The Pancreatic Cancer Action Network-AACR Pathway to Leadership Grants support outstanding early-career investigators beginning in their postdoctoral research positions and continuing through their successful transition to independence. The research proposed for funding may be basic, translational, clinical or epidemiological in nature and must have direct applicability and relevance to pancreatic cancer.
Pancreatic Cancer Action Network-AACR Pathway to Leadership Grant supported by Celgene Corporation
Stephanie K. Dougan, Ph.D.
Postdoctoral Fellow, Whitehead Institute for Biomedical Research, Cambridge, MA
Transnuclear Mice: Understanding the T Cell Response to Pancreatic Cancer
“The immune system is a powerful resource for fighting tumors. Cytotoxic T cells can distinguish tumor cells from normal tissue with pinpoint precision, and they can migrate to seek out and destroy tumor cells wherever they arise. A second type of T cell, called a regulatory T cell or Treg, blocks the function of cytotoxic T cells and prevents them from effectively fighting the tumor. Pancreatic tumors are notorious for having high numbers of Tregs and relatively few cytotoxic T cells in the tumor mass itself. At this point, we do not understand why Tregs appear in pancreatic tumors or what specific aspects of the tumor recruit and activate these cells. If we knew what aspects controlled the beneficial cytotoxic T cells and the detrimental Tregs and how these two cell types interacted, then we could design therapies to target the immune components of pancreatic cancer. One major roadblock in the design of immune therapies for pancreatic cancer is the lack of good mouse models. Through a collaboration between my mentor Dr. Hidde Ploegh and his fellow Whitehead member Dr. Rudolf Jaenisch, I will use somatic cell nuclear transfer to clone mice from the nuclei of cytotoxic and Treg cells isolated from mouse pancreatic tumors. The resulting transnuclear mice can then be used as a source of pancreatic-tumor specific T cells that can be administered to mice at various stages of pancreatic cancer.
In order to fully address the T cell response to pancreatic cancer, it is imperative to understand both the positive and negative regulators. Thus the development of transnuclear mice, aiming for lines of both cytotoxic T cell and Treg origin will be essential. This novel approach will not only generate new lines of useful mouse models, but also it will, for the first time, give us an idea of why Tregs go so readily to pancreatic tumors. Such information will allow us to create targeted therapies to specifically suppress or eliminate Tregs, while promoting cytotoxic T cell function. The mice generated here will be the foundation of my lab as an independent investigator and a valuable resource for the pancreatic tumor community at large.
I am deeply grateful to the Pancreatic Cancer Action Network and to the AACR for their generous support of my transition to independence. Initially, I will continue development of novel mouse models for pancreatic cancer under the guidance of Dr. Hidde Ploegh at the Whitehead Institute. These mouse models will provide the basis of my independent career elucidating the relationship between the immune system and pancreatic cancer.”
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Pancreatic Cancer Action Network-AACR Pathway to Leadership Grant supported by The Daniel and Janet Mordecai Foundation
Oliver Gene McDonald, M.D., Ph.D.
Fellow, Johns Hopkins University School of Medicine, Baltimore, MD
Genome-Wide Epigenetic Reprogramming During Evolution of Pancreatic Cancer
“Epithelial-to-mesenchymal transition (EMT) is an extreme example of cell plasticity, important for normal development, injury repair, organ fibrosis and malignant progression. Here we propose to investigate epigenetic reprogramming during both experimental EMT and malignant progression of pancreatic cancer, perhaps one of the most lethal of all human malignancies. This novel proposal will create a new field of study that broadly impacts our understanding of human health and disease, with the ultimate goal of identifying epigenetic drivers of pancreatic adenocarcinoma.
"Epigenetics refers to reversible biochemical modifications to DNA (e.g. cytosine methylation) or chromatin (e.g. methylation, acetylation of histones) that are not generally dependent on DNA sequence. These modifications specify functional outputs from the DNA template such as transcription, gene silencing, replication or repair. These modifications can be altered in response to environmental signals, a phenomenon often referred to as “epigenetic reprogramming.” This process is well-known to regulate stem cell differentiation. However, epigenetic reprogramming during EMT and malignant progression is poorly understood.
