Pancreatic Cancer Action Network-AACR Innovative Grants are available to independent junior and senior investigators to develop and study new ideas and approaches that have direct application and relevance to pancreatic cancer. The research proposed for funding may be basic, translational, clinical or epidemiological in nature. The Pancreatic Cancer Action Network-AACR Innovative Grants were formally known as the Pancreatic Cancer Action Network-AACR Pilot Grants and have been renamed to emphasize the focus on funding new, creative, and cutting-edge ideas and approaches.
- Yves Boucher, Ph.D. (2013)
- M. Celeste Simon, Ph.D. (2013)
- Timothy C. Wang, M.D. (2013)
- Valerie Weaver, Ph.D. (2013)
- David Allen Boothman, Ph.D. (2012)
- Paul Chiao, Ph.D. (2012)
- Channing J. Der, Ph.D. (2012)
- Peter John Espenshade, Ph.D. (2012)
- Tyler Jacks, Ph.D. (2012)
- Lisa A. Cannon-Albright, Ph.D. (2011)
- James R. Eshleman, M.D., Ph.D. (2011)
Pancreatic Cancer Action Network – AACR Innovative Grant, in memory of Abby Sobrato
Yves Boucher, Ph.D.
Associate Professor, Dept. of Radiation Oncology, Massachusetts General Hospital, Boston, MA
Targeting Desmoplasia in Pancreatic Cancer to Improve Drug Efficacy
Cancer cells in pancreatic tumors are embedded in a dense fibrous tissue / desmoplastic reaction formed of collagen fibers, hyaluronan gel and pancreatic stellate cells – activated-fibroblasts – that produce collagen, hyaluronan and other matrix molecules. This dense fibrous tissue, which occupies most of the tumor volume of pancreatic tumors, compresses and collapses blood vessels thus impairing the blood flow, drug delivery and the killing of pancreatic cancer cells. Hence, it is imperative to develop novel agents or strategies that will either solubilize this fibrous matrix or reduce its production.
"We recently discovered that the antihypertensive agent losartan reduces the collagen and hyaluronan content in several tumor types including pancreatic cancer. Furthermore, in mice with pancreatic cancer losartan improved the intratumoral delivery and effectiveness of therapeutic agents. On the other hand, the activation of the CD40 receptor on the surface of macrophages enhances the infiltration of macrophages in pancreatic cancer lesions and produces a rapid breakdown / clearance of the collagen. Interestingly, in patients with pancreatic cancer the drug gemcitabine combined with CD40 activation by an agonist antibody induced tumor regressions in 30 percent of patients. Based on these findings we will establish if telmisartan, an antihypertensive agent that reduces the proliferation of pancreatic stellate cells, combined with CD40 activation in macrophages will produce a sustained reduction in matrix production that will improve blood flow and drug delivery in pancreatic cancer. To test this hypothesis we will perform experiments in transgenic mice models of pancreatic cancer. To assess changes in matrix structure we will use a novel optical technique to image collagen fiber breakdown in real-time in living tumors. We will also determine if the breakdown of the matrix is co-localized with specific macrophage subpopulations and changes in the activity of pancreatic stellate cells. In addition, to determine if matrix-modifying agents affect the overall expression of profibrotic and antifibrotic genes we will perform a comprehensive gene analysis. This global analysis aims to identify other genes that could be targeted to further inhibit the accumulation of matrix molecules in pancreatic tumors. In complimentary experiments we will determine how telmisartan combined with CD40-activation affects blood flow, drug delivery and the effectiveness of pancreatic cancer drugs. If any of these approaches are successful, our results will form the foundation for future clinical trials led by our clinical collaborators at Massachusetts General Hospital."
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M. Celeste Simon, Ph.D.
