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.
- Jiyoung Ahn, Ph.D. (2012)
- Darren R. Carpizo, M.D., Ph.D. (2012)
- Eric A. Collisson, M.D. (2012)
- Mikala Egeblad, Ph.D. (2012)
- Kazuki N. Sugahara, M.D., Ph.D. (2012)
- David Sung-wen Yu, M.D., Ph.D. (2012)
- Dimitrios Iliopoulos, Ph.D. (2011)
- Kenneth P. Olive, Ph.D. (2011)
- Jae-Il Park, Ph.D. (2011)
- Michael N. VanSaun, Ph.D. (2010)
2012 GRANTEES
Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation
Jiyoung Ahn, Ph.D. Assistant Professor, New York University School of Medicine, New York, NY
Oral Microbiome and Pancreatic Cancer: A Prospective Case-Control Study
"Pancreatic cancer is highly fatal; almost all patients (95 percent) die within five years of diagnosis. Currently, there is no effective way to tell who will develop pancreatic cancer and how it can be prevented. Our hypothesis is that certain types of oral bacteria potentiate pancreatic cancer by causing inflammation in the pancreas. I will test our hypothesis in a large population-based prospective study of about 70,000 subjects from whom we have collected oral samples and comprehensive demographic and lifestyle information and who we have been followed for pancreatic cancer development for up to 10-years. I will measure about 300 species of oral bacteria, using a novel bacteria DNA sequencing method, from 150 study participants who subsequently developed pancreatic cancer and 150 participants who did not develop pancreatic cancer. Pancreatic Cancer Action Network-AACR grant will provide an excellent opportunity to identify specific oral bacteria associated with the development of pancreatic cancer. This study is important because identifying these bacteria may improve our limited knowledge about how pancreatic cancer develops, may provide a novel way to identify people at high risk of developing pancreatic cancer, and may help us to develop ways to prevent pancreatic cancer by administering specific drugs or probiotics to modify these oral bacteria."
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Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation
Darren R. Carpizo, M.D., Ph.D. Assistant Professor of Surgery, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
Pre-Clinical Studies of an Allele-Specific p53 Mutant Reactivating Compound in Pancreatic Cancer
"I am a surgical oncologist who specializes in the management of pancreas cancer patients, as well as a cancer researcher in the field of developmental therapeutics. One of the biggest problems that we face as pancreatic cancer surgeons is that of recurrence. Recurrence cannot be mitigated with more effective surgery but rather more effective chemotherapy. Our laboratory is interested in studying compounds that target mutant p53. The next generation of anti-cancer drugs is defined by compounds that selectively kill cancer cells while leaving normal cells undisturbed. We have identified such a compound that selectively kills cells with a p53-R175 mutation while leaving normal cells undisturbed. This compound restores the wildtype structure and function to one of the most common p53 mis-sense mutants. The potential pool of patients for this drug in the United States annually is approximately 32,000. This work has been accepted for publication in the journal Cancer Cell. My research mentor is Dr. Arnold Levine, whose laboratory discovered the p53 tumor suppressor.
"The project that will be funded by this award is to conduct pre-clinical studies of this mutant p53 reactivating compound in a transgenic mouse model of pancreatic cancer. TP53 is second only to Kras as the most commonly mutated gene in pancreatic cancer. More specifically we will learn the pharmacokinetics and pharmacodynamics of the drug that will allow us to determine if the drug has efficacy in pancreatic cancer mice driven by mutant Kras and p53 alleles. We will also determine if the drug can enhance the efficacy of cytotoxic chemotherapy as well as radiation. My co-mentor for these studies will be Dr. Joseph Bertino, an internationally recognized expert in developmental therapeutics.
"I would like to thank the AACR and the Pancreatic Cancer Action Network for giving me this Career Development Award. In addition, I would like to thank Dr. Arnold Levine for his support and mentorship as well as that of the Cancer Institute of New Jersey."
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Pancreatic Cancer Action Network-AACR Career Development Award, in memory of Skip Viragh
Eric A. Collisson, M.D.
Assistant Adjunct Professor, University of California, San Francisco, CA
Optimizing MEK Inhibition in Pancreatic Cancer; from Cytostatic to Cidal
"The vast majority (about 90 percent) of pancreatic tumors have mutations in the K-Ras gene. K-Ras becomes constantly activated by this mutation, signaling the cell to grow and ignore cues to stop growing. But, K-Ras does not act alone. Instead, K-Ras activates a complex cascade of other proteins to ultimately lead to cellular changes.
"One of the key proteins activated by K-Ras is called MEK. Because efforts to inhibit K-Ras as a means to stop the growth of pancreatic cancer have been unsuccessful, Dr. Collisson is opting to target MEK’s activity instead. So far, his studies have shown that blocking MEK does cause cancer cells to stop growing (known as a cytostatic effect), but does not kill the cells (cytocidal). Dr. Collisson, therefore, proposes to discover additional treatment strategies that, when combined with MEK inhibition, will lead to cytocidal effects. He will accomplish this by systematically turning off the expression of various genes in pancreatic cancer cells, in the presence of MEK inhibition, and then identifying which combination (or combinations) is toxic to the cells. This type of study could reveal a novel multifaceted approach to kill pancreatic cancer cells, leading to more effective and sustained treatment options."
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Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation
Mikala Egeblad, Ph.D. Assistant Professor, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Dynamics of Tumor-Stroma Interactions in Pancreatic Cancer
"Pancreatic cancer carries a dismal prognosis. Surgery is only effective in early stages and chemotherapeutic treatments are largely ineffective. In the search for better treatments, the focus has been on identifying and targeting mutations in the pancreatic tumor cells. However, intriguingly, the majority of a pancreatic tumor is not made of tumor cells but of stroma: non-cancerous cells and proteins that support and surround the cancer cells. Yet, the impact of the stroma on the disease is still poorly understood.
