The Pancreatic Cancer Action Network-AACR Career Development Awards support junior faculty who are in the first four years of a faculty appointment (at the start of the grant term) to conduct pancreatic cancer research and establish successful career paths in this field. The research proposed for funding may be basic, translational, clinical or epidemiological in nature and must have direct applicability and relevance to pancreatic cancer.
- Dimitrios Iliopoulos, Ph.D. (2011)
- Kenneth P. Olive, Ph.D. (2011)
- Jae-Il Park, Ph.D. (2011)
- Jonathan R. Brody Ph.D. (2010)
- Alec Kimmelman, M.D., Ph.D. (2010)
- Michael N. VanSaun, Ph.D. (2010)
- Maxence Nachury, Ph.D. (2009)
- Marina Pasca di Magliano, Ph.D. (2009)
- Marie-Christine Daniel, Ph.D. (2008)
- Kimberly A. Kelly, Ph.D. (2007)
2011 GRANTEES
Dimitrios Iliopoulos, Ph.D.Assistant Professor, Dana-Farber Cancer Institute, Boston, MA
Identification of Novel Molecular Circuits in Pancreatic Cancer Stem Cells
“Pancreatic cancer has the worst prognosis of any major malignancy with complex etiology involving both environmental and genetic factors. Despite increasing knowledge in tumor biology, the treatment efficacy in pancreatic cancers has not improved significantly over the past decade and the prognosis remains dismal with a five-year survival rate of 4-5 percent and a median survival period of five months. Thus, the identification of novel signaling pathways involved in pancreatic oncogenesis and the development of new and potent therapeutic options are highly desirable.
In the last years, studies in neoplastic tissues had provided evidence of self-renewing, stem-like cells within tumors, which have been called cancer stem cells (CSCs). Of high medical importance, CSCs resist standard chemotherapy and during remission CSCs can regenerate all the cell types in the tumor through their stem cell behavior, resulting in relapse of the disease. For this reason, identification of molecular networks involved in the formation of CSCs and drugs that target these networks, would offer great promise for cancer treatment. However, a major challenge in the CSC field is to identify and isolate the CSC population which has the highest tumorigenic capacity and self-renewal properties. Our laboratory is interested in identifying a pancreatic cancer cell subpopulation with stem cell properties and study the molecular circuits involved in the formation and growth of this subpopulation. Recently, we have identified that human pancreatic adenocarcinomas harbor a subpopulation which has stem cell characteristics and is highly resistant to chemotherapy treatments. Furthermore, genomic high throughput analysis revealed an inflammatory circuit that is activated in this subpopulation, implicating the importance of inflammatory pathways in the formation and growth of pancreatic CSCs.
The Pancreatic Cancer Action Network-AACR Career Development Award will allow us to investigate how intracellular and extracellular inflammatory stimuli regulate the growth and function of pancreatic cancer stem cells. In addition, we will be able to study how inflammatory signals affect the dynamic equilibrium between immune cells and pancreatic cancer stem cells. Furthermore, we are interested in identifying FDA-approved drugs able to target pancreatic cancer stem cell growth and act together with chemotherapy in pancreatic cancer cellular and animal models, due to the fact that these drugs can be rapidly brought to the clinic for pancreatic cancer patients. Overall, the proposed work will not only enhance our understanding how inflammation is linked to pancreatic oncogenesis in the molecular level, but also will identify novel drugs that potentially can be used in the clinic for treatment of pancreatic cancer.”
