Targeting Key Vulnerabilities in Pancreatic Cancer

Targeting Key Vulnerabilities in Pancreatic Cancer

Thursday, October 9, 2014

The New York Academy of Sciences

Presented By

 

Pancreatic ductal adenocarcinoma remains one of the most challenging problems in oncology, with a 5-year survival rate of just 6% and few effective therapeutic options. Genomic studies have identified only four high penetrance mutations responsible for the initiation and progression of pancreatic cancer. Unfortunately, none of these alterations can currently be targeted therapeutically. Nonetheless, core signaling programs are beginning to be identified for which therapeutic approaches may be developed. Some of these programs constitute “critical dependencies” of the tumor — biological pathways on which the tumor relies for continued growth and survival — and may serve as effective therapeutic targets. These programs include metabolic alterations that take place in pancreatic tumor cells, the behavior and biology of the tumor stroma, and interactions with the host immune system. This symposium will focus on recent breakthroughs in the pathogenesis and progression of pancreatic cancer, and efforts to exploit these key vulnerabilities as the basis for novel therapeutic interventions.

*Reception to follow.

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Mission Partner support for the Frontiers of Science program provided by   Pfizer

Agenda

* Presentation titles and times are subject to change.


October 9, 2014

8:00 AM

Registration and Continental Breakfast

8:30 AM

Welcome and Introductory Remarks
Brooke Grindlinger, PhD, The New York Academy of Sciences
Kenneth P. Olive, PhD, Columbia University Medical Center

8:45 AM

Morning Keynote Presentation

Ending the Beginning: Targeting PanIN Initiation and Progression
Steven D. Leach, MD, Memorial Sloan Kettering Cancer Center

9:30 AM

Modulation of the Pancreatic Tumor Microenvironment by SBRT and Cell Death
George Miller, MD, NYU Langone Medical Center

10:00 AM

Networking Coffee Break

10:30 AM

Translational Efforts Towards the Imaging and Treatment of Pancreatic Cancer
Kenneth P. Olive, PhD, Columbia University Medical Center

11:00 AM

Macrophages — Master Regulators of the Immune Reaction to Pancreatic Cancer
Gregory L. Beatty, MD, PhD, University of Pennsylvania Perelman School of Medicine

11:30 PM

Late-Breaking Abstract Presentation 1

Exploiting Glutamine Addiction in Pancreatic Cancer Costas A. Lyssiotis, PhD, Weill Cornell Medical College

11:45 AM

Late-Breaking Abstract Presentation 2

Control of Stress Granules by Oncogenic KRas Drives Tumor Drug Resistance in PDAC
Elda Grabocka, PhD, NYU Langone School of Medicine

12:00 PM

Networking Lunch and Poster Session

All Poster Presenters are requested to be present at their posters between 12:20 PM - 12:50 PM

1:00 PM

Imaging Pancreatic Cancer and its Microenvironment in Living Mice
Mikala Egeblad, PhD, Cold Spring Harbor Laboratory

1:45 PM

T-cell Exclusion in Pancreatic Ductal Adenocarcinoma: The Cancer-associated Fibroblast Expressing Fibroblast Activation Protein and CXCL12
Douglas T. Fearon, MD, Cold Spring Harbor Laboratory, Weill Cornell Medical College, and University of Cambridge

2:15 PM

Networking Coffee Break

2:45 PM

Afternoon Keynote Presentation

Hypoxia and Precision Medicine in Pancreatic Adenocarcinoma (PDAC): Defining the Target before Targeting the Therapy
Neesha C. Dhani, MD, FRCPC, Princess Margaret Cancer Center; The University of Toronto, Toronto, Ontario, Canada

3:30 PM

Late-Breaking Abstract Presentation 3

Enzymatic Remodeling of the Pancreatic Ductal Adenocarcinoma Tumor Microenvironment to Improve Chemotherapeutic Efficacy
Curtis B. Thompson, PhD, Halozyme Therapeutics