"We already have strong preliminary evidence that widespread reprogramming of chromatin modifications occurs during experimental models of EMT. In this proposal we will expand on these exciting results and characterize the nature and functional significance of reprogramming during pancreatic EMT, as well as identify the key factors that regulate it. Because EMT is crucial for numerous diverse biological processes, these studies will have far-reaching significance for human health and disease.
"We also have unprecedented access to several paired primary and metastatic pancreatic adenocarcinoma samples isolated from the same patients. Many of these metastases display a phenotype that is reminiscent of EMT, whereas the paired primary lesions retain their epithelial characteristics. Whole-genome sequencing of these samples has failed to identify any genetic drivers of metastasis, leading us to hypothesize that epigenetic reprogramming may drive metastasis. We, therefore, plan to utilize this unique resource to investigate genome-wide epigenetic reprogramming of chromatin during the evolution of pancreatic cancer metastasis, thereby providing the first-ever genome-wide maps detailing epigenetic modifications to chromatin for a human cancer. More importantly, these studies are designed to identify key epigenetic factors that drive cancer metastasis.
"With the support of the PanCan Action Network-AACR grant, we hope that these studies will open up an entirely new field of pancreatic cancer research and beyond, paving the way for the development of new, innovative diagnostic and therapeutic options for patients. The support of the PanCan Action Network-AACR grant will be instrumental in our pursuit of these goals during my postdoctoral studies and as I transition to my own independent laboratory dedicated to understanding and fighting pancreatic cancer."
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Jennifer M. Bailey, Ph.D.
Postdoctoral Fellow, Johns Hopkins University School of Medicine, Baltimore, MD
Stop the Start: Novel Insights into PanIN Initiation and Progression
"Despite decades of research into the treatment and diagnosis of pancreatic cancer, this disease remains the number four cause of cancer related deaths in the United States, with a two-year survival rate of less than 5 percent. The lethality of pancreatic cancer is a combination of a lack of prodromal symptoms, late diagnosis, early metastasis and aggressive metastatic dissemination, challenging scientists with the enormous task of discovering novel methods to both detect and treat pancreatic cancer. I have been dedicated to studying pancreatic cancer since I was a graduate student in the lab of Dr. Tony Hollingsworth with an interest in studying the role of inflammation, the tumor microenvironment and aberrantly activated developmental programs in the progression of pancreatic cancer. In the laboratory of Dr. Hollingsworth, we identified the hedgehog signaling pathway as a critical paracrine mediator of desmoplasia, a pathologic response characteristic of pancreatic cancer. I am now working with Dr. Steven Leach in the department of surgery and also in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University School of Medicine, where we are developing mouse models to study the initiating events in pancreatic cancer. Although it is known that greater than 90 percent of pancreatic cancer patients have mutations in the Kras gene, the exact cell type in which these mutations take place has not been defined. One of our main objectives is to study changes in gene and miRNA expression when we activate mutant Kras in different cell types of adult mice. While the genetics are a critical piece of the enigma of pancreatic cancer, there is also a complex stromal element to the disease along with the overexpression of mucins that are published to regulate tumor invasion and metastasis. With this grant, we are proposing to study the progression of pancreatic cancer with unprecedented single cell resolution, in order to identify the earliest events involved in the initiation of pancreatic cancer, even prior to the emergence of morphologically identifiable PanIN lesions."
"As an early-career scientist, I am humbled and so very grateful for the generous career development award from the Pancreatic Cancer Action Network and the AACR. With this award, I will pursue sophisticated studies of the earliest lesions in pancreatic cancer (PanIN) initiation and progression under the joint mentorship of Dr. Steven Leach and Dr. Anirban Maitra at Johns Hopkins University School of Medicine."
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E. Scott Seeley, M.D., Ph.D.
Clinical and Postdoctoral Fellow, Stanford University, Stanford, CA
Transport of Proteins as Modifiers of Oncogenic Signaling in Pancreatic Cancer
"My work concerns the wiring of oncogenic signals in pancreatic cancer and, more specifically, how intracellular transport proteins are able to control the potency and character of oncogenic signals. Typical oncogenic mutations cause cancer by removing the ‘off’ switches that are built into signaling proteins, causing them to be persistently hyperactive. Without a functional ‘off’ switch, mutated signaling proteins are difficult for the cell to control and can cause cell division and differentiation in the absence of stimuli that serve to promote tissue regeneration and repair. However, as with other cellular proteins, the activities of oncoproteins can be controlled by means that do not rely upon switching between the ‘on’ and ‘off’ states. Indeed, the actions and consequences of oncogenic mutations can be tempered by destroying the affected proteins or by segregating them from their downstream targets. It is these actions which are the work of intracellular transport proteins.