"The Career Development Award from the Pancreatic Cancer Action Network and the AACR will support a new research area for my lab, which otherwise is focused on the understanding of the role of the stroma in breast tumors. We will specifically study interaction between tumor cells, immune cells, and type I collagen, a major protein in the pancreatic stroma. One important function of type I collagen is to form a scaffold that provides stability to normal tissues. In tumors, type I collagen is expressed at increased levels and its structure is abnormal due to expression of collagen modulating enzymes. These changes may lead to changed signaling through collagen receptors, which in turn can influence cancer cell migration and survival. We will test the effects on pancreatic tumor growth after perturbing collagen structure in pancreatic tumors, blocking signaling from collagen receptors, or elimination of immune cell infiltration. We will obtain insights into the interactions between tumor cells and stroma by analysis of tissue biopsies from pancreatic cancer in mice. However, since such tissue biopsies cannot provide information on the dynamics of the interactions between cancer cells and stroma, we will also pioneer microscopy on pancreatic tumors in mice that are alive. This technique will enable us to follow the growth, the survival and the migration of tumor cells in real-time.
"We expect that our study will result in a better understanding of how tumor cells interact with the stromal parts of the pancreatic tumors. Such insights should lead to the design of further studies with the long-term goal of improving the clinical course of the disease."
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Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation
Kazuki N. Sugahara, M.D., Ph.D. Research Assistant Professor, Sanford-Burnham Medical Research Institute, La Jolla, CA
Tissue-Penetrating Drug Delivery to Desmoplastic Pancreatic Tumors
"Pancreatic cancer is one of the most challenging targets for anti-cancer agents. Pancreatic tumors are packed with fibrotic stroma that inhibits drug distribution within the tissue. The poor drug penetration leads to failure of initial therapy, and eventually, to drug resistance. We have recently identified a peptide that delivers drugs deep into solid tumors and enhances drug efficacy. The peptide, iRGD, belongs to a novel group of peptides (CendR peptides) that interact with a tissue penetration receptor, neuropilin-1 (NRP-1). Most importantly, iRGD facilitates tumor-specific tissue penetration of co-administered free drugs, as well as drugs chemically tethered to the peptide. Thus theoretically, any drug, right from the physician’s cabinet, can be easily potentiated by iRGD. Our recent data indicate that iRGD is particularly efficient in penetrating pancreatic tumors demonstrating its potential in becoming a powerful arsenal of pancreatic cancer treatment.
"PanCAN and AACR have committed a major support to our project in translating the iRGD technology to the clinic. In this project, we will examine the utility of iRGD in targeting human pancreatic cancer, and establish a method to stratify patients to iRGD therapy. First, we will test the efficacy of iRGD-drug combinations in the KPC mouse model, one of the most clinically relevant pancreatic cancer models currently available. Second, we will create a panel of patient-derived pancreatic cancer mouse models with various NRP-1 expression patterns, and validate the iRGD therapies in the mice. These studies will help us estimate the efficacy of iRGD therapies in human patients, and define the patient population that responds to the therapies based on NRP-1expression. With support from PanCAN and AACR, we hope to provide a firm basis for clinical translation of iRGD, and guide future clinical trials to success."
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David Sung-wen Yu, M.D., Ph.D. Assistant Professor, Emory University, Atlanta, GA
Exploiting the Replication Stress Response in Pancreatic Cancer
"Pancreatic cancer is a highly lethal malignancy with an expected five-year survival of less than 5 percent for all patients using current therapies. Most of these therapies rely on inducing DNA damage and interfering with DNA replication to cause cell death; however the effectiveness of these treatments is often limited to a subset of patients that respond to treatment. Thus, a better understanding of why patients respond or do not respond to specific treatments would allow the personalization of therapies that are most effective for a patient while potentially reducing toxic side effects.
"Work in my laboratory is focused on understanding how cells respond to replication stress, why this is deregulated in cancer, and how we can utilize this knowledge for improvements in cancer diagnosis and treatment. The replication stress response is a signaling network that recognizes challenges to DNA replication and mobilizes diverse activities to maintain genome integrity. The replication stress response is critical both for the prevention of pancreatic cancer by acting as a cancer barrier and for determining the response of pancreatic cancer to treatments that induce DNA damage and replication blocks. In human pre-cancerous lesions, aberrant DNA replication induces activation of the replication stress response, which maintains genome integrity or causes cell death. Mutations in the replication stress response promote the survival and proliferation of genetically unstable cells ultimately resulting in cancer. However, the genetic changes that lead to pancreatic cancer can also weaken the ability of cancer cells to respond to treatment by compromising DNA repair pathways. Often the cancer cell will become reliant on backup pathways, which can be targeted to cause cell death through the principle of synthetic lethality. Two genes or pathways are synthetically lethal when inactivation of one is sublethal but inactivation of both causes cell death.
"We recently completed a loss of function genetic screen to identify genes which when silenced cause sensitization or resistance to the replication stress and chemotherapeutic agent gemcitabine. Research supported by the Pancreatic Cancer Action Network-AACR Career Development Award will investigate the functions of these genes and determine if they can be utilized as biomarkers for therapeutic response. Completion of this work will provide new insights into how the replication stress response maintains genome integrity, elucidate novel targets for the treatment of pancreatic cancer, and identify subsets of pancreatic cancers that may benefit from gemcitabine chemotherapy. Future studies will focus on examining whether these biomarkers are useful for predicting clinical outcome in pancreatic cancer patients treated with gemcitabine so that personalized therapies can be tailored to individual patients. Our ultimate goal is to develop innovative therapies to improve the quality of care for patients with pancreatic cancer."
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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.”
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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