Scientific Director, Abramson Family Cancer Research Institute, Philadelphia, PA
Role of Hif1a in Inflammation, Tissue Repair, and Cancer of the Pancreas
"Pancreatic ductal adenocarcinoma (PDAC) is now the fourth leading cause of cancer-related deaths in the United States. Chronic pancreatitis, which is characterized by inflammation of the pancreas, is an established risk factor for PDAC in humans. However, the precise mechanisms by which chronic pancreatitis promotes pancreatic tumorigenesis have remained elusive. Inflamed tissues often become severely oxygen limited “(hypoxic)” due to vascular damage, tissue edema, and increased metabolic stress promoted by bacteria infiltrating immune cells. Experimental models of pancreatitis have suggested that this results in hypoxia and increased accumulation of hypoxia inducible factors (HIFs). Moreover, HIFs have been shown to tightly regulate inflammatory responses to myeloid cells. Given that chronic pancreatitis is a well-established risk factor for PDAC and severe hypoxia occurs during both pancreatitis and PDAC, HIF induction may provide a mechanistic link between these diseases. The main objective of our work is to define the role for HIFs in the pathogenesis of chronic pancreatitis and PDAC.
"This research will improve our understanding of the connection between hypoxia, inflammation, tissue regeneration, and cancer of the pancreas, and ultimately aid in the development of early detection and treatment tools for pancreatic cancer. Recent studies have indicated the utility of targeting inflammatory cells through modulating their activity. Since drugs modulating HIF activity are currently in clinical trials, the proposed study could be readily translated to the clinic."
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Timothy C. Wang, M.D.
Chief, Division of Digestion and Liver Disease, Columbia University Medical Center, New York, NY
Dclk1 in Pancreatic Tumorigenesis
"Pancreatic cancer remains an extremely lethal cancer and novel approaches to understand this disease are desperately needed. Mouse models of pancreatic cancer are of great help to investigators to test new drugs for pancreatic cancer treatment before they enter the clinic. Surprisingly, though, we do not know which specific cell within the pancreas actually gives rise to pancreatic cancer, clearly an important step in modeling the disease and in designing therapies. One potential source of pancreatic cancer could be adult pancreatic stem cells. Stem cells are long-lived and have the ability to self-renew, but this special characteristic makes them perhaps more susceptible to malignant transformation. These so called “cancer stem cells” are thought to be responsible for uncontrolled tumor growth and relapse after treatment.
"Preliminary studies from our group suggest that doublecortin-like kinase 1 protein (Dclk1) labels a rare and relatively quiescent pancreatic stem, as well as cancer initiating cells in the mouse pancreas. We have generated mice that give us the opportunity to visualize and follow these cells and their progeny over time. Surprisingly, Dclk1 cells appear to be pancreatic stem cells that are long-lived and quiescent, but regenerate the organ quickly after injury. Furthermore, introduction of the most common mutation seen in human pancreatic cancer into Dclk1 cells leads to pancreatic cancer with all features of the human disease, but this occurs primarily after inflammatory injury. Therefore, we believe that we have identified a novel pancreatic (cancer) stem cell.
"We propose to investigate two major questions. First, we want to use our new mouse model in order to characterize the role of Dclk1 in pancreatic cancer in mice and humans. Furthermore, it is known that Dclk1 has a function in other stem cells and plays a role in various cancers. Consequently, we would like to target the function of Dclk1 in order to specifically attack pancreatic cancer stem cells as our second specific aim. We will use available drugs as well as other experimental approaches to directly target cells expressing Dclk1. We have designed our project in order to help to answer fundamental questions about the initiation and the progression of pancreatic cancer. Targeting putative pancreatic cancer stem cells might offer a great opportunity to treat and prevent pancreatic cancer in the future."
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Pancreatic Cancer Action Network – AACR Innovative Grant, supported by the Blum-Kovler Foundation
Valerie Weaver, Ph.D.
Professor and Director, Center for Tissue Engineering, University of California, San Francisco Medical Center, San Francisco, CA
Interplay Between Tension and Inflammation in Pancreatic Tumor Progression
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies due to a lack of effective therapies. PDAC is characterized by a strong desmoplastic response including significant changes in the tumor microenvironment and the extracellular matrix (ECM), severely compromising treatment and surgical resection. Yet, the molecular mechanisms linking tissue transformation to fibrosis and tumor aggression remain unclear.