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Pancreatic Cancer Action Network-AACR Career Development Award, in honor of Tempur-Pedic Retailers
Kenneth P. Olive, Ph.D.Assistant Professor, Columbia University Medical Center, New York, NY
The Role of HIF1 and Hypoxia in Pancreatic Ductal Adenocarcinoma
“One of the major discoveries of cancer research has been our understanding of the relationship between tumor cells and the blood vessels that supply them with nutrients and oxygen. The process of growing new blood vessels is called angiogenesis, and it has become dogma over the past 15 years that angiogenesis is necessary for tumor progression. However, pancreatic tumors present an intriguing counter-example. Pancreatic tumors are among the most aggressive of all tumor types. Yet, we recently learned that pancreatic tumors have a very sparse blood supply and only low levels of angiogenesis. As a result, pancreatic tumor cells exist in a state of low oxygen, termed hypoxia. It is not clear what advantage this unusual state provides to pancreatic tumors, but it is possible that it reflects the underlying biology of normal pancreatic ductal cells, which are designed to tolerate an extreme environment in their role as a conduit for digestive enzymes.
The Career Development Award from AACR/PanCAN will support a series of investigations into the role of hypoxia in pancreatic cancer. Using advanced genetically engineered mouse models of pancreatic cancer, small animal imaging technologies and a combination of in vivo and ex vivo molecular analyses, we will study changes that occur following the onset of hypoxia in nascent tumors. We will also probe the effects of manipulating oxygen levels within tumors to learn whether hypoxia promotes or inhibits pancreatic tumorigenesis. By studying the role of hypoxia in the development and progression of pancreatic cancer, we hope to better understand any advantages hypoxia provides to these tumors, and in doing so identify additional means of counteracting their growth. We also hope to resolve the fundamental paradox of how tumors with few blood vessels can grow so rapidly and aggressively.”
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Jae-Il Park, Ph.D.Assistant Professor, UT MD Anderson Cancer Center, Houston, TX
Telomerase in the Development of Pancreatic Cancer
“Strict regulation of stem cell proliferation and differentiation is required for tissue homeostasis and repair in the setting of mammalian tissue damage. Precise orchestration of these processes is achieved via various types of developmental signaling. However, disruption of this regulation causes diseases and genetic disorders, including cancers. Of the major types of cancer, pancreatic cancer has the worst prognosis because it is only detectable at a late stage and is usually resistant to conventional chemotherapy and radiation therapy. For immortalization of cancer cells, the enzyme telomerase is an essential factor in that it protects the chromosome ends from successive shortening. Unlike somatic cells lacking telomerase expression, cancer and stem cells reactivate or retain the telomerase to support their self-renewal potential by maintaining chromosome stability. At the earliest stage of pancreatic cancer development, absence of telomerase expression increases susceptibility to genetic mutations. Paradoxically, telomerase expression is reactivated in pancreatic cancer cells. However, why telomerase is highly expressed in many human cancer cells, including pancreatic adenocarcinoma cells, remains unknown. Hence, a fundamental knowledge of how telomerase controls tumor cell self-renewal and proliferation during pancreatic cancer development is lacking. The long-term goal of the proposed study is to understand the underlying molecular mechanism of tumor development and stem cell regulation in pancreatic cancer. The objective of this particular proposal is to define the detailed mechanisms of telomerase in pancreatic cancer development using mouse models. Our central hypothesis is that telomerase-mediated genomic stability as well as its oncogenic gene regulation contributes to pancreatic cancer development. We formulated this hypothesis based on our preliminary data and previously reported studies. Guided by our preliminary results, we will test this hypothesis by pursuing two specific aims: 1) determine the effects of telomerase-induced cell proliferation on pancreatic cancer development, and 2) define the role of telomerase-expressing cells in pancreatic cancer. Our proposed research is innovative because it is a substantive departure from the molecular mechanisms of telomerase-induced gene regulation in favor of in vivo pancreatic cancer studies. Ultimately, knowledge from this proposed research has the potential to result in development of efficacious therapeutic strategies for pancreatic cancer.”
2010 GRANTEES
Pancreatic Cancer Action Network-AACR Career Development Award, in memory of Skip Viragh
Jonathan R. Brody Ph.D. Assistant Professor, Thomas Jefferson University, Philadelphia, PA
HuR is a Predictive and Prognostic Marker in Pancreatic Cancer
"This grant will provide me with the resources and confidence to pursue our recent exciting findings. Further, this grant will enable me to perform the next phase experiments for our work. These experiments will hopefully provide me the necessary preliminary data to develop a competitive R01, NIH grant application. In short, this grant is critical for my career and comes at a critical time for the funding of my laboratory.
