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Pancreatic Cancer Action Network-AACR Career Development Awards

The Pancreatic Cancer Action Network-AACR Career Development Awards represent a joint effort to encourage and support junior faculty, who have completed their most recent doctoral degree or medical residency within the past 11 years, 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.

2016 Grantees

Pancreatic Cancer Action Network-AACR Career Development Award, funded by an anonymous foundation

Amber Simpson, PhD 
Assistant Attending Computational Biologist
Memorial Sloan Kettering Cancer Center
New York, New York
  CT Texture Analysis: A Radiomics Approach to Predicting Malignancy in IPMN

Incidental pancreatic cysts are being identified at an increasing rate due to the widespread use of abdominal cross-sectional imaging. Current laboratory, endoscopic, cytologic, and imaging technologies are limited in their ability to distinguish between intraductal papillary mucinous neoplasms (IPMN) at low- or high-risk of becoming an invasive cancer. The yield from resecting branch duct IPMN is low, with about 18 percent demonstrating malignancy on pathology report. Thus, a significant proportion of these patients will undergo unnecessary surgery for benign precursor lesions. The goal of this interdisciplinary research is to develop quantitative imaging markers that define malignancy. Dr. Simpson’s hypothesis is that CT-based quantitative imaging features can better predict malignancy in IPMN than visual assessment by radiologists and can achieve comparable discriminatory power as state-of-the-art fluid markers, thus providing non-invasive disease surveillance. Dr. Simpson was the first to apply quantitative imaging techniques in the pancreas, identifying markers predictive of survival in patients with pancreatic adenocarcinoma.

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Pancreatic Cancer Action Network-AACR Career Development Award, funded by an anonymous foundation

Shuibing Chen, PhD 
Assistant Professor
Weill Cornell Medical College
New York, New York
  Targeting chemoresistant stem cells in pancreatic cancer

Chemoresistance is a primary cause of treatment failure in pancreatic cancer. Identifying cell surface markers specifically expressed in chemoresistant cancer cells (CCCs) could facilitate targeted therapies to overcome chemoresistance. From an antibody-based screen, TRA-1-60 and TRA-1-81, two “stemness” cell surface markers, were identified to be highly enriched in chemoresistant cancer cells. Moreover, TRA-1-60+/TRA-1-81+ cells are chemoresistant compared to TRA-1-60-/TRA-1-81- cells. Furthermore, a high content chemical screen of a library of 2000 FDA-approved and international drugs identified a lead hit that specifically eliminates the TRA-1-60+/TRA-1-81+ cells and increases the sensitivity of pancreatic cancer cells to chemotherapy. The aims of the proposal are 1) Define the molecular basis for chemoresistance of the TRA-1-60+/TRA-1-81+ cells; and 2) Validate the hit compounds using primary tumor samples. The proposed studies will significantly improve our knowledge of chemoresistance and repurpose an antiarrhythmic reagent for combinational therapy of otherwise intractable cancers.

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

Rushika M. Perera, PhD 
Assistant Professor
University of California, San Francisco
San Francisco, California
  Targeting nutrient scavenging pathways that fuel pancreatic cancer growth