"Our preliminary data indicate that PDAC progression is accompanied by collagen deposition and reorganization that, in turn, stiffen the ECM and activate integrin signaling. We previously demonstrated that a stiffened ECM promotes malignant progression and that inhibiting ECM stiffening delays tumor formation and reduces tumor incidence in vivo. Recently, it was demonstrated that cytokine activation of Janus Kinase (Jak) stimulates ROCK, inducing actomyosin contractility with consequent ECM remodeling and tissue stiffening. Intriguingly, we recently found that chemokine expression is greatly potentiated by ECM stiffness enhancing Jak/Stat3 activation and inflammation. Because inflammation has been associated with fibrosis potentiating PDAC aggression, we hypothesize that there is a positive feedback mechanism mediated by cellular contractility and inflammation responsible for tumor fibrosis, progression and aggressiveness in PDAC. To test this hypothesis, we will pursue the following specific aims: 1) Examine whether tissue tension increases with the progression of pancreatic cancer; 2) Test the influence of cellular contractility on pancreatic tumor aggression and inflammation; and 3) Determine whether inhibiting cellular contractility increases the efficacy of chemotherapy in pancreatic cancer treatment.
"Initial experiments will be performed to analyze the mechanical tissue properties at various stages of tumor progression using the PDAC transgenic mouse model KrasG12D/P53+/-. We will then explore the functional consequences of increased cellular contractility within the pancreatic epithelium in promoting tumor aggression and inflammation in PDACs. Finally, we will explore whether modifying cellular tension and the surrounding fibrosis in combination will enhance the efficacy of standard chemotherapy in the treatment of pancreatic cancer."
This two-year project will focus on characterizing and understanding the interplay between cellular contractility and inflammation in driving pancreatic cancer progression, a perspective currently underappreciated in cancer research. This work will elucidate new mechanisms underlying PDAC progression and aggression, providing a solid foundation for downstream clinical impact including the identification of novel pathways for the development of targeted therapies, as well as for the diagnosis and early detection of the disease.
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported by The George and June Block Family Foundation
David Allen Boothman, Ph.D.
Associate Director for Translational Research, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
NQO1-mediated 'Kiss of death' Targeted Therapy For Pancreatic Cancer
"Pancreatic cancers have significant up-regulation of the two-electron oxidoreductase, NAD(P)H:quinone oxidoreductase 1 (NQO1), 20- to 100-fold elevated levels compared to normal tissue, and importantly, to normal pancreatic tissue. mRNA analyses also reveal a significant loss of Catalase expression in pancreatic and nonsmall cell lung cancers, while normal tissue express elevated levels.
"ß-Lapachone (current clinical agents known as Arq501 or Arq761) specifically kills cancer cells that have elevated levels of NQO1. Its well delineated mechanism of action involves NQO1-mediated futile redox cycling resulting in dramatic elevations of reactive oxygen species (ROS), superoxide and hydrogen peroxide in the cytoplasm. Long-lived hydrogen peroxide causes specific DNA base damage and DNA single strand breaks (SSBs). The overwhelming levels of SSBs created in cancer cells by just a two hour ‘kiss of death’ exposure of NQO1+ cancer cells with >90 Units of NQO1 to ß-lapachone results in the hyper-activation of poly(ADP-ribose) polymerase 1 (PARP1), a DNA repair protein, and tumor-specific programmed necrosis, marked by strong TUNEL+ staining. Elevated Catalase levels (Bey et al., submitted) and lack of significant NQO1 expression provide significant resistance to normal tissue throughout the body to ß-lapachone and other NQO1 bioactivatable drugs.