"Even in this modern era of medicine, chemotherapy is often prescribed to pancreatic cancer patients with very little rationale. For example, the drug gemcitabine has been the main chemotherapeutic used to battle pancreatic and other cancers over the past 10 years, even though we know that some patients will respond, while others will not. We recently discovered that pancreatic cancer cells use a powerful survival tactic that can be manipulated and tricked in order to optimize the effectiveness of common chemotherapeutic agents such as gemcitabine. The central player in this highly specialized process is a protein termed HuR. HuR regulates gene activity by binding to the blueprint of a gene and shuttling this blueprint to a part of the cell (the cytoplasm) where it can be made into a protein. Our innovative and unprecedented work shows that the amount of cytoplasmic HuR protein can be used to predict pancreatic cancer patient response to gemcitabine-based therapy. We published that we can separate pancreatic cancer patients into two groups (i.e., gemcitabine responders and non-responders). In this proposal, we will first use state-of-the-art techniques to expand our findings to a larger and more diverse gemcitabine-treated pancreatic cancer-patient population. Additionally, we will use this database to explore further how HuR is already turned in patient’s tumors before therapy is given. Taken together, this work will validate the use of a powerful new marker, HuR, for predicting drug response in pancreatic cancer patients and also as a marker for poor prognosis in these same patients. Thus, measuring the amount of HuR protein in tumors prior to therapy holds much promise for personalizing cancer therapy by stratifying cancer patients into two groups: gemcitabine responders and non-responders. In addition, we will further explore the role of HuR on pancreatic cancer growth and treatment in a preclinical pancreatic cancer mouse model. We strongly believe the proposed work has the potential to have profound and immediate clinical implications."
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Alec Kimmelman, M.D., Ph.D. Assistant Professor, Dana-Faber Cancer Institute, Boston, MA
DNA Repair and the DNA Damage Response in Pancreatic Cancer
"Pancreatic cancer is highly lethal and is resistant to current therapies, including chemotherapy, radiotherapy and targeted agents. Many of the key genetic changes involved in pancreatic cancer progression have been identified through a variety of approaches and validated in mouse models of the disease; however these have yet to translate into effective therapies. Thus, novel approaches are needed to treat this deadly cancer.
"Work in my laboratory focuses on understanding the pathogenesis of pancreatic cancer. In this regard, we utilize genetically engineered mouse models of pancreatic cancer as well as cell culture-based systems to study the disease. One particular focus of our group is to explore the DNA damage response in pancreatic cancer and how this may relate to therapeutic resistance. In order to continually survive and grow, cells must repair “breaks” in their DNA or genetic code. These breaks can occur from natural processes in the cell such as cell division or from external agents such as chemotherapy and radiation. An additional source of internal DNA damage in tumors such as pancreatic cancers is the rampant genomic instability that causes “breaks” in the DNA. Our data suggests that pancreatic cancer may be highly reliant on DNA repair for continued survival in the setting of constant genomic instability. Consistent with these findings, we demonstrated that pancreatic cancer cells are highly sensitive to inhibition of DNA repair utilizing inhibitors to various DNA repair pathways. These finding have tremendous implications on our understanding of the disease as well as why pancreatic cancer is so resistant to therapy.