Pancreatic adenocarcinoma (PDA) is a highly aggressive malignancy that thrives in nutrient poor, hypoxic environments. Recent evidence suggests that this remarkable resilience to nutrient limitation is overcome through constitutive activation of nutrient scavenging pathways namely autophagy (cellular self-catabolism) and macropinocytosis (bulk uptake of extracellular material). Importantly, both of these pathways converge on the lysosome, an acidic organelle that harbors within its lumen a complex series of enzymatic reactions that enable degradation of incoming cargo material. Dr. Perera’s recent work has shown that the lysosome is greatly expanded and qualitatively different in PDA cells compared to normal tissue. Moreover, she identified the MiT/TFE transcription factors (TFE3, MITF, and TFEB) as master regulators of autophagy-lysosome activation in PDA where they orchestrate transcriptional control of the biogenesis and function of the autophagosome-lysosome system. Furthermore, Dr. Perera determined that autophagy-lysosomal activation is specifically required to maintain intracellular amino acid (AA) pools. Thus, contrary to the long held view that the lysosome is a metabolic "dead end," devoid of any regulation or fine-tuning Dr. Perera proposes that lysosomes function as major integrators of extracellular and intracellular information and are important mediators of global rewiring of cellular state. Building on these findings, Dr. Perera and her team will test the hypothesis that the lysosome actively remodels PDA metabolism to enable adaptation to a variety of stress conditions. By developing and systematically applying novel proteomics and metabolomics approaches, the proposed studies aim to uncover dynamic changes in lysosome composition during tumor evolution and following exposure to cellular stress, particularly in the form of nutrient starvation and treatment with anti-cancer agents. Through a comprehensive analysis of lysosome function in PDA, Dr. Perera’s goal is to identify key targets for development of novel lysosome-based inhibitors.

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Pancreatic Cancer Action Network-AACR Career Development Award, supported by Laurie MacCaskill

Kian-Huat Lim, MD, PhD 
Assistant Professor
Washington University in St. Louis
St. Louis, Missouri
  Deactivating the innate immune defense mechanism of pancreatic cancer

Extreme resistance to anticancer agents and radiation underlies the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC). Mechanisms that contribute to such malignant feat of PDAC include strong intrinsic survival signaling events including expression of KRas oncoprotein and upregulation of the NF-kB pathway, as well as an intensely inflamed extrinsic tumor microenvironment which limits the delivery of anticancer agents. Dr. Lim’s team recently found that PDAC cells commonly upregulate their intrinsic innate immune defense mechanism through activating the Interleukin-1 Receptor Associated Kinase 4 (IRAK4). Notably, presence of activated IRAK4 in resected PDAC tumors is significantly associated with poor prognosis, indicating IRAK4 as a regulator that drives the aggressive behavior of PDAC. His team went on to show that therapeutic targeting of IRAK4 significantly reduces the NF-kB activity, cripples the in vivo tumorigenic ability of various PDAC lines, augments the effect of chemotherapeutics and reduce stromal formation in xenograft models.

Dr. Lim’s team will now go on to investigate the mechanism that leads to activation of IRAK4 by focusing on the contribution of the closely associated Toll-like receptors. Using the state-of-the-art genetically-engineered mouse model, the KPC mice, Dr. Lim’s team will further dissect the role of IRAK4 in stromal and immune cells, which will have important clinical implication in the future. Finally, Dr. Lim’s team will test the preclinical efficacy of a newly developed IRAK4 inhibitor as single agent and in combination with chemotherapeutics in mouse models. 

In summary, Dr. Lim’s team believes that deactivating the innate immune defense mechanism of PDAC cells represents a promising therapeutic strategy that could improve patient outcome.

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

Christopher Vakoc, MD, PhD 
Associate Professor
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York
  Enhancer reprogramming as a driver of pancreatic cancer progression

An emerging body of evidence has linked deregulation of enhancers to the pathogenesis of human cancer. In this proposal, the Vakoc laboratory will perform mechanistic research that tests the hypothesis that enhancer deregulation by transcription factors promotes metastasis in late-stage pancreatic cancer. This proposal is based on preliminary evidence that identifies massive aberrations of enhancer activity in organoid cultures derived from distal metastases relative to primary pancreatic tumors. A key hypothesis underlying the proposed research is that aberrant enhancer activation is a major reason why pancreatic cancer cells gain the ability to metastasize to distant organs, such as the liver. To test this idea, enhancers will be genetically modified in pancreatic cancer cells to examine how this alters the behavior of the disease. In addition, experiments will investigate how transcription factors bind to enhancers to turn nearby genes ON or OFF. It is anticipated that targeting transcription factors might allow restoration of enhancer configurations back to their normal state, and an attenuation of metastatic potential of cancer cells.