"The hypothesis to be tested in this grant is that alterations in base excision repair (BER), using selective BER component knockdown (e.g., XRCC1), PARP1 inhibitors, or the BER modifier, methoxyamine (MeOX), can be used to synergistically kill NQO1+ expressing pancreatic cancers. If correct, this strategy will confer tumor-specificity to DNA repair inhibitors, including PARP1 inhibitors developed (or being developed), since DNA damage to tumors is specifically generated in an NQO1-dependent manner. Furthermore, lowered Catalase levels in pancreatic cancers would augment SSB formation and induce cell death in pancreatic cancer tissue. In contrast, normal tissue (including the pancreas) will be ‘protected’ by the lack of NQO1 expression and Catalase-dependent detoxification of hydrogen peroxide. Intriguingly, blocking BER using MeOX for synergistic cell death with ß-lapachone will be fundamentally different than cell death caused by ß-lapachone and PARP1 inhibitor treatment. ß-Lapachone + MeOX will result in synergistic programmed necrosis, mediated by PARP1 hyperactivation. In contrast, PARP1 inhibitors will shift cell death caused by ß-lapachone to caspase-dependent apoptosis, driven by conversion of repairable SSBs into irrepairable DSBs that trigger Caspase-dependent cell death. Either approach will result in NQO1-dependent, tumor-selective cell death responses leading to effective therapies against NQO1 over-expressing pancreatic cancers. Since most solid tumors, namely pancreatic, nonsmall cell lung, breast (specifically triple-negative) and prostate cancers, have elevated levels of NQO1, such synergistic regimen using ß-lapachone should be applicable to various difficult-to-treat neoplastic diseases."
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported in part by the Lefkofsky Family
Paul Chiao, Ph.D.
Professor, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
TAK1 is a Novel Therapeutic Target in Pancreatic Cancer
"Despite advances in pancreatic cancer research, current therapeutics against pancreatic cancer remain largely ineffective. Discovery of novel drug targets against pancreatic cancer is the first step for improving patient survival. One of the most promising approaches that we are currently investigating is to target the downstream signaling pathways of the signature genetic alterations such as Kras mutation found in pancreatic cancer. We demonstrate that activation of TAK1 kinase is induced by mutant Kras, that genetic approach to silence the expression of TAK1 suppressed the tumorigenesis in multiple pancreatic cancer cell lines, and that TAK1 overexpression is associated with poor survival in pancreatic cancer patients. We hypothesize that TAK1 plays key roles in pancreatic cancer cell growth and is a novel therapeutic target for pancreatic cancer. In this funded proposal, we aim to establish genetically-engineered mouse models to further study the function of TAK1 in pancreatic tumorigenesis, and develop TAK1 inhibitor, a potential novel therapeutic agent, and test the activity of TAK1 inhibitor in mouse models for pancreatic cancer."
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported by Tempur-Pedic Retailers
Channing J. Der, Ph.D.
Professor of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, Chapel Hill, NC
TAK1 is a Novel Therapeutic Target in Pancreatic Cancer
"The near 100 percent incidence of KRAS oncogene mutations in pancreatic cancer, together with compelling evidence that ablation of mutant K-Ras protein function can greatly impair pancreatic cancer growth, has stimulated strong interest in developing K-Ras inhibitors for pancreatic cancer treatment. However, despite three decades of intense effort, to date no effective anti-K-Ras inhibitors have been developed. Perhaps the most attractive current approach for anti-K-Ras targeted therapy involves inhibitors of the most central K-Ras effector signaling pathway, the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. However, despite their promise for blocking K-Ras function, inhibitors of Raf or of MEK have also met with disappointing outcomes in the clinic. This is due to the ability of pancreatic cancers to adapt and compensate to overcome pathway blockade, often by upregulating other kinases. In this PanCAN-AACR Innovative Grant, our goal is to elucidate the mechanisms of resistance and to establish new directions to overcome this compensatory process. We will focus on the final step in this pathway, the ERK protein kinases. We believe that important keys to our studies are the novel experimental tools that we will develop to study the ERK MAPKs, as well as our utilization of cell culture models of pancreatic cancer that better reflect the tumor cell heterogeneity of pancreatic cancer in the patient. Our studies will define mechanisms of acquired ERK MAPK inhibition-induced resistance. With this information, we will then identify therapies inhibiting specific combinations of protein kinases that are capable of more effective impairment of K-Ras-dependent pancreatic cancer growth."