3:45 PM

Closing Remarks
Kenneth P. Olive, PhD, Columbia University Medical Center

4:00 PM

Networking Reception

5:00 PM

Adjourn

Speakers

Organizers

Kenneth P. Olive, PhD

Columbia University Medical Center

Dr. Kenneth P. Olive began his doctoral studies in 1998 with Tyler Jacks at the MIT Center for Cancer Research, investigating the neomorphic effects of mutant p53 in a mouse model of Li-Fraumeni Syndrome. While at MIT, he also helped develop a conditional mutant model of advanced lung adenocarcinoma. After graduating in 2005, Dr. Olive began a postdoctoral fellowship in the laboratory of David Tuveson at the University of Pennsylvania, later moving with the lab to the University of Cambridge in England. There he built a translational research facility for studying novel anticancer therapeutics in genetically engineered mouse models of pancreatic cancer. His studies into chemoresistance and the effects of Hh pathway inhibitors on drug delivery in pancreatic cancer were published in Science in 2009, and have led to multiple clinical trials to evaluate the approach in patients with metastatic pancreatic cancer. In 2010, Dr. Olive joined the faculty of the Columbia University Herbert Irving Comprehensive Cancer Center, where he has established a laboratory dedicated to translational science and experimental therapeutics in pancreatic ductal adenocarcinoma.

George B. Zavoico, PhD

MLV & Co.

Jennifer S. Henry, PhD

The New York Academy of Sciences

Keynote Speakers

Neesha Dhani, MD, FRCPC

Princess Margaret Hospital, Toronto

Dr. Neesha Dhani completed her undergraduate medical training at the University of Western Ontario, subsequently pursuing internal medicine and medical oncology subspecialty training at the University of Toronto. She then pursued a translational research fellowship at the Princess Margaret Cancer Center, combining training in clinical research through the Drug Development Program with basic and translational research towards a PhD focusing on hypoxia related invasion and metastasis in pancreatic cancer. She is now a staff medical oncologist at the Princess Margaret Cancer Center in Toronto Ontario with a clinical focus in the management of patients with GI (pancreatic, biliary, HCC) and gynecologic cancers. Her on-going research includes developing and evaluating novel techniques of functional imaging for characterization of the tumoral microenvironment with a goal of improving drug development in this area.

Steven D. Leach, MD

Memorial Sloan Kettering Cancer Center

Steven D. Leach is the inaugural Director the David Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center (MSKCC).  He is also a member of the Human Oncology and Pathogenesis Program (HOPP).  Prior to this he served as the Paul K. Neumann Professor in Pancreatic Cancer at Johns Hopkins, where he was also Professor of Surgery, Oncology and Cell Biology.  Dr. Leach received his bachelor’s degree with high honors in Biology from Princeton University, where he currently serves as a member of the Board of Trustees.  This was followed by medical school at Emory University, where he was a Robert W. Woodruff Scholar. Dr. Leach then pursued residency training in General Surgery at Yale University, where he also completed a two-year research fellowship studying acinar cell biology in the laboratory of Fred Gorelick.  Following an additional fellowship in Surgical Oncology at M.D. Anderson, he joined the faculty at Vanderbilt University, first as an Assistant Professor and then as Associate Professor of Surgery and Cell Biology.   In 2000, he moved to Johns Hopkins to become the first Paul K. Neumann Professor, and moved to MSKCC in 2014.    Dr. Leach’s lab has a long track record of research productivity in the field of pancreatic cancer biology.  His lab is credited with discovery of abnormal Notch pathway activation as an important driver of pancreatic tumorigenesis, development of the first zebrafish model of pancreatic cancer, identification of adult acinar cells as effective cells of origin for the initiation of pancreatic “ductal” neoplasia, and the recent identification of a hematopoietic-to-epithelial IL-17 signaling axis required for PanIN initiation. Together with his group’s additional studies of pancreatic developmental biology and pancreatic epithelial plasticity, Dr. Leach’s work has contributed significantly to our understanding of early pancreatic cancer.

Speakers

Gregory Beatty, MD, PhD

University of Pennsylvania Perelman School of Medicine

Gregory Beatty, MD, PhD is an Assistant Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and in the Division of Hematology/Oncology within the Abramson Cancer Center at the Hospital of the University of Pennsylvania. Dr. Beatty graduated from Bucknell University and received his PhD in Immunology followed by an MD from the University of Pennsylvania Perelman School of Medicine. He went on to complete a residency in Internal Medicine and a fellowship in Medical Oncology at the Hospital of the University of Pennsylvania. Dr. Beatty's research interest is in understanding the role of macrophages in regulating innate and adaptive immunosurveillance in cancer. He has developed a research platform within his laboratory that uses genetically engineered mouse models of cancer to study leukocyte biology within the tumor microenvironment and to screen novel immunotherapeutic strategies, including cell and gene therapies, for the treatment of cancer. In addition, he is currently leading the clinical investigation of T cell adoptive therapies and other immunotherapeutic approaches for pancreatic cancer.