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2015 Grantees

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

Cosimo Commisso, PhD  
Assistant Professor
Sanford-Burnham Medical Research Institute
La Jolla, California

Targeting macropinocytosis via Na+/H+ exchanger inhibition in PDAC

Oncogenic KRAS mutations initiate the progression of pancreatic cancer and have been found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC). A prominent feature of oncogenic KRAS-expressing cells is the stimulation of macropinocytosis, an endocytic mechanism of fluid-phase uptake. Recently, we have linked macropinocytosis to nutrient internalization in pancreatic tumor cells. By stimulating the uptake of extracellular serum albumin and targeting it for lysosomal degradation, macropinocytosis functions as an amino acid supply route. Macropinocytosis is unique in relation to other endocytic pathways because it is selectively sensitive to 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and other amiloride analogs that target Na+/H+ exchange. Na+/H+ exchange is regulated by a family of integral membrane transporters known as Na+/H+ exchangers (NHEs). We found that targeting NHEs in vivo via treatment with EIPA attenuates macropinocytosis and causes growth suppression or regression of pancreatic tumor xenografts. While the antitumor effects exerted by EIPA could be multifactorial in nature, the selectivity of the drug for tumors with a high macropinocytic index suggests that the abrogation of macropinocytosis accounts for the majority of this effect. In addition, our preliminary data indicates that the pharmacological inhibition of NHEs has the capacity to diminish the growth of syngeneic tumors and to modulate the tumor stroma. It is unclear which of the NHEs play a role in the fitness of pancreatic cancer cells and whether more potent, next-generation NHE inhibitors can be effective at modulating pancreatic tumor growth. Moreover, how NHE inhibition leads to a stromal collapse-like phenotype and whether this feature can be harnessed for the delivery of chemotherapeutics is unknown. These questions are the conceptual motivators for this new project in which we propose to investigate the functionality of the NHEs in pancreatic cancer and determine whether the targeting of NHEs is a potential novel therapeutic strategy for PDAC.

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Pancreatic Cancer Action Network – AACR Career Development Award, supported by an anonymous foundation

Nada Y. Kalaany, PhD 
Assistant Professor
Boston Children's Hospital
Boston, Massachusetts

Role of arginine metabolism in obesity-associated pancreatic cancer

A strong correlation exists between obesity and the incidence of/mortality from pancreatic cancer. Interestingly, this correlation is also evident in lean patients that display a prediabetic state characterized by elevated blood insulin and insulin-like growth factor-1 (IGF-1) levels that typically accompany obesity. However, the mechanisms underlying this association remain unknown.

Pancreatic cancer is a highly lethal malignancy, whose poor outcomes have remained stagnant for several decades. Thus, alternative therapeutic approaches are urgently needed. Recognized as a hallmark of cancer formation, altered cellular metabolism is evident in pancreatic tumors. However, how distinct metabolic pathways are differentially regulated in the pancreatic tumors under an obese/prediabetic state, and whether elevated insulin and IGF-1 blood levels mediate these effects, remain unknown.

Dr. Kalaany plans to investigate whether and how obesity and its associated metabolic changes can alter pancreatic tumor metabolism, so as to enhance its growth and worsen disease outcome. Preliminary studies using human pancreatic cancer cells implanted into the pancreas of lean or obese mice indicate a striking enhancement in the utilization of a specific metabolic pathway (arginine metabolism) by pancreatic tumors grown in obese mice, compared to lean mice. Interestingly, this pathway is largely mediated by a pro-tumorigenic protein (Akt), whose activity can be induced by elevated insulin and IGF-1 levels, independent of obesity.

Using lean or obese transplant and genetically engineered mouse models of pancreatic cancer, Dr. Kalaany's team will investigate the significance of these findings, with regards to pancreatic cancer growth and progression. To that end, a variety of molecular, biochemical, and metabolic approaches will be applied, to alter the arginine metabolic pathway within the tumor cell and suppress its utilization by the tumors.