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Pancreatic Cancer Action Network-AACR Innovative Grant, in memory of Bonnie L. Tobin
Peter John Espenshade, Ph.D.
Associate Professor, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD
SREBP Pathway as a Target for Pancreatic Cancer Therapy
"Pancreatic cancer is one of the most lethal cancers with a five-year survival rate of less than 5 percent. While detection and early treatment are the best approach to reducing deaths due to pancreatic cancer, improved therapeutics that effectively manage tumor growth are an essential component of the anti-cancer armamentarium.
"Tumor growth requires that cancer cells adapt to a low nutrient environment since tumor expansion outpaces the blood supply. Adaptation to low oxygen supply (a condition known as hypoxia) is critical for tumor growth because production of essential cell building blocks, such as cholesterol and fat, requires oxygen. Using a model yeast system, our lab discovered that hypoxia activates the SREBP signaling pathway and that SREBP is required for hypoxic adaptation and growth. SREBP is the master regulator of cholesterol and fat production in cells.
"In this project, we propose that blocking the ability of tumor cells to adapt to hypoxia through the SREBP pathway will prevent the essential production of cholesterol and fat, thus blocking pancreatic tumor growth. We will test whether existing chemical and genetic inhibitors of the SREBP pathway prevent proliferation of pancreatic tumor cells and development of pancreatic cancer in mice. Collectively, these studies will validate the SREBP pathway as a new target for treatment of pancreatic cancer.
"To date, SREBP inhibitors have been tested for their properties in preventing atherosclerosis and heart disease, but this is the first use of SREBP inhibitors as anti-tumor agents. Our lab has partnered with experts in pancreatic cancer at Johns Hopkins to test this idea because our lab is new to cancer biology. Funding from PanCAN-AACR demonstrates their commitment to sponsoring innovative research in pursuit of a cure for pancreatic cancer."
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported by Blum-Kovler
Tyler Jacks, Ph.D.
Director, David H. Koch Institute for Innovative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
Mechanisms of K-RAS Independent Growth in Pancreatic Cancer
"Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States and remains a major unsolved problem worldwide. Despite advances in surgical techniques, radiation approaches and chemotherapy regimens, nearly all patients eventually die of their disease. While newer targeted therapies have vastly improved the care of patients with chronic leukemia, lung cancer, melanoma and breast cancer, the same improvements in drug response and survival with targeted therapies have not manifest in the treatment of pancreatic cancer. Several important genetic mutations involved in pancreatic tumor formation have been identified, including mutations in the K-ras gene, yet drugs that target K-RAS have not been effective to date. Further research to understand alternate mechanisms of growth and tumor formation in pancreatic cancer is needed to find new targets for therapy.
"Our laboratory has developed a K-ras mutation-based mouse model of pancreatic cancer that closely mimics the human disease. We have derived pancreatic cancer cell lines from these mice as a tool for discovering mechanisms of cell growth. Using RNA interference technology to knockdown K-RAS and abrogate its function, we have observed that cells in culture can persist and continue to grow, suggesting K-RAS independent means of pancreatic cancer cell growth. We plan to analyze these cells through various genetic and biochemical approaches to understand the important players in promoting growth in a K-RAS independent manner.
"Additionally, we propose to validate the results from our mouse cells in human pancreatic cancer cell lines derived from patient biopsies and surgical specimens. We will test drug inhibitors of pathways that mediate K-RAS independence in mouse models developed through the transplant of mouse and human pancreatic cancer cell lines directly into the pancreas of mice. Our mouse models provide a method for the preliminary testing of the safety and effectiveness of potential drug therapies prior to introduction into clinical trials for pancreatic cancer patients.
"We anticipate that our results will reveal new targets that may be amenable to drug therapy and provide advanced knowledge of mechanisms of resistance to K-RAS inhibitors when they become available."
Lisa A. Cannon-Albright, Ph.D.
