Ruth Fredman Cernea – Pancreatic Cancer Action Network – AACR Fellowship

Philippe Foubert, PhD

University of California, San Diego

Role of Inflammation in Pancreatic Cancer 

During disease progression, inflammatory cells rush into pancreatic tumors and these cells cause increased tumor growth and spread throughout the abdominal cavity and the body. These cells also stop disease fighting immune cells from recognizing the tumor as a foreign body. This “immunosuppression” is caused by inflammatory cells that rush into the tumor. These cells release factors that inhibit immune system cells.

Dendritic cells are immune system cells that can play pivotal roles in anti-tumor responses. However, during pancreatic cancer progression, dendritic cells remain unable to activate an adequate immune response towards cancer cells. Factors produced by tumor cells and inflammatory cells keep these dendritic cells in an immature state. This study will investigate how inflammatory cells interact with tumors and how they suppress the anti-tumor response. More importantly, I will study the role of alpha4 integrin, an inflammatory cell adhesion molecule, in the regulation of immunosuppression during pancreatic cancer progression.

This study could provide new insights into the mechanisms that cause tumor-induced immunosuppression. It may also lead to development of new therapeutic strategies to treat pancreatic cancer progression and metastasis.

Samuel Stroum – Pancreatic Cancer Action Network – AACR Fellowship

Eric Humke, MD, PhD

Stanford University

A Novel Paracrine Hedgehog Signaling Loop in Pancreatic Adenocarcinoma

Pancreatic Cancer Action Network – AACR Fellowship

David Ting, MD

Massachusetts General Hospital

Characterizing Circulating Tumor Cells in Pancreatic Cancer

The detection of circulating tumor cells (CTCs) in the blood of patients with solid tumors is a promising diagnostic tool to help develop new strategies to combat pancreatic cancer. Circulating tumor cells have been found in a number of different malignancies, and there have been encouraging studies indicating that the detection of circulating tumor cells can predict response to treatment and survival. However, the true nature of these cells remains a mystery. Many believe these cells are the critical cells that cause metastatic disease.

Studies of circulating tumor cells have not been done due to limitations in current cell capture technologies. A novel device named the CTC chip is able to capture higher numbers of purified circulating tumor cells that is not possible with current systems. This allows the opportunity to perform more sophisticated molecular analyses on these cells. These studies will be the first of their kind to demonstrate the potential the CTC chip has to provide insight into the nature of circulating tumor cells, personalize current therapies, and to create a platform for developing novel pancreatic cancer therapeutics.

Larry Kwicinski – Pancreatic Cancer Action Network - AACR Career Development Award

Maxence Nachury, PhD

Stanford University

Role of the Primary Cilium in the Initiation of Pancreatic Cancer

Pancreatic cancer has a unique ability to resist current therapies, probably reliant upon the complex molecular pathology that begins early in disease progression. In turn, our ability to treat pancreatic cancer will likely depend upon a better understanding of the mechanisms that promote and sustain these multiple molecular abnormalities during disease progression. This research project is focused on a candidate tumor suppressor organelle, the primary cilium, an antenna-like structure that emanates from the surface of virtually all cells in the mammalian body. The primary cilium receives both mechanical and chemical signals from other cells and the environment, and transmits these signals to the nucleus to elicit a cellular response. This project aims to provide insights enabling therapeutic strategies capable of normalizing many of the signaling abnormalities seen in pancreatic carcinomas.

Paul Mitchell – Pancreatic Cancer Action Network – AACR Career Development Award

Marina Pasca di Magliano, PhD

University of Michigan

Notch Signaling in Pancreatic Cancer Initiation and Progression

In order to identify potential new therapeutic targets, it is essential to understand the contribution of different genes to cancer formation. This research project will investigate the role of the Notch signaling cascade in pancreatic cancer. Notch signaling plays an important role during embryonic development of several organs including the pancreas. However, it is inactive in most adult cell types. It has been previously shown that the genes that constitute the Notch pathway get re-activated at high levels in pancreatic cancer.

This research will address the role of Notch signaling during pancreatic cancer formation and whether inhibition of Notch signaling would block formation of tumors in the pancreas. This work will not only enhance our understanding of the biology of pancreatic cancer, but may also have strong therapeutic potential: inhibition of Notch signaling is currently being tested in clinical trials for other human tumors, but its potential for the treatment of pancreatic cancer is currently unknown.

Pancreatic Cancer Action Network – AACR Pilot Grant

Qingshen Gao, MD

NorthShore University HealthSystem Research Institute

Discovery of Novel Pancreatic Cancer Susceptibility Genes

Approximately 5-10% of individuals with pancreatic cancer report having one or more first or second-degree relatives with the disease. However, the responsible genetic 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. While genome-wide association studies have shown promise in identifying high-prevalence, low-penetrance genes, there remains an important role for the candidate gene approach in the discovery process.

