The Pancreatic Cancer Action Network-AACR Pilot Grants represent a joint effort to promote and support new ideas and innovative models that have direct application and demonstrate direct relevance to pancreatic cancer. In addition to pancreatic cancer researchers, investigators with experience in other areas of cancer research who have promising and realistic research approaches that can be applied to pancreatic cancer are also invited to apply.
2009-2011 Pancreatic Cancer Action Network-AACR Pilot Grant, in memory of Seena Magowitz
George A. Calin, M.D., Ph.D.
UT M.D. Anderson Cancer Center
Project: Roles of MicroRNAs and Ultraconserved Genes in Pancreatic Cancers
"One of the most unexpected and fascinating discoveries of the last few years in molecular oncology is that the interplay between abnormalities in both protein coding genes (PCGs) and non-coding RNAs (ncRNAs), including short microRNAs are causally involved in cancer initiation, progression and dissemination. A growing amount of evidences proves that miRNAs can work as tumor suppressors (blocking the malignant potential) or oncogenes (activating the malignant potential). The pathogenetic mechanisms of the final steps of tumorigenesis - the invasion and the metastases in adjacent or at distance sites for the pancreatic ductal adenocarcinoma (PDAC), the most dangerous form of cancer in the Western world, is still largely unknown. Based on the new concept of direct interaction between miRNAs and long non-coding ultraconserved genes (UCGs), as well as between these ncRNA and PCGs, the broad, long-term purpose of this application is to decipher the roles of miRNAs and UCGs during the metastatic process of PDAC. To achieve this, in collaboration with Dr. Tom Schmittgen from Ohio State University, we will use high-throughput genomics profiling and functional studies applied to cell lines and to laser-microdissected paired normal/tumor samples with and without disemination. In this way we will be able to identify new genetic pathways involved in late-stage PDAC by establishing the interactions of non-coding RNA networks with PCGs and their functional consequences. The AACR PanCAN grant is significant for my work as it offers me a great opportunity to explore this high-risk/high-gain concept of non-codingRNA networks and to reveal new markers for molecular diagnosis and prognosis in PDAC and new targets for drug therapy."
2009-2011 Pancreatic Cancer Action Network-AACR Pilot Grant
Qingshen Gao, M.D.
Evanston Northwestern Healthcare Research Institute
Project: Discovery of Novel Pancreatic Cancer Susceptibility Genes
"Approximately 5-10 percent of individuals with pancreatic cancer report having one or more first- or second-degree relatives with the disease. However, the responsible germline mutation is rarely identified. The failure of traditional genetic approaches such as linkage to identify the remainder of these genes suggests that heterogeneity (many genes) and/or lower prevalence/penetrance (rare and low lifetime cancer risk) are at play. Our objective is to discover novel pancreatic cancer susceptibility genes by dissecting the BRCA2 pathway. BRCA2 mutations likely account for the largest percentage of familial pancreatic carcinoma. BRCA2 cannot work alone. It must coordinate with many other proteins, usually by interacting with them. These components of BRCA2 pathway are also likely direct targets of tumorigenesis. We have identified 13 BRCA2 binding proteins, including DSS1, MAGE-D1, and centrobin that we have published recently. We have strong evidence indicating that genes encoding these 13 BRCA2 binding proteins are likely pancreatic cancer susceptibility genes. In 2002, we created the Pancreatic Cancer Family Registry. We now have 276 participants with DNA samples suitable for analysis, most of them with a family history of pancreatic cancer. Here, we propose to screen all the 13 candidate genes for germline mutations in our collection of samples to uncover novel pancreatic cancer susceptibility genes. If we discover germline mutations of our candidate genes in this group of patients, it will demonstrate that germline mutation of these genes likely predispose to hereditary pancreatic cancer. Sequencing these genes for clinical purposes should have similar value to sequencing BRCA2. This kind of test will likely have important clinical utility for patients with family histories of pancreatic cancers."
2009-2011 Pancreatic Cancer Action Network-AACR Pilot Grant, in memory of Constance Williams
Brian Lewis, Ph.D.