Mikala Egeblad, PhD

Cold Spring Harbor Laboratory

Mikala Egeblad obtained degrees in Medicine (B.S., 1993), Human Biology (M.Sc., 1996), and Cancer Biology (Ph.D., 2000) from the University of Copenhagen, Denmark. In 2001, Mikala Egeblad joined Dr. Zena Werb’s lab at University of California, San Francisco as a postdoctoral fellow. There, she began employing mouse models to understand how the microenvironment influences tumor progression, focusing on innate immune cell responses and protease-mediated extracellular matrix remodeling. With Zena Werb and postdoctoral fellow Dr. Andrew Ewald, she also developed methods for using spinning disk confocal microscopy to image tumor-stroma interactions in breast cancer. In 2009, she came to Cold Spring Harbor Laboratory as an Assistant Professor and in 2014; she was promoted to Associate Professor. For her research in breast cancer, she was in 2014 awarded the Era of Hope Scholar Award from the Department of Defense, Congressionally Directed Medical Research Programs.

Douglas T. Fearon, MD

Weill Cornell Medical College and Cold Spring Harbor Laboratory

Douglas Fearon received his MD from Johns Hopkins Medical School and completed his internal medicine training on the Osler Medical Service of the Johns Hopkins Hospital.  After serving as a physician in the Army, he was a post-doctoral fellow in rheumatology at Harvard Medical School.  He continued at that institution and was appointed Professor of Medicine in 1984.  He moved back to Johns Hopkins in 1987 as Professor of Medicine and as Director of the Division of Molecular Rheumatology, and of the Graduate Program in Immunology.  In 1993, he moved to the University of Cambridge as a Wellcome Trust Principal Research Fellow.  He was elected a Fellow of Trinity College in 2001, and as the Sheila Joan Smith Professor of Immunology in 2003.  He recently returned to the United States as the Walter B. Wriston Professor of Pancreatic Cancer Research at Weill Cornell Medical College, and as a Professor at Cold Spring Harbor Laboratory.  He is a Fellow of the Royal Society, a member of the National Academy of Sciences, a Fellow of the American Academy of Arts and Sciences, and a Fellow of the Academy of Medical Sciences.  His recent research has focused on cancer immunology.

Elda Grabocka, PhD

Department of Biochemistry and Molecular Pharmacology, NYU Langone School of Medicine, New York, NY

Dr. Grabocka completed her undergraduate studies in Biology at Washington College.  She received her PhD degree in Molecular Pharmacology and Structural Biology at Thomas Jefferson University and is currently a postdoctoral fellow in the laboratory of Dafna Bar-Sagi, PhD at NYU Langone Medical Center. Dr. Grabocka’s research is centered on elucidating dependencies of oncogenic KRAS cancers on tumorigenic stress adaptation mechanisms, and their integration in therapeutic intervention modalities.

Costas A. Lyssiotis, PhD

Weill Cornell Medical College

Dr. Costas A. Lyssiotis obtained his bachelor’s degree in chemistry and biochemistry from the University of Michigan and his PhD in chemical biology at The Scripps Research Institute in La Jolla, CA. In 2010, he joined the laboratory of Prof. Lewis C. Cantley at Harvard Medical School as the Amgen fellow of the Damon Runyon Cancer Research Foundation. He is currently a Pancreatic Cancer Action Network Pathway to Leadership Postdoctoral Fellow in Prof. Cantley’s laboratory, now at Weill Cornell Medical College. His research is focused on understanding the biochemical pathways and metabolic requirements that enable pancreatic tumor growth and, in particular, how this information can be used to design targeted therapies to treat this dreadful disease. Among his many contributions, he demonstrated that pancreatic cancers are addicted to glucose and glutamine and use these nutrients in previously undescribed pathways to make DNA and to generate free radical-combating antioxidants, respectively. For this work, he was recently awarded a Dale F. Frey Award for Breakthrough Scientists.

