatostain receptor antagonists. In this project we will study the second generation somatostatin receptor antagonists, 68Ga-DOTA-JR11 and 177Lu-DOTA-JR11, as a pair of diagnostic/therapeutic radiopharmaceuticals (theragnostics) in patients with neuroendocrine tumors. Specifically, we will (i) assess biodistribution and tumor uptake of 68Ga-DOTA-JR11 and to compare the sensitivity of 68Ga-DOTA-JR11 PET with conventional staging procedures; (ii) determine tumor and normal organ doses after administration of 177Lu-DOTA-JR11; and (iii) obtain preliminary data on tumor response to 177Lu-DOTA-JR11.
We will conduct a clinical trial including 8 patients with well to moderately differentiated, progressive and inoperable midgut carcinoids. Patients will first undergo a PET/CT with 68Ga-DOTA-JR11. Patients with sufficient tumor uptake of 68Ga-DOTA-JR11 will be offered therapy with 177Lu-DOTA-JR11. Therapy will be preceded by a dosimetric study to determine the amount of radioactivity that can be safely administered.
Understanding the Tumor Suppressor Activities of ATRX-Daxx Through Epigenomic Profiling and Animal Models
The chromosomes in our cells are composed of equal amounts of DNA and protein. The cellular machine of ATRX-Daxx helps to build and maintain chromosome structure at specific sites in our genome, including telomeres, the special structures that cap and protect the ends of our chromosomes.
Previous CFCF-funded researchers discovered mutations in the genes ATRX and Daxx among tumors from patients with non-functioning pancreatic neuroendocrine tumors. Despite these exciting and promising findings, the precise role of ATRX and Daxx in neuroendocrine tumor development is yet to be understood and treatments exploiting these findings have yet to be developed.
Dr. Lewis began working on this project alongside Dr. C. David Allis at The Rockefeller University. We are delighted that Dr. Lewis will be establishing his own lab at the University of Wisconsin-Madison, made possible by support from the MTH Foundation.
Dr. Lewis’ team will conduct experiments and create models to understand the role of ATRX and Daxx in neuroendocrine tumor development with the ultimate goal of developing new therapies for patients by targeting these processes. Furthermore they will establish the precise changes in chromosome structure resulting from mutations in ATRX and Daxx. Knowledge of these changes could shed light on not only neuroendocrine cancers but many other cancer types as well.
University of Wisconsin-Madison
Peter W. Lewis, Ph.D.
- Transcriptome and epigenomic analyses of pancreatic neuroendocrine tumor subtypes
- Faithfully recapitulate pancreatic neuroendocrine tumor initiation and progression through conditional deletion of ATRX and Daxx tumor suppressors
In this research project Dr. Lewis and his team will conduct a set of experiments to understand 1) why pancreatic neuroendocrine cells that lack ATRX-Daxx are more likely to become tumor cells and 2) how ATRX-Daxx act as tumor suppressors in pancreatic neuroendocrine cells.
Specifically they will focus on understanding how chromosome structure and the turning on and off of genes change when pancreatic neuroendocrine cells lack ATRX-Daxx. Results from these studies will identify new molecular targets for novel treatments for neuroendocrine tumor patients.
This project will: identify new molecular targets for neuroendocrine tumor treatment, diagnosis and prognosis; generate mouse models to test new, targeted therapies for patients; and determine how mutations in ATRX and Daxx affect chromosome structure in neuroendocrine tumors.
Epigenomic Analysis of Intestinal Neuroendocrine Cells and the Epigenetic Basis of Neuroendocrine Tumors
With prior funding from CFCF, the Shivdasani lab has made significant progress in understanding the cell of origin for intestinal neuroendocrine tumors. Intestinal stem cells have the capacity to replicate indefinitely or to become any of many different types of intestinal cells. Dr. Shivdasani’s laboratory studies how these gastrointestinal stem cells make the decision to stop behaving like a stem cell and instead to differentiate into a neuroendocrine cell that might someday become a neuroendocrine tumor cell.