"With support from the AACR and PanCAN, the proposed work seeks to take a comprehensive approach to understand the role of DNA repair in pancreatic cancer and to identify whether this “addiction” to DNA repair is exploitable for therapeutic purposes. We will investigate the capacity of pancreatic cancer cells to repair DNA damage caused both by internal sources as well as external sources such as radiation and chemotherapy. The specific pathways that these cells are using to repair their DNA will be determined to see if they are more reliant on a particular pathway. Based on these results, we will perform in vivo experiments in mice with transplanted pancreatic tumors to validate these approaches as potential therapies in human patients. We will also combine appropriate DNA repair inhibitors with radiation and chemotherapy to look for potential synergy. These mouse “clinical trials” will provide a stringent validation of the various approaches. It is our goal to identify a rationally designed combination therapy, capitalizing on the “wiring” of these tumors which causes them to rely on various DNA repair pathways. The ultimate hope is that these findings can be rapidly translated to the clinic."
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Michael N. VanSaun, Ph.D.Research Instructor, Vanderbilt University Medical Center, Nashville, TN
Influence of Adipokines on Pancreatic Cancer Progression
"Pancreatic cancer remains a malignancy with high mortality as early-stage tumors tend to be asymptomatic and remain undetected, while late-stage disease has few effective treatment options. The biological influences that cause pancreatic cancer to rapidly grow and become so aggressive remain undetermined.
"Initial studies demonstrate that consumption of a high-fat diet in mice increases adipose accumulation and inflammation in and around the pancreas. I believe that alterations in adipokines, or fat associated factors, exacerbated by high-fat diet leads to changes in the normal pancreatic environment; which enhances the growth and progression of pancreatic cancer. Cancers are commonly labeled as wounds that do not heal. Similarly, obesity can be viewed as a wound affecting the adipose tissue, which after repetitive injury induces an inflammatory reaction. This reaction induces changes in the release of adipokines that confer variations in cellular function. To demonstrate the central role of adipokines and their receptors, I will genetically alter adipokine receptor levels in models of pancreatic cancer and assess effects on multiple aspects of tumor behavior and progression.
"I am grateful for the Pancreatic Cancer Action Network-AACR Career Development Award, which provides the necessary time and funding to conduct experiments to assess how factors generated from adipose tissue contribute to the progression of pancreatic cancers. Understanding the impact of adipose on the pancreatic tissue will elucidate novel targets and present new approaches for pancreatic cancer prevention."
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2009 GRANTEES
Pancreatic Cancer Action Network-AACR Career Development Award, in memory of Larry Kwicinski
Maxence Nachury, Ph.D.
Assistant Professor, Stanford University, Palo Alto, CA
Role of the Primary Cilium in the Initiation of Pancreatic Cancer
"Our laboratory has traditionally been focused on the understanding of molecular machines that build the primary cilium, an organelle that concentrates signaling receptors for developmental signaling pathways. Recent research on polycystic kidney disease shows that loss of cilia in kidney epithelia leads to phenotypes that are highly reminiscent of neoplastic transformation, such as de-differentiation and hyperproliferation. Fascinatingly, the forced ablation of cilia from the pancreas also leads to hyperproliferation and trans-differentiation. Finally, the examination of pre-cancerous lesions of the pancreas has revealed that cilia are lost at the earliest detectable stage of pancreatic cancer. We are, therefore, proposing that cilia fulfill the role of tumor suppressor organelle and we now intend to directly test this hypothesis.
"The proposed work represents a new and innovative research program in my laboratory, applying my expertise in cell biology and biochemistry of the primary cilium to the devastating pathology of pancreatic cancer. We will test the hypothesis that cilia suppress tumor progression or initiation by generating mice in which expression of oncogenic K-Ras oncogene will be combined with mutations that affect cilia assembly within the pancreas. Our general approach will be to determine whether the loss of the primary cilium accelerates the development of pancreatic cancer and to characterize the molecular consequences of the loss of this organelle via comparative analyses.
"The long-term objective of these studies is to determine if and how the loss of the primary cilium contributes to the development of aggressive pancreatic cancer, to identify the mechanisms arresting cilia assembly during oncogenic transformation, and to develop targeting strategies which can restore the assembly of primary cilia in patients with pancreatic cancer. Our work on a candidate tumor suppressor organelle, the primary cilium, may provide insights enabling therapeutic strategies capable of normalizing many of the signaling abnormalities seen in pancreatic cancer."