George Miller, MD

NYU Langone Medical Center

Dr. Miller is Associate Professor at NYU School of Medicine with appointments in the Departments of Surgery and Cell Biology where he has been on faculty for 7 years. He is Vice-Chairman for Research in the Surgery Department and co-leader of the Multidisciplinary Gastrointestinal Cancer Program. Dr. Miller’s lab is studying inflammation and the inflammation-cancer paradigm within the liver and pancreas. They are interested in numerous aspects of the biology of the pancreatic tumor microenvironment and its influence on epithelial mutagenesis. Their recent investigations have examined the role of novel pattern recognition receptors, intra-tumoral dendritic cells, and novel T cell subpopulations. They have also examined the role of chemokines and signaling molecules in mediating epithelial-stromal crosstalk. Their research in liver inflammation has focused on the role of antigen-presenting cells and novel innate cellular subsets and signaling receptors in mediating acute liver injury and chronic liver inflammation leading to fibrosis and carcinoma. Dr. Miller is a summa cum laude graduate of Columbia College and obtained his MD from McGill University Faculty of Medicine. He completed his clinical and research training at NYU and Memorial Sloan Kettering Cancer Center. His lab is supported by grants from the National Cancer Institute, the National Institute of Diabetes and Digestive Diseases, the US Department of Defense, and numerous foundations.

Kenneth P. Olive, PhD

Columbia University Medical Center

Dr. Kenneth P. Olive began his doctoral studies in 1998 with Tyler Jacks at the MIT Center for Cancer Research, investigating the neomorphic effects of mutant p53 in a mouse model of Li-Fraumeni Syndrome. While at MIT, he also helped develop a conditional mutant model of advanced lung adenocarcinoma. After graduating in 2005, Dr. Olive began a postdoctoral fellowship in the laboratory of David Tuveson at the University of Pennsylvania, later moving with the lab to the University of Cambridge in England. There he built a translational research facility for studying novel anticancer therapeutics in genetically engineered mouse models of pancreatic cancer. His studies into chemoresistance and the effects of Hh pathway inhibitors on drug delivery in pancreatic cancer were published in Science in 2009, and have led to multiple clinical trials to evaluate the approach in patients with metastatic pancreatic cancer. In 2010, Dr. Olive joined the faculty of the Columbia University Herbert Irving Comprehensive Cancer Center, where he has established a laboratory dedicated to translational science and experimental therapeutics in pancreatic ductal adenocarcinoma.

Curtis B. Thompson, PhD

Halozyme Therapeutics, Inc., San Diego, CA

Dr. Thompson has over 15 years of preclinical experience in the pharmaceutical industry across a broad range of research disciplines, including: hypertension and vascular biology, antisense technology (ssDNA, RNAi), inflammation, osteoporosis and osteoarthritis, asthma and cancer. Curt currently is Senior Director of Pharmacology at Halozyme Therapeutics, Inc, in San Diego, California. His group is responsible for the final design of internal / external experiments in pharmacology supporting the development of new biologics.

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

Grant Support

Supported by a grant from Genentech.

Exhibitor

HistoWiz, Inc.

Promotional Partner

American Society for Therapeutic Radiology and Oncology (ASTRO)

The Lustgarten Foundation

Nature


Mission Partner support for the Frontiers of Science program provided by   Pfizer

Abstracts

Keynote Presentation
Steven D. Leach, MD, Memorial Sloan Kettering Cancer Center

Pancreatic intra-epithelial neoplasia (PanIN) represents a common precursor lesion for invasive pancreatic cancer. Beyond the ability of oncogenic Kras to initiate PanIN formation, little is known regarding fundamental mechanisms of PanIN origin and progression. Our group has utilized different tamoxifen-inducible, pancreatic cell type-specific Cre driver lines to simultaneously activate oncogenic Kras and an mTmG lineage label in different adult pancreatic cell types.  These studies have led to new insights regarding the ability of different cell types to serve as PanIN “cells-of-origin”, and also allowed identification of PanIN cell subpopulations with unique functional capacities.  In addition, this approach has allowed us to identify critical interactions between epithelial and non-epithelial cell types during the earliest stages of PanIN initiation.  Using whole genome transcriptional profiling of FACS-sorted PanIN epithelial cells, we observed significant upregulation in IL-17RA, a receptor for the pro-inflammatory cytokine IL-17.  At the same time, FACS analysis of immune cells infiltrating early PanIN lesions demonstrated expanded populations of IL-17 producing TH17 and gdT-cells. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using either genetic or pharmacologic techniques effectively prevents PanIN formation. These studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation, and that therapeutic targeting of IL-17 signaling may represent a potentially effective strategy for the chemoprevention and/or treatment of early pancreatic cancer.
 

