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Current Research Grants
Enlightenment of a New Era of Cancer Therapy: Prognostication, Target Selection, and Subsequent Therapy Determined by the Dual Tumor-Immune Phenotype
A tumor’s capacity to evade and suppress the immune response is a well-established hallmark of cancer. That harnessing the immune response could result in cure of a subset of patients with cancer is a revolution in cancer therapy. However determining the potential of immunotherapy to be efficacious for patients with NETs necessitates an understanding of the tumor-immune phenotype which today remains unknown
The ultimate goal of this project is to identify tumor-immune biomarkers that represent prognostic, predictive, and therapeutically actionable targets in patients with neuroendocrine tumors.
Stanford University School of Medicine
Holbrook Kohrt, M.D., Ph.D.,
Pamela Kunz, M.D.
- To characterize the tumor-immune phenotype including a comprehensive immune profile and tumor genome utilizing the Stanford neuroendocrine tumor tissue microarray that includes 1031 tumors from 690 neuroendocrine tumor patients.
- To (a) characterize the tumor-immune phenotype including a comprehensive immune profile and tumor genome in serial samples among 20 patients enrolled in a Stanford investigator initiated clinical trial of intratumoral anti-CTLA4 (ipilimumab) immunotherapy with anti-PD-L1 (MPDL3280A) in patients with well-differentiated, progressive neuroendocrine tumors.
Monoclonal antibodies provided a major advance in cancer therapy however, their application is dependent on tumor expression of specific antigens. As cancer treatment enters a new era, that of the immunotherapy revolution, application of immune targeting agents is dependent on understanding the immunogenicity of a tumor based on genetic analysis and immune competency of the patient, based on immunophenotyping of the infiltrating and systemic immune response. The most promising new immunotherapy agent which removes the local immune tolerance blocks the interaction of PD-1 on antitumor immune cells and PD-L1 on tumor cells with likelihood of response predicted by presence and amplitude of expression of PD-L1. Tumor expression of PD-L1 is one of numerous considerations, which remain unexplored and therefore poorly characterized in neuroendocrine tumors. To ensure patients with neuroendocrine tumors benefit from and are not left behind in the new era of immunotherapy, we will perform an in-depth assessment of tumor genome and immune phenotyping applying state of the art genetic and immune analytic tools to over 1000 retrospective neuroendocrine tumor samples, and 20 serially sampled prospective neuroendocrine tumor patients enrolled in an immunotherapy trial at Stanford.
Molecular analysis of the immune environment of neuroendocrine tumors and associations with clinical outcomes
Immune based therapies have demonstrated clear promise in the treatment of a number of human malignancies. In this project, Dr. Kulke and his team will evaluate a large cohort of neuroendocrine tumors to better understand how these tumors interact with the immune system, and to assess their potential to respond to immune therapies. This project could identify new ideas for treating neuroendocrine tumors based on knowledge about how they interact with the immune system.
Dr. Kulke’s findings will shed light on the potential for neuroendocrine tumors to respond to currently available immune checkpoint inhibitors, and inform future strategies for immunotherapy in neuroendocrine tumors.
Matthew H. Kulke, M.D.
- To assess the expression of the key immune receptors PD-1 and PD-L1, in both tumor cells and associated stromal cells, in a large cohort of neuroendocrine tumors.
- To characterize the tumor associated T-cell immune response, by measuring expression of the T cell markers CD3, CD8, CD45RO, and FOXP3 in tumor associated lymphocytes in the above cohort of tumor samples.
- To assess associations between expression of PD-1, PD-L1, tumor associated lymphocytic response and the presence of CDKN1B mutations (in small intestine neuroendocrine tumors) or mutations in MEN1, DAXX, or ATRX (in pancreatic neuroendocrine tumors).
- To assess associations between expression of PD-1, PD-L1, tumor associated lymphocytic response, and clinical outcomes in the above cohort.
Immune checkpoint inhibition has emerged as a promising treatment approach in human malignancies. The potential for neuroendocrine tumors to respond to immune checkpoint inhibitors is unknown, and the immune environment of neuroendocrine tumors remains relatively unexplored. We propose to systematically evaluate the immune microenvironment of neuroendocrine tumors in a large and highly annotated biospecimen database that comprises a diverse set of neuroendocrine tumors. We will assess expression of key immune receptors in tumor and associated stromal cells. We will further assess whether these characteristics are associated with clinical outcomes.
The status of the immune ‘landscape’ of neuroendocrine tumors before therapy and after modulation by therapy is unknown. The proposed study will analyse reactive T cell subsets including characterization of the regulatory factors limiting effective immune-mediated tumour elimination. This will inform the development of a truly personalized medicine approach capable of inducing tumour regression and durable disease control.
