American Association for Cancer Research

Pancreatic Cancer Action Network-AACR Career Development Awards

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.

2013 GRANTEES

Eric R. Lutz, Ph.DEric R. Lutz, Ph.D.
Assistant Professor, Johns Hopkins University, Baltimore, MD

Exploiting the Cancer Mutome for Personalized Tumor Immunotherapy 

Pancreatic cancer is the fourth leading cause of cancer-related deaths due to the lack of adequate interventions for treatment and prevention, and screening methods. Because pancreatic cancer is naturally resistant to current chemotherapy and radiation approaches, new therapeutic strategies that specifically target cancer-specific pathways are required for the successful treatment and prevention of this disease. Vaccine-based immunotherapy is one form of targeted therapy that has the ability to target proteins involved in pancreatic cancer initiation, progression, and metastases, some of which include mutated oncogenes (such as KRAS) and tumor suppressor genes (such as p53). 

"The goal for pancreatic cancer vaccines is to train the immune system to see pancreatic cancer cells as foreign, ultimately resulting in their destruction. Accomplishing this goal depends on activating immune effector T cells capable of specifically recognizing and killing tumor cells. A major obstacle has been identifying targetable T-cell antigens expressed by pancreatic cancer cells, but not normal cells. This is important not only for minimizing the risk of inducing autoimmunity, but also because natural immune tolerance mechanisms exist for depleting and inhibiting T cells that recognize antigens expressed by normal tissues. Recent advances in DNA sequencing technologies have provided the opportunity to perform large-scale genomic analysis of large numbers of human pancreatic cancers. These sequence analyses have shown that pancreatic cancer cells possess an average of 63 non-synonomous somatic mutations (called the “mutome”). Since these mutations occur during tumor development, and are not encountered by the patient prior to the onset of tumorigenesis, each mutation generates a novel and essentially foreign antigen. Although some mutations in pancreatic cancers are in common genes and cellular pathways, the majority are unique and not shared between patients’ tumors. Because these mutant antigens are not only unique to the tumor, but also to each patient, we propose that vaccines targeting them provide a new and innovative approach for personalized pancreatic cancer-specific immunotherapy.

"The Pancreatic Cancer Action Network-AACR Career Development Award will allow us to develop the rationale and methods required for testing this approach in patients with pancreatic cancer. For this approach to work, we must establish methods for comprehensively identifying each patient’s tumor-specific mutations; show that tumor mutations generate antigens capable of being recognized by patient T cells; develop vaccination strategies for stimulating mutation-specific T cells and inducing potent antitumor responses; and develop strategies for measuring vaccine activity. Strategies for identifying tumor mutations directly from tumor tissue are already established. However, since it will be important to target at least one mutation expressed by every tumor cell, in this study, we will investigate whether the analysis of one small piece of tumor results in the identification of mutations present in the total population of cancer cells within a tumor. Recent work from our group and others suggest that a substantial fraction of tumor mutations generate immunogenic antigens capable of being recognized by T cells. Furthermore, in mice, activation of tumor mutation-specific T cells by immunizing with mutation-spanning synthetic peptides has been shown to result in protective antitumor responses. In this study, we will use two mouse pancreatic cancer models to optimize vaccination strategies for inducing tumor mutation-specific T cells and antitumor responses. Finally, we will establish strategies for measuring vaccine activity by analyzing the induction of tumor mutation-specific T cell responses in patients treated with a whole-cell pancreatic cancer vaccine also being developed by our group. If successful, we expect to employ the strategies developed by this study in the first clinical trial testing personalized immunotherapy in patients with pancreatic cancer."

Top of Page

Andrew D. Rhim, M.D.Andrew D. Rhim, M.D.
Assistant Professor of Medicine at the University of Michigan Medical School, Ann Arbor, MI

Using Human Circulating Pancreas Cells as a Biomarker for Early PDAC 

At the time of diagnosis, more than 80 percent of patients with PDAC have late-stage disease, when tumor cells have already metastasized and are refractory to therapy. One strategy to improve survival in patients with PDAC is to diagnose this cancer at early stages, prior to metastasis, when current treatments are most efficacious. 