Hypoxia & Precision Medicine in Pancreatic Adenocarcinoma (PDAC): Defining the Target before Targeting the Therapy
Neesha C. Dhani1

The relevance of hypoxia in promoting aggressive tumour biology is well accepted but variable across cancer types. Although PDAC has been historically considered hypoxic, direct evidence is limited. Up-regulation of indirect markers of hypoxia suggests an importance of hypoxia-related pathways, however may also reflect oxygen independent, oncogenic signaling.
 
We have developed a translational program to explore the clinical relevance of hypoxia across the spectrum of PDAC. Histology-based analyses and functional imaging using nitroimidazole markers identify tissue at p02 < 10mmHg, allowing for evaluation of severe hypoxia and its biological consequences. Patient-derived xenograft (PDX) models are used to explore the efficacy of hypoxia-directed therapeutic strategies.
 
Resected tumours from patients receiving pre-operative pimonidazole demonstrated a range of hypoxia (hypoxic percentage (HP): 0 to 26%) in both stromal and epithelial compartments. There was significant heterogeneity within and across tumours and a small number (3 of 10 tumours) demonstrated minimal to no measureable pimonidazole. Similar trends were noted with [18F] FAZA-PET imaging of patients with advanced disease, with 5 of 20 patients demonstrating no significant hypoxia. These clinical observations are consistent with those made in PDX models where 6 of 16 demonstrated minimal hypoxia by EF5. The more hypoxic PDX models also had faster growth rates with a predilection for distant metastases. Further, these models demonstrated greater sensitivity to hypoxia targeting therapy with TH-302. This data suggests that nitroimidazole hypoxia markers are able to differentiate amongst PDAC with different levels of hypoxia. This has implications for the further development of hypoxia-targeting therapies in PDAC.
 
Coauthors: Cristiane Metran-Nascente1, Stefano Serra2, Ines Lohes1, Melania Pintilie3, Ivan Yeung4, Ines Lohes1, Trevor McKee4, Michael Milosevic4, Steven Gallinger5, Ming-Sound Tsao2, Richard Hill4, David Hedley1
1. Division of Medical Oncology & Hematology
2. Department of Laboratory Medicine & Pathobiology
3. Department of Biostatistics
4. Radiation Medicine Program
5. Division of Hepato-biliary Pancreatic Surgical Oncology, University Health Network and Mount Sinai Hospital

University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Ave, Toronto ON M5G 2M9
 

Macrophages — Master Regulators of the Immune Reaction to Pancreatic Cancer
Gregory L. Beatty, MD PhD, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

Macrophages accumulate at the earliest stages of neoplasia in pancreatic ductal adenocarcinoma (PDAC). Because of their potential to promote tumor growth, invasion and metastasis, strategies that block macrophage pro-tumor activity or re-direct macrophages with anti-tumor properties may hold promise as a therapeutic approach in cancer. We have previously demonstrated the capacity of a CD40 agonist to induce major tumor regressions in both mice and humans with PDAC. This anti-tumor activity is dependent on macrophages which reside outside of the tumor microenvironment and never infiltrate tumor lesions. We hypothesized that these extratumoral macrophages may coordinate anti-tumor activity mediated by CD40 agonists by regulating the trafficking of leukocytes into tumor lesions. Consistent with this hypothesis, we have found that extratumoral macrophages direct the infiltration of anti-tumor inflammatory monocytes into tumor tissue while inhibiting the infiltration of T cells with anti-tumor properties. Our findings demonstrate a key role for extratumoral macrophages in orchestrating immune biology within the tumor microenvironment of PDAC and suggest that tumor immunogenicity can be regulated, at least in part, by macrophages residing outside of the tumor microenvironment.
 

Imaging Pancreatic Cancer and its Microenvironment in Living Mice
Mikala Egeblad, PhD, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

A characteristic feature of pancreatic cancer is its stroma, consisting of fibroblasts, immune cells and extracellular matrix (ECM), including fibrillar type I collagen. To determine how type I collagen influences cancer cell behavior, we developed approaches to perform confocal microscopy in live mice. We used mice that expressed GFPtopaz fused to the α2 chain of type I collagen, expressed under control of the COL1A1 promoter [α2(I)-col-GFP mice]. Live imaging of pancreatic tumors (formed after orthotopic injection of cells from the KPC mouse model) in α2(I)-col-GFP mice showed that cancer cells invaded on linear type I collagen.
 