In this proposal we bring together a team of NET specialists from one of the largest NET Centres in Europe, and the first ENETS Centre of Excellence, with internationally recognised leaders in the field of immunotherapy and tumour genetics, in order to systematically evaluate the potential for immunotherapy to bring benefit to patients with NET.
Professor Tim Meyer, MD Ph.D.
1. To characterize the immune microenvironment of neuroendocrine tumors and understand how it responds to therapy
2. To develop the rationale for combination immunotherapy for patients with neuroendocrine tumors.
Currently, surgery is the only treatment that cures patients with neuroendocrine cancer but this is not feasible for the majority of patients because they present with inoperable metastatic disease. Medical therapies, at best, slow the disease and new approaches are needed. Immunotherapy, which releases the brakes from the patient’s immune system and allows immune cells to attack the cancer is resulting in long term survival in other tumour types. These new approaches have not been explored in NETs and our project aims to provide a rationale for their clinical evaluation in the hope that patients with NET may also benefit from the revolution in immunotherapy.
Phase I/II Study of Intratumoral Ipilimumab with Anti-PD-L1 in Patients with Advanced, Progressive, Well-Differentiated Neuroendocrine Tumors
The Caring for Carcinoid Foundation is pleased to announce this grant, part of a multi-pronged strategy to harness the potential of the breakthrough field of immunotherapy to treat patients with neuroendocrine cancer.
This project is a clinical trial combining two immune-therapies to treat both carcinoid and pancreatic neuroendocrine tumor patients. The trial involves not only combining two therapies, but also delivering one in a novel way with the potential to minimize what can be dangerous and prohibitive side effects.
The investigators have requested substantial funding to conduct extensive immunologic testing, which will ensure that this clinical trial will be informative: both helping to identify potential biomarkers of immune-response and guiding future immune-based clinical trials.
Click here to watch the video of Dr. Pamela Kunz explaining the Stanford Immunothearpy Clinical Trial, from the Stanford & Caring for Carcinoid Foundation's 4th Annual Neuroendocrine Tumor Patient & Caregiver Educational Conference.
Pamela Kunz, MD
Holbrook Kohrt, MD, PhD
- To determine the safety and feasibility of combining intratumoral anti-CTLA4 treatment with anti-PD-L1 treatment in patients with well-differentiated, progressive, neuroendocrine tumors.
- To assess efficacy endpoints of this regimen in neuroendocrine tumors.
- To assess the immune pharmacodynamic correlates of this treatment.
The first approved immunotherapy for melanoma has already demonstrated striking clinical efficacy, with 1 in 10 patients experiencing long-term remissions. However, up to 1 in 2 patients develop significant toxicity. We hypothesize that an alternative route of administration of anti-CTLA-4 therapy, via direct injection into a tumor site, will have the clinical potential to yield a systemic effect in combination with inhibition of the immune stop sign through anti-PD-L1 therapy.
The goal of the Phase I/II clinical trial is to establish the proof-of-concept that we can further enhance the antitumor activity by being the first to demonstrate that intratumoral CTLA-4 therapy is safe, immunologically active, and therapeutically augments the systemic efficacy of intratumoral anti-CTLA-4 injection in combination with anti-PD-L1 therapy in patients with well-differentiated, progressive, neuroendocrine tumors. Given that limited immunotherapeutics have been approved for tumors other than melanoma, this trial and the immune biomarkers identified have the capacity to be the first example.
If successful, the proof-of-concept demonstrated here will be applied to other cytotoxic and immunotherapeutics, thereby both reducing toxicity and maintaining efficacy, while also extending the clinical benefit and improved quality of life to cancer patients of any tumor histology type.
The Caring for Carcinoid Foundation is pleased to announce this grant, part of a multi-pronged strategy to harness the potential of the breakthrough field of immunotherapy to treat patients with neuroendocrine cancer.
This project relies on the expertise of Carl June, MD, renowned for his work in immunotherapy. In particular, Dr. June’s team spent many years developing CAR T “serial killer” T cells, which have been very successful in clinical trials treating patients with forms of leukemia and other cancers.
This project brings together the multi-disciplinary team of Xianxin Hua, Carl June, and David Metz to develop CAR T cells to target receptors found on neuroendocrine tumor cells and then kill those cells.
Xianxin Hua, MD, PhD
Carl June, MD
David Metz, MD
- Generate and optimize somatostatin receptor specific CAR T cells that target the surface of human neuroendocrine tumors.