To build on prior progress, CFCF has awarded a second grant to Dr. Shivdasani to study how epigenetic regulation controls the process by which a stem cell becomes a neuroendocrine cell and to identify how changes in epigenetic regulation can promote development of neuroendocrine tumors.
Epigenetic regulators determine which genes are turned on or off under specific conditions in a cell. While genes contain the instructions for assembling proteins, it is through epigenetic regulation that cells are able to control whether or not these proteins are actually produced.
Epigenetic regulation controls the processes by which intestinal stem cells decide between remaining a stem cell and differentiating into a neuroendocrine cell. Epigenetic regulation has recently been identified as a potential cause of neuroendocrine tumor development as mutations in epigenetic regulating genes have been identified in neuroendocrine tumors.
Dana-Farber Cancer Institute
Ramesh Shivdasani, MD, PhD
Amount:This project is supported by CFCF’s Pan Mass Challenge Teams.
- Elucidate key epigenetic regulatory steps in differentiation of intestinal stem cells into neuroendocrine cells.
- Determine how epigenetic regulation controls proliferation and differentiation of neuroendocrine cells.
- Identify new genes and pathways to target for treatment of patients with neuroendocrine tumors.
Intestinal neuroendocrine tumors arise from rare hormone secreting progenitor cells that in turn arise from self-renewing stem cells. In current views, a key cell population in cancers, including intestinal and pancreatic neuroendocrine tumors, manifests the stem-cell properties of lifelong self-renewal, incessant replication, and immaturity. Therefore, it is very important to understand the normal basis for these properties and how individual cancers adopt them. Such understanding will inform rational approaches toward cancer prevention and therapy.
Mutations in protein-coding genes drive cancer development and progression. Knowledge of such mutations in several cancers has identified prime molecular targets for therapies that are starting to extend patients’ lives. Mutations affect the primary DNA sequence in the single cell that eventually turns cancerous. However, the bulk of DNA in human cells does not encode proteins; much of the genome is devoted to ensuring tight control of protein-coding genes, specifically, in determining whether they will be turned on or off. This process is known as epigenetics and its vital role in normal and cancer cells is coming into sharper focus, for two reasons.
First, epigenetics control cell differentiation, the process by which stem cells make the choice between indefinite replication and maturing into a committed cell type such as an intestinal or pancreatic neuroendocrine cell.
Second, mutations in epigenetic regulatory genes are found in many cancers, including neuroendocrine tumors, pointing to altered gene regulation as a second key driving force. In fact, the few mutations identified to date, in pancreatic neuroendocrine tumors, occur in genes that control other genes (epigenetic regulators). However, we know so little about normal epigenetic control that it is difficult to know where to begin to translate these seminal discoveries into useful treatments for patients.
To narrow this gap in knowledge, here I propose timely studies to investigate the normal epigenetic control of intestinal stem and enteroendocrine progenitor differentiation and to characterize the epigenetic basis of neuroendocrine tumorigenesis.
All cells require an adequate blood supply to survive. Cancer cells, since they tend to replicate faster than normal cells, require an even greater blood supply. In order to achieve this, many tumors, including pancreatic neuroendocrine tumors, undergo angiogenesis, the development of new blood vessels.
In 2011, sunitinib malate (an angiogenesis inhibitor) was approved by the US FDA to treat patients with pancreatic neuroendocrine tumors. This was an important advance, however; therapeutic resistance frequently emerges over time. A better understanding of why resistance emerges and strategies to overcome resistance are needed.
University of California - San Francisco
Gabriele Bergers, Ph.D.
- Identify and investigate the composition and function of innate immune cells in human pancreatic neuroendocrine tumors.
- Elucidate the functional significance of Gr1- and Gr1+ innate immune cell oscillation in the proangiogenic relapse and identify combinatorial treatment modalities that sustain response to sunitinib and sorafenib.