"Our recent studies suggest a novel strategy to identify patients with the earliest forms of cancer. We discovered a new type of cell that arises when precancerous lesions that are destined to form tumors are found in the pancreas: the circulating pancreatic cell (CPC). CPCs are unique pancreas-derived cells found in the blood circulation. We found CPCs in genetically engineered mice with precancerous lesions of the pancreas destined to turn into cancer, before overt tumors formed (Rhim et al, Cell 2012). Furthermore, using a sensitive microfluidic device, we detected CPCs in a portion of patients with precancerous cystic lesions of the pancreas, up to a third of whom will develop PDAC (CPCs were found in 0 percent of controls and 88 percent of PDAC patients). Thus, CPCs can be found in patients who may harbor early, undetectable PDAC.

"The PanCAN Career Development Award will allow me to assess if CPC analysis can predict which patients at high-risk for PDAC (patients with strong family history and those with precancerous lesions of the pancreas) will develop cancer. We will perform a novel prospective clinical study to enumerate, isolate and characterize CPCs from patients and attempt to correlate our findings to the development of cancer. In this way, we hope to learn more about the earliest steps of tumor formation and metastasis and determine if CPC analysis may have utility in stratifying PDAC risk in our patients."

Top of Page

Pankaj Kumar Singh, Ph.D.Pankaj Kumar Singh, Ph.D.
Assistant Professor, University of Nebraska, University of Nebraska Medical Center, Omaha, NE

Targeting a Novel Metabolic Chemoresistance Mechanism in Pancreatic Cancer 

"Pancreatic cancer is the fourth leading cause of cancer-related deaths with a five-year survival rate of 6 percent. The poor prognosis of this malignancy also reflects resistance to the current standard of care (gemcitabine). The resistance to gemcitabine is mostly due to intrinsic factors or the stromal (non-tumor cell component of the tumor) environment that limits the accessibility of the tumor cells to the drug. By utilizing our unique cell-based models, animal models and unique techniques, we will delineate and target the mechanism of gemcitabine resistance in pancreatic cancer. Our preliminary data demonstrate a novel metabolic mechanism of gemcitabine resistance in pancreatic cancer. We demonstrate that the glucose flux through pyrimidine biosynthetic pathway is enhanced in our gemcitabine-resistant models. Although over five hundred-fold more resistant to gemcitabine, these cells are less viable under low glucose conditions, in comparison to the control cells. Furthermore, increased expression of enzymes in pyrimidine biosynthetic pathway correlates with poor prognosis of pancreatic cancer patients on pyrimidine analog therapies (gemcitabine and 5-FU).

"Research supported by the Pancreatic Cancer Action Network-AACR Career Development Award will investigate, for the first time, the efficacy of targeting pyrimidine biosynthetic pathway in improving gemcitabine response. We will also determine if modulating metabolism in tumor cells can alter their surrounding environment to make the tumor cells more accessible and responsive to the chemotherapy. Thus, the resulting information is likely to generate novel diagnostic and therapeutic targets, and biomarkers for managing chemotherapy resistance that is associated with significant mortality in pancreatic cancer."

Top of Page

Daolin Tang, M.D., Ph.D.Daolin Tang, M.D., Ph.D.
Assistant Professor, Department of Surgery, University of Pittsburgh, Pittsburgh, PA

Role of HMGB1 in Pancreatic Cancer Initiation and Progression 

"Why is pancreatic cancer so aggressive and deadly? What controls early events in pancreatic tumorigenesis? The Pancreatic Cancer Action Network-AACR Career Development Award will allow us to answer these questions by using a novel genetically modified mouse model of pancreatic cancer that was recently developed in my lab. This award will hopefully provide me the necessary preliminary data to develop a competitive NIH R01 grant application.