University of Massachusetts
Project: Involvement of miRNAs in Kras-Induced Pancreatic Tumorigenesis
"Pancreatic cancer, the fourth-leading cause of cancer-related deaths in the United States, is characterized by the presence of activating mutations in the KRAS oncogene. We have previously shown that the expression of an activated Kras allele in isolated primary pancreatic ductal epithelial cells enhance their proliferation, as well as their survival after exposure to death-inducing insults. However, our knowledge of the mechanisms through which Kras exerts these effects remains incomplete. MicroRNAs (miRNAs) are short non-coding RNAs that affect the stability and translation of target messenger RNAs. Previous studies have demonstrated that the levels of several miRNAs are altered in pancreatic cancers, yet the roles of these miRNAs in tumor pathogenesis, and the mechanisms that regulate their expression remain unknown. We have now shown that Kras regulates the levels of several miRNAs in pancreatic epithelial cells, and, therefore, our proposed studies seek to identify whether miRNAs are required for the ability of Kras to enhance the proliferation and survival of pancreatic epithelial cells and the ability of these cells to form tumors when transferred into recipient animals. We will also analyze the roles of individual candidate miRNAs in these processes. Through these experiments, we expect to generate new insights into the mechanisms by which Kras initiates pancreatic tumorigenesis. Such insights will be important for the refinement of new therapeutic approaches. We are very honored to receive support for this project through the AACR/PanCAN pilot grants program. This vital support will allow us to dedicate the effort needed, in personnel and reagents, to make significant progress on these important scientific questions."
2009-2011 Pancreatic Cancer Action Network-AACR Pilot Grant
Jiayuh Lin, Ph.D.
Research Institute at Nationwide Children's Hospital
Project: Dual Inhibitors Target JAK2/STAT3 for Novel Pancreatic Cancer Therapy
"Pancreatic cancer is one of the most serious of cancers. There is an urgent need to develop more effective treatments. Patients with any stage of pancreatic cancer can appropriately be considered candidates for clinical trials using new agents because of the poor response to chemotherapy and radiation therapy as conventionally used. The proposed studies are focused on targeting the constitutive Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in pancreatic cancer cells as a novel therapeutic approach. We will design and synthesize novel small molecules that target JAK2/STAT3 pathway. We will examine the inhibitory effects of the novel small molecule JAK2/STAT3 inhibitors in pancreatic cancer cells in vitro and in a mouse pancreatic tumor model in vivo. Because constitutive activation of STAT3 is frequently activated in pancreatic cancer and can contribute to pancreatic cancer progression and survival, our proposed studies using novel STAT3 inhibitors will provide a promising potential to enhance the efficacy of pancreatic cancer treatment and may make an important contribution to the goal of eradicating pancreatic cancer and reducing the mortality of cancer patients."
2008-2010 Pancreatic Cancer Action Network-AACR Pilot Grant, in honor of Randy Pausch, Ph.D.
Nabeel Bardeesy, Ph.D.
Massachusetts General Hospital
Project: Molecular Markers of Drug Sensitivity in Pancreatic Cancer
"I became interested in pancreatic cancer research during my postdoctoral fellowship at the Dana-Farber Cancer Institute. Another postdoctoral fellow in the laboratory had lost two family members to pancreatic cancer and encouraged me to work on this disease. I learned about the critical need for an improved understanding of pancreatic cancer biology. My current project is designed to enable the development of improved approaches to treating pancreatic cancer. In contrast to many other cancer types, there have been no significant improvements in pancreatic cancer therapy over the past decade. In other cancers, progress has come from the observation that some patients respond to certain therapies and that this response is due to specific genetic alterations in the tumor cells. This discovery enables treatments to be ‘tailored' for patients with these genetic changes. In other words, different drugs can be matched to patients who are most likely to benefit from a specific drug. The goal of this proposal is to identify similar drug sensitive subsets of pancreatic cancer. Our approach is to analyze the responsiveness of cells derived from many different pancreatic cancer patients to a large set of anti-cancer drugs. We will then compare the drug sensitivity with the genetic features of the cancer to determine which features predict drug responsiveness. We will test our predictions using a series of mouse models that resemble the human disease. Overall, our studies will define distinct subgroups of PDAC, provide new insights into cancer therapeutics, and directly inform the design of refined clinical trials."
