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.
2011 GRANTEES
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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2010 GRANTEE
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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