"High mobility group box 1 protein (HMGB1), a chromatin-associated nuclear protein and extracellular damage associated molecular pattern molecule (DAMP), is an evolutionarily ancient and critical regulator of cell death and survival. To examine the role of HMGB1 in pancreatic carcinogenesis, we generated mice with pancreas-specific disruption of HMGB1 in the presence of oncogenic K-Ras. To our knowledge, this genetically engineered mouse model develops pancreatic intraepithelial neoplasia the fastest of any vertebrate. Our central hypothesis is that intracellular HMGB1 functions as a previously unrecognized tumor suppressor gene and is a key regulator of pancreatic cancer initiation and progression. This research aims to elucidate how intracellular HMGB1 acts in pancreatic tumorigenesis, with the ultimate goal of devising better prevention and treatment strategies for pancreatic cancer."

Top of Page

Pancreatic Cancer Action Network – AACR Career Development Award, in memory of Skip Viragh

Monte M. Winslow, Ph.D.Monte M. Winslow, Ph.D.
Assistant Professor, Department of Genetics, Stanford University, Stanford, CA

Molecular Dissection of Hmga2 Function during Pancreatic Cancer Progression 

“Pancreatic ductal adenocarcinoma (PDAC) is a prevalent and almost uniformly fatal cancer. Several factors contribute to the poor outcome of PDAC patients but, as in most solid tumors, the ability of cancer cells to leave the primary tumors and establish inoperable metastases is a major impediment to successful therapy. Many of the mutations that occur in human PDAC have been identified, but the molecular and cellular changes that underlie tumor progression and metastasis remain less well characterized.

“The Pancreatic Cancer Action Network-AACR Career Development Award will support our efforts to better understand PDAC invasion and metastasis. We previously identified the chromatin associate protein, Hmga2 as an important regulator of lung cancer metastasis. Hmga2 is highly expressed during development, absent in most adult tissues, and re-expressed in several human cancers. Based on the hypothesis that metastasis of different cancers might be driven by similar mechanisms, we analyzed several mouse models of PDAC and found a striking correlation between Hmga2 expression and invasive cancer cell cytology. We hypothesize that Hmga2 is a key regulator of PDAC invasion and metastatic progression. We will use a genetically engineered mouse model to quantitatively assess the role of Hmga2 on PDAC progression in vivo. Unbiased characterization of PDAC cells with altered Hmga2 expression will also uncover the Hmga2-regulated genes and pathways that drive the malignant features of advanced PDAC. We anticipate that this study will be the beginning of our efforts to systemically understand the functional networks that make PDAC so aggressive.

“Our study will advance our understanding of PDAC and provide insight into common mechanisms the drive tumor progression and metastasis. This may allow the clinical development of therapies to inhibit PDAC invasion or uncover vulnerabilities that could be exploited to irradiate PDAC metastases and significantly improve pancreatic cancer patient outcome.”

Top of Page

2012 GRANTEES

Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation

Jiyoung Ahn, Ph.D., Pancreatic Cancer Action Network-AACR Career Development Award 2012 GranteeJiyoung 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."

Top of Page

Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation

Darren R. Carpizo, M.D., Ph.D., Pancreatic Cancer Action Network-AACR Career Development Award 2012 GranteeDarren R. Carpizo, M.D., Ph.D.
Assistant Professor of Surgery, Rutgers University, 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."  

Top of Page

Pancreatic Cancer Action Network-AACR Career Development Award, in memory of Skip Viragh

Eric A. Collisson, M.D., Pancreatic Cancer Action Network-AACR Career Development Award 2012 GranteeEric 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."

Top of Page

Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation

Mikala Egeblad, Ph.D., Pancreatic Cancer Action Network-AACR Career Development Award 2012 GranteeMikala 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."

Top of Page

Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation

Kazuki N. Sugahara, M.D., Ph.D., Pancreatic Cancer Action Network-AACR Career Development Award 2012 GranteeKazuki N. Sugahara, M.D., Ph.D.
Postdoctoral Residency Fellow and Adjunct Associate Research Scientist in the Department of Surgery, Columbia University, New York, NY

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."

Top of Page

David Sung-wen Yu, M.D., Ph.D., Pancreatic Cancer Action Network-AACR Career Development Award 2012 GranteeDavid 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."


Top of Page