"With key mentors and collaborators, we have discovered that a unique transport machinery determines the outcome of activating Kras mutations in the pancreatic epithelium. Originally characterized as a protein complex required for flagellum assembly in Chlamydomonas, a biflagellate alga, Intraflagellar Transport (IFT) complexes are now known to regulate the assembly and function of non-motile sensory cilia, termed primary cilia, that are assembled by cancer-prone epithelial cells of the pancreas and other organs. In concert with another transport complex comprised of proteins that are mutated in Bardet-Biedl Syndrome, a profound developmental disorder, IFT regulates oncogenic signaling proteins by moving them in and out of the primary cilium in response to environmental stimuli. Overall, it is thought that primary cilia represent a central regulatory hub for developmental and adaptive signaling and that IFT and BBS proteins represent the wiring.
"In pancreatic cancer cells from patients, we have found that one of two copies of many of the IFT and BBS genes are frequently deleted. However, we also find that it is very rare for both copies of these genes to be deleted. When these findings are recapitulated in mouse pancreata harboring oncogenic Kras mutations, we find that, while single-copy deletions accelerate pancreatic cancer development, complete losses of certain IFT proteins block the ability of Kras to initiate pancreatic carcinoma and, instead, lead to the formation of benign cysts that are not associated with mortality in patients. Thanks to the support of the Pancreatic Cancer Action Network and the American Association for Cancer Research, I will now be able to determine the molecular basis for these findings and, potentially, develop applications that will benefit patients with pancreatic cancer."
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Pancreatic Cancer Action Network-AACR Pathway to Leadership Grant supported by Tempur-Pedic Retailers
Zeshaan A. Rasheed, M.D., Ph.D.
Clinical Fellow, Johns Hopkins University School of Medicine, Baltimore, MD
Are Cancer Stem Cells Relevant in Pancreatic Adenocarcinoma?
"Pancreatic cancer continues to have the highest mortality rate of any malignancy as less than 5 percent of patients with this disease survive more than five years. The high mortality is due to this malignancy’s unrelenting growth and propensity to metastasize. One area of recent focus has been on cancer stem cells (CSC), a subset of cells hypothesized to contribute to tumor growth and spread. Because of these unique properties, inhibition of pancreatic CSCs may lead to more effective therapies. However, in order to develop CSC-targeting therapies, it is critical to understand how different populations of pancreatic cancer cells are related to one another and what factors play a role in CSC growth and spread. We and others identified pancreatic CSCs based on the expression of specific proteins [CD44+CD24+, CD133+, or aldehyde dehydrogenase (ALDH+)] that have the ability to form tumors in mice. The relationship between these different CSC populations and the factors that maintain CSC activity are unknown. In previous work, we found that CSC populations may have distinct biological functions. We have begun to study factors that influence CSC behavior and found that exposure of pancreatic cancer cells to TGF-β, a protein that controls cellular processes such as growth and maturation, or type I collagen, an extracellular protein, enhances CSC activity. In this proposal we will look at the defining features and activity of pancreatic CSC sub-populations and test the hypothesis that TGF-β and type I collagen can induce mature pancreatic cancer cells to acquire features of CSCs. This work will lead to a better understanding of how pancreatic CSCs contribute to disease progression and will identify new drugs to treat patients with pancreatic cancer.
"As a medical oncologist with a dedicated interest in basic and translational research this generous career development award from the Pancreatic Cancer Action Network and the AACR will allow me to continue this exciting research and help me develop into an independent researcher. I will continue to work under the mentorship of Drs. Elizabeth Jaffee and William Matsui, experts in pancreatic cancer and CSC biology, respectively. Bringing together the expertise of Drs. Jaffee and Matsui will be valuable in better understanding the biological and clinical importance of CSC in pancreatic cancer. Their mentorship along with resources at Johns Hopkins University will help advance this work and help me build a career in pancreatic cancer research."
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