Advanced pancreatic neuroendocrine tumors (PNETs) are a lethal group of tumors for which no standard therapy exists. New therapies are desperately needed to improve the quality of life and survival of PNET patients. Inhibitors of the VEGF-signaling pathways have yielded promising results and the angiogenesis inhibitor sunitinib was recently FDA approved in PNET patients with advanced disease. Notwithstanding, the beneficial effects are transient and demonstrate the limitations of one of the so far most promising drugs for PNET patients that facilitate tumor stasis instead of shrinkage and is successful only in a subset of patients. Inevitably, the tumors begin to grow again and the disease progresses, after a fleeting period of clinical benefit that is typically measured in months.
The goal of this project is to improve the anti-angiogeneic treatment strategy for pancreatic neuroendocrine tumor patients. Based on our preliminary data obtained from a transgenic model of PNET, we propose that distinct infiltrating innate immune cells oscillate in the tumor in response to therapy to override vascular growth restrictions and that the intratumoral monocyte composition and their expression pattern might be indicative of resistance to anti-angiogenic therapy. Utilizing a microfluidic single cell real time PCR platform in conjunction with 8-color FACS to isolate innate immune cells from human PNET tissues and murine PNETR during therapy, we intend to understand how the distinct innate immune cell populations endorse resistance, how they oscillate to compensate for each other and how one can more successfully inhibit innate immune cell infiltration and action to re-sensitize therapy, increase response rate and prolong survival of patients undergoing antiangiogeneic therapies. Since Sunitinib has become a FDA-approved drug, we believe that the intended studies in this proposal are timely and seminal investigating mechanisms that can be translated into new treatment modalities to hopefully guide and advance the therapeutic effort in the clinic.
Dr. Lozano’s laboratory has extensive experience in generating mouse models to study the effects of specific mutations on tumor development. They have focused on the p53 pathway, in particular, and understanding how it regulates tumor development. The p53 pathway is mutated in over half of all human malignancies.
Previous CFCF-funded researchers discovered mutations in the genes Daxx and ATRX among tumors from patients with non-functioning pancreatic neuroendocrine tumors. Despite these exciting and promising findings, the precise role of ATRX and Daxx in neuroendocrine tumor development is yet to be understood and treatments exploiting these findings have yet to be developed.
Furthermore, researchers do not have the research tools they need to develop potential new therapies for patients exploiting these mutations.
In this project, Dr. Lozano will create the mouse models necessary to identify the cellular changes that occur with loss of Daxx and ATRX to determine the impact of Daxx and ATRX mutations on tumor growth. The mouse models that the team creates will both define the importance of the p53 pathway in the maintenance of pancreatic neuroendocrine tumors and be useful to test potential new therapies.
MD Anderson Cancer Cancer Center
Guillermina Lozano, Ph.D.
- Evaluate conditional loss of Daxx in development and tumorigenesis.
- Evaluate tumorigenesis in cooperation with inactivation of the p53 pathway.
Recently, the sequencing of DNA from pancreatic neuroendocrine tumors has revealed recurring mutations in six specific genes, three of which encode proteins that may have global effects on gene expression. This proposal aims to generate and characterize mouse models to better understand the etiology of the disease and the cooperating events that lead to tumor growth.
In 2011, everolimus (an mTOR inhibitor) was approved by the US FDA to treat patients with pancreatic neuroendocrine tumors. This was an important advance however; therapeutic resistance frequently emerges over time. Models to study resistance to mTOR inhibition and strategies to overcome resistance are needed.
Dr. Nakakura’s lab has developed a new mouse model of pancreatic neuroendocrine tumors that they will use to identify therapeutic strategies to overcome resistance to currently available mTOR inhibiting treatments.
University of California, San Francisco
Eric Nakakura, M.D., Ph.D.
- To identify mechanisms of resistance to everolimus in pancreatic neuroendocrine tumors and determine whether the novel mTOR inhibitor, INK128 can overcome them.