2008-2010 Pancreatic Cancer Action Network-AACR Pilot Grant
Dafna Bar-Sagi, Ph.D.
New York University
Project: Impact of Diet-Induced Hyperlipidemia on Pancreatic Inflammation and Cancer
"Dr. Bar-Sagi's involvement in pancreatic cancer research resulted from her interest in making a difference in understanding and curing a disease for which things have been hopelessly the same for the past few decades. The funded project focuses on the relationship between high-fat diet-induced hyperlipidemia and the development of pancreatic cancer. Hyperlipidemia is an excess of fatty substances called lipids, largely cholesterol and triglycerides, in the blood. High-fat diet and obesity have been implicated in the etiology of chronic pancreatitis (inflammation of the pancreas) and pancreatic cancer. However, the mechanistic basis of this association remains unknown. The overall goal of the project is to establish a mouse model and investigate this link. The experimental design will take advantage of mice that have been genetically engineered to develop hyperlipidemia following feeding of a high-fat diet. These mice will be employed to: (1) characterize the structural changes that the pancreas endures in response to hyperlipidemia, and (2) assess the effects of hyperlipidemia on pancreatic cancer development. By exploring the cause-and-effect relationships between hyperlipidemia and pancreatic carcinogenesis, these studies will provide new insights into the epidemiological connection between obesity, high-fat diet and pancreatic cancer."
2008-2010 Pancreatic Cancer Action Network-AACR Pilot Grant, in honor of Michael C. Sandler
Matthias Hebrok, Ph.D.
University of California, San Francisco
Project: NFkB Signaling in PanIN Formation
"Pancreatic adenocarcinoma (PDAC) develop through pre-neoplastic lesions of increasing cellular and nuclear atypia that ultimately become aggressively malignant. Pancreatic Intraepithelial Neoplasias (PanINs) are believed to represent a significant class of lesions heralding the disease. We have used caerulein-induced pancreatitis to accelerate and synchronize the development of early stage PanINs in a mouse PDAC model driven by tissue-specific activation of constitutively active KrasG12D in pancreatic progenitor cells. Our preliminary data indicate that NF-kB signaling, a well-established modulator of inflammation and cell survival known to be frequently upregulated in PDAC and pancreatitis in humans, plays an important role in PanIN development. The goal of this proposal is to determine at what stage NF-kB signaling is required for PanIN progression in mice where Kras is activated in pancreatic epithelial cells. We will investigate how NF-kB signaling contributes to the activation of developmental signaling pathways in the earliest stages of PDAC and which cells in the transition from normal epithelium to lesions display NF-kB activity. We anticipate that results from these experiments will not only help evaluate NF-kB as a therapeutic target, but also help to characterize critical transitional cells that could aid in determining relevant diagnostic factors."
2008-2010 Pancreatic Cancer Action Network-AACR Pilot Grant
Bin Liu, Ph.D.
University of California, San Francisco
Project: Internalizing Human Antibodies Targeting Pancreatic Tumor Cells In Situ
"Dr. Liu's interest in pancreatic cancer research, and particularly in developing novel anti-body based diagnostics and therapeutics, was sparked by interactions with his colleagues who are treating patients and studying the origin and development of the disease. The funded project aims to identify internalizing human antibodies that target pancreatic adenocarcinorma cells in situ in their natural tissue microenvironment. Currently, there are very few human antibodies that target pancreatic tumors and even fewer detect early stage tumors. The study examines the following two key hypotheses: (1) pancreatic tumors, like other tumors, possess unique cell surface molecules that distinguish tumors from non-neoplastic tissues; and (2) a subset of these tumor cell surface molecules are internalizing, and thus can be exploited for tumor-targeted intracellular payload delivery. The methods and strategies used in this study are based on precise procurement of staged tumor cells by laser capture microdissection to select internalizing human antibodies that target pancreatic cells in situ. These novel antibodies, which are human in sequence, can be used in the future to develop noninvasive imaging-based strategies for early pancreatic tumor detection and targeted therapeutics based on tumor-specific intracellular drug delivery."