BRCA2 mutations likely account for the largest percentage of familial pancreatic carcinoma. Our approach to identify the pancreatic cancer susceptibility genes is to dissect the BRCA2 pathway. BRCA2 can not work alone. It must coordinate with many other proteins, usually by interacting with them. These components of the BRCA2 pathway are also likely direct targets of tumor formation. 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.

With this project, we will screen all the 13 candidate genes for mutations in our collection of DNA samples from our Pancreatic Cancer Family Registry, with the aim of uncovering novel pancreatic cancer susceptibility genes.

Constance Williams – Pancreatic Cancer Action Network – AACR Pilot Grant

Brian Lewis, PhD

University of Massachusetts

Involvement of miRNAs in Kras-Induced Pancreatic Tumorigenesis

Previous studies have demonstrated the significance of tumor promoting mutations in the KRAS2 oncogene. These mutations occur early in pancreatic cancer lesions, suggesting that they contribute to the initiation of pancreatic tumor formation. However, the understanding of how KRAS gene mutations contribute to pancreatic tumor initiation remains incomplete.

Recent studies have show that the levels of microRNAs, a class of small non-protein-coding RNAs, are altered in human cancers, including pancreatic cancer. Yet, it remains unknown whether KRAS regulates the expression of specific microRNAs, and whether microRNAs are required for KRAS-mediated transformation of normal pancreatic cells.

This proposal therefore seeks to answer the following questions: (1) Are microRNAs required for KRAS-mediated transformation of normal pancreatic cells? And (2) Do individual microRNAs mediate KRAS-induced proliferation and survival?

The findings from these proposed studies will shed light on the functional roles of microRNAs during KRAS-induced pancreatic tumor formation, an area that heretofore has been unexplored. It is therefore anticipated that these studies will contribute significantly to the understanding of the molecular mechanisms of pancreatic tumor formation.

Pancreatic Cancer Action Network – AACR Pilot Grant

Jiayuh Lin, PhD

Research Institute at Nationwide Children's Hospital

Dual Inhibitors Target JAK2/STAT3 for Novel Pancreatic Cancer Therapy

The goal of this proposal is to develop new drugs for the targeted therapy of pancreatic cancer. Other and our laboratories have found that a protein called Signal Transducer and Activator of Transcription 3 (STAT3), which regulates expression of genes that control cellular function, is persistently and frequently turned on in pancreatic cancer. This abnormality drives the malignant behavior of pancreatic cancer. Inhibition of STAT3 leads to a loss of the ability of tumor cells to grow, survive, and spread to distant organs. Furthermore, it has been found that normal human cells can tolerate the inhibition of STAT3 with little consequence, which may be due to the presence of back-up systems that are lost in cancer cells. These reports suggest that inhibition of STAT3 abnormality could be an effective therapeutic approach in pancreatic cancer.

To inhibit STAT3 in pancreatic cancer, we have recently developed novel and potent drug-like small molecule compounds. The preliminary results have demonstrated that our drug-like compounds are effective to inhibit STAT3 and induce cell death in pancreatic cancer cells with the STAT3 abnormality, but are much less toxic to normal human cells without the STAT3 abnormality.

The research goal of this proposal is to evaluate the ability of these small molecule compounds to inhibit STAT3, along with the growth and malignant behavior of human pancreatic cancer cells in tissue culture-based and animal-based models. It is also a goal for this proposal to provide pre-clinical evidence of our pharmacological compounds that inhibit STAT3 for future clinical trials.

Seena Magowitz – Pancreatic Cancer Action Network – AACR Pilot Grant

Kapil Mehta, PhD

MD Anderson Cancer Center

Therapeutic and Biological Significance of Tissue Transglutaminase

Understanding of molecular pathways and tumor-coded genes whose expression contribute to the intrinsic resistance and rapid metastasis could yield immediate clinical benefits and reveal new therapeutic targets for effective control and treatment of pancreatic cancer.

We recently found that: a) a majority of pancreatic tumor samples from patients and tumor cancer cell lines express high basal levels of tissue transglutaminase (TG2). TG2 is a unique multifunctional protein implicated in cell adhesion, matrix-stabilization, wound healing, apoptosis and invasion, all processes important in tumor formation and progression; b) over-expression of TG2 promotes activation of the focal adhesion kinase (FAK), Akt, and NF-kappaB, proteins implicated in the spread of tumors; c) inhibition of TG2 by small interfering RNA (siRNA) inhibited invasion and induced death in pancreatic cancer cells; conversely, expression of TG2 promoted cell survival and invasion; d) importantly, inhibition of TG2 by liposomal-siRNA significantly inhibited the growth and metastasis of tumors growing in a mouse model.

Based on these observations, we hypothesize that abnormal expression of TG2 contributes to the development of drug resistance and metastasis in pancreatic cancer cells. The information gained through these studies will further validate the possibility of using TG2 as a therapeutic target for treatment of pancreatic cancer.