- Evaluate the utility of (68)GA-DOTATOC PET-CT to monitor tumor response to mTOR inhibition.
For most patients with pancreatic neuroendocrine tumors, surgery, the only potentially curative treatment, is not possible because of extensive metastatic disease. Systemic therapy options for tumor control remain limited. Dysfunction of the mTOR pathway is a critical event in pancreatic neuroendocrine tumors. Everolimus, a partial inhibitor of mTOR, demonstrated anti-tumor activity in a phase III study leading to its approval for the treatment of pancreatic neuroendocrine tumors. However, therapeutic resistance frequently emerges. Our goal is to use a novel in vivo model of pancreatic neuroendocrine tumors to identify therapeutic strategies to overcome resistance to mTOR inhibition.
We propose to test the hypothesis that the novel drug INK128, a complete mTOR inhibitor can overcome resistance to everolimus in pancreatic neuroendocrine tumors. Our approach is transformative because: 1) We have the unprecedented ability to study how to overcome resistance to everolimus in pancreatic neuroendocrine tumors using our unique animal model and a powerful new drug; and 2) We will use the radiolabeled somatostatin analog (68)Ga-DOTATOC to perform PET-CT of treated pancreatic neuroendocrine tumors in vivo. We hypothesize that this new imaging modality will permit us to follow the response to therapy in real-time.
Dr. Wong's laboratory specializes in integrating genomic information with relevant mouse models to study novel treatments with the ultimate goal of moving new treatments into clinical trials for patients.
Previous CFCF-funded researchers discovered mutations in the genes ATRX and DAXX among tumors from patients with non-functioning pancreatic neuroendocrine tumors. Despite these exciting and promising findings, the precise role of ATRX and DAXX in neuroendocrine tumor development is yet to be understood and treatments exploiting these findings have yet to be developed. Furthermore, researchers do not have the research tools, including mouse models, they need to develop new therapies for patients.
In this project Dr. Wong will create the mouse models necessary to determine the impact of recently identified mutations in neuroendocrine tumor development. Next Dr. Wong will conduct experiments using his mouse models to identify the cellular pathways that are deregulated as a result of these mutations. Any pathways identified represent potentially new and novel therapeutic targets for treatment of patients with neuroendocrine tumors.
Dana-Farber Cancer Institute
Kwok-Kin Wong M.D., Ph.D.
- Create mouse models to determine the impact of the genes: MEN1, DAXX, ATRX, and PTEN in pancreatic neuroendocrine tumor development.
- Determine the epigenetic and expression profiles of the mouse pancreatic islet cells derived from these mouse models.
The roles of several genes found to be frequently mutated in non-familial pancreatic neuroendocrine cancer are mostly unknown. In this project, Dr. Wong's laboratory will introduce these mutations specifically in mouse pancreatic cells and study how these mutations might cause neuroendocrine tumors to develop.
This project will: generate models to test new, targeted therapies for patients; and identify genes and pathways that can be targeted to develop new therapies for patients.
"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, enteroendocrine cells found in the digestive and respiratory tracts, to both generate models of carcinoid cancer and simultaneously identify genes and pathways that promote carcinoid cancer formation.
The lack of model systems that accurately recapitulate the behavior of neuroendocrine cancers has long been a significant hurdle to developing targeted treatments for patients. This project has the promise to create faithful animal models; therefore, eliminating one of the barriers to treatment development.
Cold Spring Harbor Laboratory
David Tuveson M.D., Ph.D.
- To generate the first accurate mouse models of neuroendocrine tumors
- To identify genes and pathways that cause neuroendocrine tumor formation following transposon-mediated mutagenesis in adult enterochromaffic cells
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 neuroendocrine tumors. Also, the cause of neuroendocrine cancer has been difficult to establish from previous studies of clinical specimens. In this application, I proposed to develop mouse models of neuroendocrine cancer by taking advantage of a new method of generating tumor models with "jumping genes" that are called transposons. Any neuroendocrine tumors that develop in such mice will then be studied to quickly determine the genes that cause neuroendocrine tumors, and this information will both be useful to determine the cause of neuroendocrine tumors and to establish reproducible models of neuroendocrine tumors for the field. This proposal will involve the training of a new physician scientist to facilitate the development of an independent neuroendocrine cancer specialist.