Professor, University of Utah Health Science Center, Salt Lake City, UT
Informative Linkage Analysis of High-Risk Pancreatic Cancer Pedigrees
Nearly every person to be diagnosed with pancreatic cancer will eventually die from it, usually in less than four to six months. Not only does this highlight pancreatic cancer as a clinically significant disease, but it has also resulted in significantly limited resources for genome-wide linkage studies. About 10 percent of pancreatic cancer is recognized to have a familial component. Although pedigrees with multiple pancreatic cancer cases have been identified, they are typically small, and few DNA samples from cases are available. It is well recognized that the late age at onset and short survival have made it difficult or impossible to build resources of high-risk pancreatic cancer pedigrees. Since few collections of powerful high-risk pedigrees exist, informative linkage studies of high-risk pancreatic cancer pedigrees have not been performed.
Genome-wide association studies (GWAS) have been performed for pancreatic cancer. Such studies are expected to find common variants with low penetrance, but are not informative for rare variants. A rare variant(s) hypothesis may be one explanation for the relatively small amount of heritability that is explained by current GWAS findings in pancreatic cancer. An important aspect of this proposal is that an optimal search for genes affecting pancreatic cancer risk has not been completed. A genome-wide linkage scan could identify rare segregating variants.
“We will create the first powerful linkage resource for pancreatic cancer, making innovative use of existing resources in Utah. We will use a computerized genealogy of Utah, linked to cancer registration in Utah from 1966, to identify extended high-risk pancreatic cancer pedigrees. The difficulty will be in obtaining DNA samples for the cases in these extended pedigrees, most of whom are deceased. We will collect stored DNA samples from the two largest health care systems in Utah, together serving 80-90 percent of the state, which have collected and stored DNA and tissue samples for over six decades. We will identify and collect DNA samples from cases seen locally since 2000, and for all other cases we will extract DNA from normal tissue, stored as part of FFPE tissue blocks, from two statewide bio-repositories that together serve the entire state of Utah. The largest bio-repository has stored all tissue samples for over six decades, and serves 60-70 percent of Utah. We will identify and gather DNA samples in 15 informative extended high-risk pedigrees with at least six sampled cases each. We innovatively propose that sufficient genotyping data for a linkage analysis can be derived from these DNA samples, and that an informative linkage scan can thus be performed for the first time in multiple high-risk pancreatic cancer pedigrees.”
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James R. Eshleman, M.D., Ph.D.
Professor, Johns Hopkins University, School of Medicine, Baltimore, MD
Identifying Familial Pancreatic Cancer Predisposition Genes
Pancreatic cancer is generally a lethal cancer with a five-year survival of less than 5 percent. One bright spot is the discovery of several genes, in which defective copies are inherited and these are the direct cause of pancreatic cancer in these families. Since these genes are critical for one way that our cells repair DNA (so called double-strand break repair), and since the cancer cells have inactivated the second normal copy of the same gene, this creates a potential Achilles’ heel for the cancer. Parp inhibitor drugs inhibit a second type of DNA repair (single-strand break repair) and others have recently demonstrated that these drugs are synergistically toxic to cancer cells with double-strand break repair defects.
“We recently discovered another such gene by “brute force” sequencing all genes that a familial pancreatic cancer patient received at birth, in addition to all genes in their cancer. Based on the work of the human genome project, we were able to identify genes where this patient inherited one defective copy, and their cancer had mutated the second copy. In this way, we were able to identify the Partner and Localizer of BRCA2 (Palb2) gene.”
“Because of our longstanding interest in this problem, over the past eight years, the Eshleman lab has been producing familial pancreatic cancer cell lines. Using this panel of nine familial pancreatic cancer cell lines and the corresponding patient DNA, we will use the same approach to identify the predisposition gene defect in these cases. We will then confirm any candidate familial predisposition genes in a panel of 96 additional cases. This work only can be accomplished because of the Pancreatic Cancer Action Network-AACR Innovation Grant funding and an outstanding collaborative team, including Drs. Kinzler, Vogelstein, Velculescu, Klein, Goggins, Kern and Hruban.”
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