Accomplishing these studies will identify and underscore a novel metabolic dependency in pancreatic cancers harboring activated Akt, resulting from either tumor-promoting mutations, or elevated insulin/IGF-1 levels that accompany obesity. This metabolic liability could serve as an Achilles heel for therapeutic targeting in both lean and obese pancreatic cancer patients. Importantly, it will pave the way for the development of novel antipancreatic cancer strategies that could be used in combination with currently available chemotherapies.

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Pancreatic Cancer Action Network – AACR Career Development Award, supported by an anonymous foundation

Gregory L. Beatty, MD, PhD 
Assistant Professor of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania

Immune escape mechanisms in metastatic pancreatic cancer

Metastatic disease remains the primary cause of morbidity and mortality in pancreatic ductal adenocarcinoma (PDAC). However, the factors that regulate metastasis in PDAC remain ill-defined. The process of metastasis is dependent on cancer cell-intrinsic properties as well as the receptiveness of the local microenvironment where tumor cells seed. To study metastasis in PDAC, Dr. Beatty's laboratory has used a mouse model, called the KPC model, in which mice spontaneously develop PDAC. This model reproduces many of the salient features of human disease including metastasis. In both KPC mice and humans, Dr. Beatty's research team has found that the immune response to PDAC can be reprogrammed with antitumor properties. However, antitumor immune responses are often short-lived and heterogeneous indicating a need for understanding the mechanisms by which malignant cells escape immune elimination. Because the liver is the most common site of metastasis in PDAC, Dr. Beatty plans to focus his team's efforts on liver metastasis. He and his team hypothesize that immune cells recruited to the liver microenvironment are critical for establishing a niche that is supportive of cancer cell metastasis. Because of the inherent plasticity of the immune system, Dr. Beatty has proposed that this leukocyte reaction may also be redirected to inhibit metastasis. To test this hypothesis, he and his research team will study the capacity of immune stimuli to shift the phenotype of leukocytes within the liver from pro- to antitumor. In addition, they will examine the role of cancer cell intrinsic properties in promoting immune evasion during metastasis. It is expected that findings from these studies conducted in clinically relevant mouse models will 1) provide insight into factors that regulate metastasis in PDAC; and 2) inform the development of novel immunotherapeutic approaches for inhibiting and treating metastatic disease.

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2014 Grantees

David G. DeNardo, PhDDavid G. DeNardo, PhD
Assistant Professor
Department of Medicine and Department of Pathology and Immunology
Washington University in St. Louis
St. Louis, Missouri

Origins and Impact of Macrophages in Pancreatic Cancer 

Pancreatic cancer carries a dismal prognosis. The success of current treatments is measured by response rates instead of cures. A promising way to improve outcomes for patients is to target the tissue and cellular environment within which the tumor exists. Tumor-associated macrophages (TAMs) reside within the environment of pancreatic tumors and the presence of high numbers of these macrophages correlates with poor clinical outcomes in patients with pancreatic cancer. Thus, TAMs have become important targets for drugs in recent clinical trials. The classical assumption has been that TAMs are recruited from cells in the blood, which are continuously generated in the bone marrow. This assumption has been the basis for several clinical trials targeting macrophage recruitment. However, using several novel techniques to track these immune cells, we found that pancreatic tumors are often heavily infiltrated with macrophages derived from cell division rather than recruitment from the blood. These resident proliferating macrophages are prominent in human pancreatic cancer and can predict poor patient outcomes. However, the mechanisms by which this macrophage subset might impact tumor progression or response to current clinical treatments have not been examined. We hypothesize that resident proliferating macrophages are critical early mediators of tumor inflammation and drivers of tumor metastasis. We will test this hypothesis using a combination of mouse models of pancreatic cancer in combination with unique cellular tracing to follow macrophages; and assessment of proliferating macrophages in human PC tissue samples to determine their impact on patient outcomes.