This project will generate models researchers need to test potential new therapies for patients, identify genes and pathways that are involved in neuroendocrine tumor development, and allow a young physician scientist to pursue a career in neuroendocrine tumor research.
With funds raised by Team CFCF’s Cycle for Survival riders, Diane Reidy-Lagunes, MD, and her team will use both molecular and radiologic approaches to develop biomarkers to personalize care for patients with neuroendocrine tumors. In particular, Dr. Reidy will focus on biomarkers to predict patient response to targeted therapies.
“Personalized cancer care is increasingly promoted for a simple reason: Not all tumors behave the same, even when they share the same origin. Genetic errors, or mutations, are the basis of cancer. However, tumors also evolve as they grow over time, acquiring new mutations that turn them more aggressive, and less responsive to conventional therapies. Understanding the individual mutations that drive a tumor to grow can help us find the most effective drugs available with the fewest side effects.” – Dr. Reidy-Lagunes
Dr. Reidy-Lagunes is a medical oncologist who specializes in treating patients with neuroendocrine tumors and gastrointestinal malignancies. Her research focuses on developing methods to integrate molecular-based, targeted therapies into the treatment of neuroendocrine tumors, as well as designing and conducting clinical trials to improve treatment options for patients with neuroendocrine tumors.
Memorial Sloan Kettering Cancer Cancer Center
Diane Reidy-Lagunes, MD
Amount:2012 Team CFCF Cycle for Survival Proceeds
• Develop molecular biomarkers to 1) predict patient response to targeted therapies and 2) stratify pancreatic neuroendocrine tumor patients for treatment with targeted therapies or traditional chemotherapy.
• Study a new imaging technique to monitor the biology of neuroendocrine tumors and determine if it can be used as a biomarker for patient response to targeted therapies.
Through a collaboration between clinical oncologists, radiologists, and basic scientists, the long-term goal of our research is to develop biomarkers that can lead us to personalized cancer care for pancreatic neuroendocrine tumor patients. A biomarker is essentially a blueprint that allows us to look inside a tumor. If we understand the vulnerabilities of a specific tumor, we can then target them with the most appropriate therapies. A biomarker can be in the form of a blood test, a genetic map, or an imaging pattern. Our team hopes to approach pancreatic neuroendocrine tumors with both a molecular and a radiological approach.
Our molecular approach consists of finding mutations in genes that drive a tumor to grow. Finding every possible genetic mutation in cancers is costly and ineffective. Instead, we will focus our search on selected mutations that are believed to be most important to drug response in pancreatic neuroendocrine tumors. By targeting only a few mutations, we can do this quickly and cost effectively. By identifying individual patients’ mutation profile, we hope to develop a molecular biomarker that can help us find patients who are likely to respond to conventional drugs and distinguish those who may need more experimental therapy.
Our second approach is based on magnetic resonance imaging. MRIs are routinely used to monitor patient progress following therapy, to see how tumors grow or shrink over time. Our team of radiologists and medical physicists are collaborating on new imaging tools used during MRIs to monitor the biology of tumors. As opposed to the molecular approach, this technique provides a bird’s eye view of a tumor. It has provided insight into the biology of many different cancers, and can sometimes predict response before a specific treatment is started.
The technologies for both our molecular and imaging approaches already exist, but their implementation require expertise and time from dedicated research staff at Memorial Sloan-Kettering Cancer Center. Our researchers are motivated, but they also require funding for laboratory equipment and tests. With your support, and a true collaborative effort from our staff, we hope to meet the challenge of personalized cancer care in pancreatic neuroendocrine tumor. Our methods, once validated, will be applicable to other types of neuroendocrine tumors as well.