- Test the anti-tumor activity of anti-SSTR2 or SST-ligand CAR T cells in vitro.
There is a critical need to develop better treatments for patients with neuroendocrine tumors. A salient feature for many neuroendocrine tumors is the abnormally high level of somatostatin receptors on the surface of the tumor cells. Octreotide, a long acting analog of normal hormone somatostatin, and other similar derivatives have been long used to target somatostatin receptors on tumor cells to suppress the secretion of hormones from the tumor cells and growth of tumors. But Octreotide and its derivatives rarely kill tumor cells and reduce tumor mass. Tragically, 5-year survival for metastatic neuroendocrine tumors remains very low. Therefore, it is highly desirable to develop new and more effective therapies for patients with neuroendocrine tumors.
Recently, adoptive T cell therapy involving engineered chimeric antigen receptors (CARs), which specifically target tumor associated antigens, has been reported to successfully eradicate human chronic lymphocytic leukemia and prevent its recurrence. These recent advances raise an exciting and real possibility that neuroendocrine tumor cells can be targeted and killed to improve the treatment of patients with neuroendocrine tumors. We will first develop CAR T cells designed to eradicate neuroendocrine tumors via targeting somatostatin receptors on the surface of the neuroendocrine tumor cells. Second, the best CAR T cells will be tested for their capability to specifically kill the cancer cells in cultured cells.
These studies will aid the development of an entirely new and effective therapy for neuroendocrine tumor patients who have failed previous treatments.
This project is based on the concept of “synthetic lethality.” This concept originated in genetics where synthetic lethality occurs between two genes when mutation of either alone is compatible with life but mutation of both leads to death. Thus, targeting a synthetic lethal partner to a cancer relevant mutation kills cancer cells and spares normal cells.
What makes this research unique and new is that previously, Dr. German’s lab has identified a synthetic lethal gene partner for the MEN1 gene mutations commonly found in pancreatic neuroendocrine tumors. Dr. German believes that a synthetic lethal relationship exists between MEN1 loss and Mek1/2 inhibition. To study this hypothesis they will test an FDA approved inhibitor of Mek1/2 (approved for metastatic melanoma) in mouse models of pancreatic neuroendocrine tumors.
The results will provide insight into the unique mechanisms that drive neuroendocrine cancer growth; and with positive results from the preclinical studies, use of an FDA approved drug may provide rapid translation to patients with neuroendocrine cancers including pancreatic neuroendocrine cancer and carcinoid cancer.
University of California, San Francisco
Michael German, MD
- Test the synthetic lethal interaction between Menin loss and Mek1/2 inhibition in preclinical models of pancreatic neuroendocrine tumors.
- Analyze the interaction between MEN and RASSF1A in pancreatic neuroendocrine tumors.
Most of the genetic alterations relevant to neuroendocrine tumors are associated with tumor suppressors, most of which cannot be directly targeted since they are either not enzymes or simply not expressed. One possible solution to this problem could be to identify synthetic lethal interactions between these tumor suppressor mutations and proteins that can be targeted, or which already serve as targets of existing drugs. This concept originated in genetics where synthetic lethality occurs between two genes when mutation of either alone is compatible with viability but mutation of both leads to death. Thus, targeting a synthetic lethal partner to a cancer relevant mutation kills cancer cells and spares normal cells.
Our laboratory has identified just such a synthetic lethal partner for the MEN1 gene mutations commonly found in pancreatic neuroendocrine tumors. While studying the specific pathways that control islet cell proliferation, we unexpectedly discovered that the classic oncogene K-Ras works differently in these cells to inhibit proliferation by activating the tumor suppressor RASSF1A, while Menin blocks the pro-proliferative B-raf/MEK/ERK arm of K-Ras signaling. These studies revealed a synthetic lethal interaction between Menin loss and Mek1/2 inhibition. We now propose to test the FDA approved inhibitor of Mek1/2 tramenitib in preclinical mouse and human models of pancreatic neuroendocrine tumors. We will also investigate the mechanisms underlying the unique growth suppressive action of K-Ras in neuroendocrine cell cancer by examining in cell lines and human PNET tumor samples the interaction between MEN1 and RASSF1A, which is frequently silenced in gut and pancreatic neuroendocrine tumors.
The results from the proposed experiments should provide insight into the unique mechanisms that drive neuroendocrine cell cancer and help identify a synthetic lethal interaction for RASSF1A. Also, use of an FDA approved drug in preclinical animal studies may provide rapid translation to patients with carcinoid and pancreatic neuroendocrine tumors.