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

Eugene J. Koay, MD, PhD Eugene J. Koay, MD, PhD   
Assistant Professor
University of Texas MD Anderson Cancer Center
Houston, Texas

Changes in Mass Transport as a Biomarker of Response in Pancreatic Cancer 

There has been significant progress in the understanding of the biology of pancreatic cancer. As novel strategies emerge from these scientific discoveries and are tested in phase I/II clinical trials, it will be increasingly important to have an early biomarker of response to therapy so that promising strategies can reach patients quickly. Currently, such a biomarker has not been identified for pancreatic tumors.

Dr. Koay’s pilot studies have revealed a promising candidate for this purpose. He worked with a multidisciplinary team to develop a method to quantify enhancement properties of pancreatic tumors from diagnostic computed tomography (CT) scans and correlated these properties with patient outcome. In two trials of chemoradiation for unresectable pancreatic cancer, patients who had a measureable decrease in enhancement of their pancreatic tumors after chemoradiation treatment showed significantly better tumor control (86 percent with tumor control at two years) compared to patients whose tumors exhibited stable or increased enhancement after treatment (34 percent with tumor control at two years), independent of therapy regimen, change in tumor size, and receipt of curative-intent surgery.

This PanCAN proposal involves a multi-institutional collaboration to test the idea that tumor control is associated with changes in tumor enhancement. In collaboration with investigators at Johns Hopkins, the measurements of enhancement from CT scans before and after treatment will be compared with tumor control for large datasets of patients with pancreatic cancer who received chemotherapy and radiation. Simultaneously, a prospective registry trial at MD Anderson will test the same idea for patients who receive chemotherapy alone for unresectable, non-metastatic pancreatic cancer. To understand the underlying biology of the observation, the researchers will analyze pancreatic tumors that were treated with chemoradiation prior to surgery, correlating the CT enhancement profiles with specific markers of therapy resistance in the specimens.

In summary, Dr. Koay and his team will perform a large-scale validation plan to establish a clinically useful and scientifically meaningful method to help accelerate promising new treatment strategies for pancreatic cancer and more rapidly improve patient outcomes.

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Florencia McAllister, MDFlorencia McAllister, MD
Assistant Professor
University of Texas MD Anderson Cancer Center
Houston, Texas

Targeting IL-17 signaling Axis in Pancreatic Ductal Adenocarcinoma 

Even though a Kras mutation is enough to initiate early pre-malignant lesions, the mechanisms required for the progression to pancreatic cancer are unknown. It is well known that inflammation is a risk factor for cancer and it has been well established that pancreatic chronic inflammation can accelerate the development of pancreatic cancer. Dr McAllister has recently found that activation of KrasG12D in murine adult acinar cells induces expression of functional IL-17 receptors (IL-17RA) on emerging PanIN epithelial cells, accompanied by pancreatic infiltration by IL-17-producing CD4+ and gd-T cells. Furthermore, she has shown that IL-17-producing T cells are early drivers of pancreatic neoplasia and mediate much of the increase in PanIN formation observed in chronic pancreatitis. She is now going to extend these studies to determine the role of IL-17 signaling in advanced disease, including the preclinical evaluation of clinical-grade neutralizing antibodies targeting IL-17 signaling in established murine pancreatic cancer. Furthermore, she is planning to dissect the specific compartment required for the pro-tumorigenic IL-17 signaling in pancreatic tumor development. Finally, she will also investigate how systemic TH17 immune responses, including changes in the gut microbiome, can affect pancreatic tumorigenesis.

In sum, she considers that better understanding of the pancreatic hematopoietic-to-epithelial pro-tumorigenic IL-17 signaling axis can result in more effective strategies for the prevention and treatment of pancreatic cancer.  