Transcriptome and Methylome of Pancreatic Neuroendocrine Tumors With and Without ATRX/DAXX Mutations
With prior funding from CFCF, Nickolas Papadopoulos, Ph.D., and his team published the results of the first large-scale genome sequencing study of pancreatic neuroendocrine tumors in Science.
Specifically, Dr. Papadopoulos announced the discovery of mutations in two genes (DAXX and ATRX) not previously associated with cancer. Further study of these genes suggests they may play a broader role in the development of not only neuroendocrine cancers but certain types of adult and pediatric brain tumors as well. Identification of mutations within these genes suggests a novel approach to neuroendocrine cancer diagnostics and treatment by targeting epigenetic processes.
DAXX and ATRX are epigenetic regulators, meaning they determine which genes are turned on or off under specific conditions in a cell. While genes contain the instructions for assembling proteins, it is through epigenetic regulation that cells are able to control whether those proteins are actually produced. Mutations within these epigenetic regulating genes can cause them to malfunction, leading to the inactivation of a cancer-suppressing gene, or activation of a cancer-driving gene.
To build on these compelling results, CFCF has awarded a second research grant to Dr. Papadopoulos to explore further the role of DAXX and ATRX mutations in neuroendocrine tumors.
Click here to support Dr. Papadopoulos' research
Sidney Kimmel Comprehensive Cancer Cancer Center, Johns Hopkins University
Nickolas Papadopoulos, Ph.D.
• To determine the epigenetic landscape of pancreatic neuroendocrine tumors by studying the gene expression and methylation patterns of pancreatic neuroendocrine tumors with or without DAXX or ATRX mutations.
• To develop novel therapeutic approaches for patients with neuroendocrine tumors.
• To study the role of epigenetic regulation in neuroendocrine cancer development.
Virtually all the biologic properties of cancer cells are governed by the genetic changes present in them. With the help of CFCF, we have defined the genomic landscapes of pancreatic neuroendocrine tumors. The most intriguing and novel components of these landscapes were mutations of genes called DAXX and ATRX. These genes are master regulators of chromatin packaging – proteins that surround DNA in the nucleus of the cell and determine which genes are turned on or off under specific conditions. In the next phase of our work, we will explore which genes are actually turned on or off in pancreatic neuroendocrine tumors containing mutations of either of these two genes. The long-term objective is to use this information to develop new therapeutic approaches based on a better understanding of these commonly altered pathways in pancreatic neuroendocrine tumors.
In this project, Matthew Kulke, M.D., will utilize his extensive Neuroendocrine Tumor Biobank to identify and then confirm predictors of survival in patients with neuroendocrine tumors.
Dr. Kulke will evaluate genetic variation and protein expression in key molecular pathways including the angiogenesis and mTOR signaling pathways. This project will not only inform clinical management of patients but also has the potential to personalize medicine, by identifying markers to select patients for specific targeted therapies, and identify new treatment targets.
Dr. Kulke’s research project is supported by the 2011 Caring for Carcinoid Foundation Pan-Mass Challenge Team.
Click here to support the project.
Dana-Farber Cancer Institute
Matthew Kulke, M.D.
Amount:2011 Team CFCF Pan-Mass Challenge Proceeds
- To evaluate whether genetic variation and protein expression in key molecular pathways affect survival in patients with neuroendocrine tumors
- To identify new treatment targets for patients with neuroendocrine tumors.
The incidence of neuroendocrine tumors is increasing, and the annual prevalence of these malignancies is estimated to exceed 100,000 individuals in the United States. The identification of genetic and molecular prognostic factors for neuroendocrine tumors was identified as a key research priority at a National Cancer Institute summit meeting in September, 2007. Currently used general prognostic factors do not accurately predict the highly variable clinical course of patiesnt with neuroendocrine tumors, some of whom life for decades while others pursue a course that is rapidly fatal.