This research project brings together a multidisciplinary team to develop a new targeted treatment strategy for neuroendocrine cancer patients, including carcinoid cancer patients. This new treatment strategy combines a new anti-cancer drug with a new delivery method to target somatostatin receptors present on neuroendocrine cancer cells.
The investigators will conduct preclinical experiments to establish the feasibility of this new treatment strategy for treating patients with neuroendocrine, including carcinoid, cancers.
University of Wisconsin-Madison
- Investigate whether a new anti-cancer medication, TDP-A, optimally inhibits carcinoid cancer cell proliferation and bioactive hormone secretion in vitro.
- Determine if tumor-targeted TDP-A loaded multifunctional drug nanocarriers can improve carcinoid tumor uptake and anticancer efficacy while decreasing systemic toxicity.
The incidence of carcinoid tumors has increased from 3% to 10% over the past 30 years. While surgical resection can be potentially curative, many patients develop metastatic disease precluding an operative cure. Moreover, patients with carcinoid metastases often develop malignant carcinoid syndrome with the associated endocrinopathies. This emphasizes the need for the development of new forms of therapy to prevent carcinoid cancer progression and to palliate hormone associated symptoms.
This project combines the expertise of three professionals – a chemical biologist who recently discovered a new and potent anticancer drug (ie, thailandepsin A [TDP-A]), a nanotechnologist/materials chemist who develops multifunctional drug nanocarriers for targeted cancer therapy, and a surgeon/neuroendocrine cancer biologist – to develop multifunctional nanomedicines for targeted carcinoid cancer therapy. At the completion of the project, we intend to demonstrate that TDP-A is a potent anticancer drug for carcinoid cancers and that tumor-targeting TDP-A loaded nanocarriers have the potential to significantly enhance the efficacy of therapeutic treatments in carcinoid cancers while minimizing any undesirable side-effects.
Identifying altered epigenetic states and drivers in intestinal 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 Chung, 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.
Considerable effort, including exome sequencing, has identified few recurrent mutations in intestinal carcinoid and pancreatic neuroendocrine (PNETs) tumors (1) (Francis et al, Nat Genet 2013, In Press). This suggests that epigenetic changes rather than mutations may disrupt normal cell behaviors to produce and sustain these unusual, often indolent cancers. Indeed, genes that regulate chromatin, such as MEN1, ATRX and DAXX, dominate the short list of recurrent mutations in these diseases (2, 3). One effect of ATRX and DAXX mutations is to lengthen telomeres through a telomerase-independent “alternate” pathway (4, 5), but chromatin-modifying genes mutated in NETs are also implicated in transcriptional control (6, 7) and the relative importance of these distinct effects in disease pathogenesis is unclear. The epigenomes (profiles of covalent histone modifications) in primary human carcinoid tumors and PNETs might illuminate disease mechanisms and key nodes of transcriptional dysregulation, revealing both pathogenic insights and potential therapeutic targets among the root causes of these cancers.
Recent advances support this idea. First, diverse cancers carry mutations in chromatin regulator (CR) genes, including 25-75% of non-Hodgkin lymphomas, 35% of pancreas adenocarcinoma, and nearly 100% of rarer entities such as papillary thyroid and NUT midline carcinoma (reviewed in (8). Because such mutations are common and widespread, many drug companies have prioritized the development of epigenetic-based therapies. Thus, drugs with the potential to treat carcinoid and PNET tumors may be developed for other, more common indications; knowing the particular derangements in carcinoid and PNET tumors will help match the latter with appropriate drugs. Second, technical and computational advances now make it possible to determine epigenetic states across the genomes of normal and cancer tissues (9). In-depth characterization allows one to know exactly which chromatin modifications occur at individual genes and their regulatory elements; how these modifications respond to perturbation; which ones may be especially important for cancer pathogenesis; and which may present opportunities for therapy. Our overarching hypothesis is that epigenome (histone) alterations in carcinoid and PNET tumors will yield vulnerabilities that can be targeted with drugs. We propose to test this hypothesis in primary tumor samples, hence uncovering both inherent vulnerabilities and corresponding therapeutic opportunities (Specific Aim 1).
Fresh-frozen tumor tissue is essential for this work and we propose in parallel to use portions of the same tissue samples to achieve another vital CFCF goal: construction of new cellular models that retain the epigenetic state of the primary tumors (Specific Aim 2). We will do this as part of a wider effort between the Broad Institute and our respective cancer centers, dividing surgical specimens into portions that are suited to each goal: epigenome analysis (Aim 1) and cell model construction (Aim 2). If we are successful, the new cell models will be invaluable tools for perturbation experiments that directly test the chromatin-related hypotheses we will generate in Aim 1.
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.
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.
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.