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Pancreatic Cancer Action Network-AACR Career Development Award, in memory of Paul Mitchell
Marina Pasca di Magliano, Ph.D.
Assistant Professor, University of Michigan, Ann Arbor, MI
Notch Signaling in Pancreatic Cancer Initiation and Progression
"Pancreatic cancer has a very poor prognosis, with a median survival of less than one year after diagnosis. Pancreatic cancer is highly resistant to current treatment options such as chemotherapy and radiotherapy and, therefore, there is a dire need for new therapeutic options.
"In order to identify potential new therapeutic targets, it is essential to understand the contribution of different genes to cancer formation. The funded project proposes to 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. In this proposal, I will address the role of Notch signaling during pancreatic cancer formation and whether inhibition of Notch signaling would block tumorigenesis in the pancreas. Moreover, I will study the interactions between Notch signaling and other signaling pathways that are important for pancreatic cancer initiation and progression. I will use a mouse model of pancreatic cancer that closely mimics the human disease, and use genetic means to regulate the Notch signaling pathway.
"I believe that the proposed work will not only enhance our understanding of the biology of pancreatic cancer, but also have strong therapeutic potential: inhibition of Notch signaling is currently being tested in clinical trials for other human malignancies but its potential for the treatment of pancreatic cancer is currently unknown."
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2008 GRANTEE
Marie-Christine Daniel, Ph.D. Assistant Professor, University of Maryland, Baltimore County, Baltimore, MD
Multifunctional Nanovectors for Pancreatic Cancer Therapy
After losing her mother from a rare cancer, Dr. Daniel, classically trained as a synthetic inorganic chemist, chose to devote her research to this terrible disease. Struck by the aggressiveness of the pancreatic cancer and its very low survival rate, she decided to contribute to the efforts for improved treatment of pancreatic cancer. Nanocarriers are devices with a size comparable to biological entities such as proteins or viruses but are much smaller than cells. Along with other properties, this confers upon them distinct advantages over traditional small molecule approaches. Among others, they increase the blood circulation time compared to small drugs, provide protection of active agents against enzymatic or environmental degradation and allow combination of several different agents. Nanovectors are, in general, composed of three parts: a core constituent material, a therapeutic and/or imaging payload, and some biological surface modifiers that enable tumour targeting of the nanoparticle dispersion. The objective of this research is to prepare nanoparticles that combine multiple agents, for example, a cell-selective cytotoxin, an enhancer and a targeting moiety, and to test the effectiveness of such an entity against transformed pancreatic cell lines. Upon the preferential entry of a nanovector into a cell, a very large quantity of therapeutic agents will be delivered. This targeted combination therapy is predicted to allow for a dramatic enhancement in potency and efficacy in pancreatic cancer treatment along with a decrease of the side effects. In vitro testing of these nanovectors will be performed in collaboration with an allied group in experimental therapeutics.
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2007 GRANTEE
AACR-PanCAN Career Development Award for Pancreatic Cancer Research, in honor of Laurie and Paul MacCaskill
Kimberly A. Kelly, Ph.D. Assistant Professor, University of Virginia, Charlottesville, VA
Molecular Imaging Agents for Early Detection of Pancreatic Cancer
"My research will identify novel molecular markers and develop imaging probes for pancreatic ductal adenocarcinoma (PDAC), a disease with a five-year survival rate of only 3 percent. Clinical imaging and early detection of pancreatic cancer with the developed imaging agents may substantially decrease the morbidity and mortality of patients diagnosed with pancreatic cancer. Given the lack of diagnostic tools for PDAC, the AACR-PanCAN Award is important since it will allow me to focus on these important studies and further this much needed research. Ralph Weissleder, M.D., Ph.D., has been inspirational in the role of mentor as I have learned much about molecular imaging and translating bench discoveries into clinically relevant agents with the potential for improved disease management and, hopefully, cures."
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