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Kenneth L. Scott, PhDKenneth L. Scott, PhD
Assistant Professor, Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas

Functionalizing Metabolic Pathway Driver Aberrations in Pancreatic Cancer 

Dr. Scott’s proposal focuses on identifying genes that promote pancreatic ductal adenocarcinoma (PDAC) development and progression (referred to here as PDAC “driver” genes). Identifying PDAC drivers and understanding their mechanism-of-action is critically important, as this information could inform new PDAC diagnostics and therapeutics. To identify such drivers, Dr. Scott’s laboratory developed a novel genetic screening platform that integrates (1) their collection of over 32,000 human genes; (2) an innovative strategy that enables rapid modeling of barcoded mutant genes based on large-scale PDAC genome sequencing efforts; and (3) a unique human cell system that allows simultaneous expression of genes found mutated in PDAC to identify those that cooperate with KRAS, the major driver gene found in pancreatic cancer, to promote PDAC tumor development and metastasis in mice. Dr. Scott’s team used these tools to identify novel PDAC driver genes, one of which (NADK) is known to influence metabolic pathways that regulate cell growth and resistance to growth-related cell stress. Recent work by others demonstrated the importance of metabolic pathways in promoting and maintaining PDAC tumor growth, thus Dr. Scott hypothesizes that inactivating the NADK protein or inhibiting NADK’s activated pathways will provide new ways to treat pancreatic cancer patients. Dr. Scott will test this notion using a series of genetic experiments employing a panel of PDAC cell models and metabolic assays to better understand the mechanisms-of-action for both normal and mutated (found in patients) NADK. Dr. Scott’s team will also assess NADK as a new drug target by examining tumor growth and signaling through metabolic pathways following inhibiting NADK expression by genetic means or inhibiting NADK activity by use of pharmacological agents. Finally, Dr. Scott’s team will mine large-scale genomics data collected from PDAC tumors to create collections of other mutated genes with high probability of impacting metabolic pathways. These genes will be entered into innovative screens similar to those that identified NADK to identify new metabolic drivers, which with his combined studies on NADK, will illuminate gene pathways promoting PDAC progression with the goal of identifying new drug targets and/or detection biomarkers critically needed for pancreatic cancer patients who currently have few effective treatment options.

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Kathryn E. Wellen, PhDKathryn E. Wellen, PhD
Assistant Professor, Department of Cancer Biology
University of Pennsylvania
Philadelphia, Pennsylvania

Understanding Metabolic Control of the Pancreatic Cancer Epigenome

Novel strategies are desperately needed for the treatment of pancreatic ductal adenocarcinoma, a disease with a dismal prognosis and an average survival of six months after diagnosis.  Deregulation of cellular epigenetics (reversible chemical modifications to DNA and DNA-associated proteins) is essential for normal cells to transform into cancer cells. The mechanisms that cause epigenetic alterations in cancer cells are poorly understood, however, and insight into these mechanisms would facilitate the design of more specific therapeutics.  Recently, evidence has emerged showing that epigenetic modifications are regulated by cellular metabolites (substances produced by nutrient breakdown in the cell). Mutations in Kras, a cancer gene that is almost universally mutated in pancreatic ductal adenocarcinoma, have been shown to orchestrate extensive rewiring of nutrient metabolism. This research plan will address the hypothesis that mutant Kras causes cells to shift the balance of cellular metabolites, resulting in an altered epigenetic state that facilitates tumor cell growth. This hypothesis is based on findings that changes in the availability of one particular metabolite – acetyl-CoA – has dramatic effects on one type of epigenetic modification known as histone acetylation.  Preliminary findings indicate that Kras mutations within the mouse pancreas lead to altered levels of histone acetylation, and that signaling pathways activated by Kras control acetyl-CoA production. Thus, Kras might cause pancreatic cancer in part through its effects on metabolism and epigenetics. The objective of our work is to investigate the mechanisms linking Kras activation to the regulation of histone acetylation and to functionally test the importance of Kras-driven acetyl-CoA production and histone acetylation on gene expression, tumor development, and tumor growth. Results of this study could pave the way towards innovative new strategies to target pancreatic cancer, exploiting the interface between metabolism and epigenetics.

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2013 Grantees

Andrew D. Rhim, MDAndrew D. Rhim, MD
Assistant Professor of Medicine
University of Michigan Medical School
Ann Arbor, Michigan

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.

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