Our proposed studies leverage the resources of a large databae of neuroendocrine tumor patients and specimens, developed by our PI. Our aims are informed by recent preclinical and clinical data suggesting key roles for angiogenesis and mTOR signaling, as well as by a previous analysis of genomic aberrations in neuroendocrine tumors. We propose a two-stage candidate SNP (single nucleotide polymorphism) approach to identify and then confirm genetic predictors of survival in key molecular signaling pathways. The results of our studies will inform our understanding of neuroendocrine tumor prognosis, and biology. Our studies will also potentially identify new therapeutic targets for these diseases.
He recently characterized the mTOR signaling pathway in neuroendocrine tumors, identifying key downstream proteins that are activated and lead to adverse outcomes; these proteins may represent new therapeutic targets. He is currently exploring additional genetic and molecular predictors of both treatment outcome and of neuroendocrine tumor risk that should shed light on new pathways involved in neuroendocrine tumorigenesis, and lead to new therapeutic approaches.
Dr. Hua is one of the recipient's of the 2011 Caring for Carcinoid Foundation - AACR Grants for Carcinoid Tumor and Neuroendocrine Tumor Research. CFCF is pleased to announce the first cohort of winners of this award issued in partnership with the American Association for Cancer Research to: advance the understanding of neuroendocrine tumors; elucidate the mechanisms of currently available therapies; and identify new treatment targets for neuroendocrine tumors.
“This project suggests a novel treatment approach by targeting a new signaling pathway to treat carcinoid and neuroendocrine tumors. We are well-poised to…unravel the pathway as a new potential target to treat neuroendocrine cancers...” – Dr. Xianxin Hua
Dr. Hua’s lab has expertise in studying the function of oncogenes and tumor suppressor genes, including menin, a protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene. Patients with MEN1 syndrome have a mutation in the MEN1 gene.
Patients with MEN1 syndrome may develop pancreatic neuroendocrine and bronchial carcinoid tumors (among other tumors). We also know from other CFCF-funded research that sporadic pancreatic neuroendocrine tumors can have mutations in the MEN1 gene.
Dr. Hua’s lab has found that menin appears to suppress a pro-proliferative signaling pathway via protein methylation. Because menin mutations are linked to pancreatic neuroendocrine tumors, his findings suggest that targeting the menin-regulated signaling pathway may be crucial for treating neuroendocrine tumors. This goal of this project is to unravel the crucial role of the menin-regulated cascade in the maintenance of neuroendocrine tumors, underscoring the pathway as an important target for therapy.
By studying menin Dr. Hua seeks to uncover a new treatment strategy for patients with neuroendocrine tumors.
Abramson Cancer Research Institute, University of Pennsylvania
Xianxin Hua, MD, PhD
The goal of this proposal is to develop novel modalities that will be useful for treating pancreatic neuroendocrine tumors, by targeting the pathway that is regulated by menin, a tumor suppressor that is mutated in patients with the inherited Multiple endocrine neoplasia type I (MEN1) syndrome.
Carcinoid tumors and pancreatic neuroendocrine tumors pose serious threats as neoplastic diseases. Multiple Endocrine Neoplasia type I (MEN1) is a hereditary tumor syndrome including neuroendocrine tumors in several endocrine organs. With the grant support from CFCF, Dr. Xianxin Hua’s group has discovered that a menin mutation leads to an increase in Hedgehog signaling, a pro-proliferative and tumor-related pathway, via repression of a protein, PRMT5. Importantly, pharmacologic inhibition of Hedgehog signaling inhibits tumor cell growth. These findings thus uncover a new link between menin and Hedgehog signaling, and pave the way to conduct clinical trials to treat the neuroendocrine tumors using an already FDA approved drug.
Dr. Rudin is one of the recipient's of the 2011 Caring for Carcinoid Foundation - AACR Grants for Carcinoid Tumor and Neuroendocrine Tumor Research. CFCF is pleased to announce the first cohort of winners of this award issued in partnership with the American Association for Cancer Research to: advance the understanding of neuroendocrine tumors; elucidate the mechanisms of currently available therapies; and identify new treatment targets for neuroendocrine tumors.
“By studying the Seneca Valley Virus, we hope to define a novel, targeted therapeutic strategy for patients with neuroendocrine cancers, in particular more aggressive neuroendocrine cancers such as atypical carcinoid.” – Dr. Charles Rudin
Dr. Rudin’s laboratory focuses on the development of novel cancer therapeutics including the Seneca Valley Virus, a small RNA virus that can selectively infect and destroy certain cancers, especially cancers with neuroendocrine features. Dr. Rudin developed and directed the first in-human phase 1 clinical trial of the Seneca Valley Virus (SVV-001). Neotropix, a biotechnology company based in Malvern PA, is currently developing SVV-001 commercially under the trade name NTX-010.
This innovative project will study the only anti-cancer virus with selective affinity for neuroendocrine tumor cells and define the population of neuroendocrine patients most likely to respond to SVV-001.
Specifically, Dr. Rudin and his team propose to elucidate the determinants of Seneca Valley Virus permissivity into neuroendocrine tumor cells. This information will enable molecular profiling of patient’s tumors to focus future clinical development on the patient population most likely to benefit.
This research is both exciting and innovative:
- It represents a novel, targeted treatment strategy for neuroendocrine cancer patients;
- It offers a personalized medicine approach to guide future clinical development;
- Patients with the most aggressive neuroendocrine cancers may benefit most!
Johns Hopkins University School of Medicine
Charles M. Rudin, MD, PhD
- To define components of the SVV-001 viral entry pathway;
- To explore determinants of productive cytolytic infection with SVV-001;
To allow future clinical trials of SVV-001 to target the patient population most likely to benefit from this approach.
My research group has focused on the development of novel cancer therapeutics, both in the laboratory and in the clinic. We have a particular interest in small cell lung cancer and other aggressive neuroendocrine cancers, including atypical carcinoid. Standard approaches to aggressive neuroendocrine cancers have changed minimally over the past 20 years. Novel therapeutic concepts are critically needed for these relatively rare but deadly cancers. My laboratory has been characterizing a novel picornavirus, SVV-001, which can selectively infect and destroy cancers with neuroendocrine differentiation. SVV-001 demonstrates a broad spectrum of activity against neuroendocrine tumors: about 50% of small cell carcinoma lines are permissive for the virus, as are a variety of other aggressive neuroendocrine cancers. The molecular and cellular determinants of SVV-001 permissivity have not been defined. We are seeking to identify the mechanisms of SVV-001 tumor cell entry as well as other cellular determinants of susceptibility to viral infection and lysis, using both innovative approaches and strategies that have been successfully used in defining the biology of other picornaviruses such as poliovirus. With the generous support of the Caring for Carcinoid Foundation and the American Association for Cancer Research, we will conduct a series of studies to define the basis of the selective tropism of SVV-001 for neuroendocrine tumors. These studies may identify biomarkers of viral permissivity, which will help guide subsequent clinical application of SVV-001 in patients with advanced neuroendocrine tumors. It is a terrific honor to receive this award in support of our work.
Dr. Rudin’s project sought to define the characteristics of neuroendocrine cancers that might be successfully treated with an anti-cancer virus called SVV-001. He focused mostly on neuroendocrine cancers of the lung, in particular the most deadly type, small cell lung cancer. Approximately 40% of small cell lung cancers are sensitive to this viral therapy. Dr. Rudin found a single pair of key genes (called ASCL1 and NEUROD1) whose relative levels are an easy and clinically applicable predictor of sensitivity to this treatment. These findings have clear implications for future clinical trials of SVV-001, suggesting a clear selection strategy to identify patients most likely to benefit from this novel therapeutic approach.
"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.
Click here to support Dr. Meyerson's research project.
Dana-Farber Cancer Institute, The Broad Institute
Matthew Meyerson, M.D., Ph.D.
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.