Cross-linking and linearization of type I collagen by lysyl oxidases (LOXs) is inversely correlated with metastasis-free survival in breast cancer. We examined whether inhibiting the LOXs could limit pancreatic cancer progression. LOX and LOX-like 2 (LOXL2) were expressed at higher levels in tumors than in normal pancreatic tissue. However, inhibition of LOX activity, using a small molecule inhibitor (β-aminoproprionitirile [BAPN]) or RNA interference against either LOX or LOXL2, significantly increased tumor size and metastasis. Using live imaging, we found that LOX inhibition increased the thickness of the collagen fibers in the tumors. LOX inhibition also altered the activities of signaling molecules downstream of integrins, with more cancer cells staining positive for active focal adhesion kinase.
 
In conclusion, our data strongly suggest that targeting collagen cross-linking enzymes would be a poor strategy for the treatment of pancreatic cancer.
 
Coauthors: Mario Shields1, Pascal Maguin1, Priyanka Kumar1, Sarah L. Dallas2
1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
2. University of Missouri, Kansas City, Missouri

 

Control of Stress Granules by Oncogenic KRas Drives Tumor Drug Resistance in PDAC
Elda Grabocka, PhD1

Oncogenic mutations in KRAS are prevalent in PDAC and critical for tumor initiation and maintenance. It is widely accepted that oncogenic KRas leads to the acquisition of stress-resistant properties. Consequently, stress-coping mechanisms represent a vulnerability of KRAS-driven tumors and may function as therapeutically beneficial targets. A major hurdle for the successful implementation of such therapies is the substantial sub-clonal heterogeneity and heterotypic interactions within tumors. Tumorigenic fitness and resistance to endogenous and exogenous stresses require cooperation between cancer cell sub-clones and cancer cells and the surrounding stromal cells. We have found that oncogenic KRas drives the response to a variety of stresses by upregulating stress granules (SGs), which are intracellular granules composed of protein and RNA that have emerged as critical components of the cellular stress response. Using a variety of preclinical mouse models, we have established that KRas-mutant PDAC cells display robust SG formation in vivo. Furthermore, we have found that KRas-induced SGs confer cytoprotection against different stressors and chemotherapeutic agents. Importantly, we have discovered that oncogenic KRas promotes SG formation in a paracrine manner, thus conferring stress resistance to multiple cell types within the tumor. The paracrine regulation of SGs occurs through Ras-dependent secretion of PGJ2, a critical parameter for SG assembly. Consistent with this finding, disruption of the Ras-mediated PGJ2 secretory loop impairs SG formation and confers sensitivity to chemotherapeutic agents. These results suggest that KRas regulates SG formation as a means of hijacking the stress response within PDAC tumors and point to the possibility of exploiting this dependence for therapeutic benefit.
 
Coauthors: Yuliya Pylayeva-Gupta, PhD1, Cosimo Commisso, PhD1, Dafna Bar-Sagi, PhD1
1. Department of Biochemistry and Molecular Pharmacology, NYU Langone School of Medicine, New York, NY
 

Exploiting Glutamine Addiction in Pancreatic Cancer
Costas A Lyssiotis, PhD, Cancer Center, Weill Cornell Medical College, New York, New York

Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts. Among these addictions is an increased utilization of glutamine (Gln). We identified a non-canonical pathway of Gln utilization in human pancreatic cancer that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to fuel the TCA cycle, pancreatic cancer relies on a distinct pathway such that Gln-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate (OAA) by aspartate transaminase (GOT1). Subsequently, this OAA is converted into malate and then pyruvate, increasing the NADPH/NADP+ ratio and thereby maintaining the cellular redox state. Pancreatic cancer cells are dependent on this series of reactions, as Gln deprivation or genetic inhibition of any enzyme in this pathway leads to a redox imbalance and a pronounced suppression of growth. Furthermore, the reprogramming of Gln metabolism is mediated by mutant Kras, the signature genetic alteration in pancreatic cancer, via the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in pancreatic cancer and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumors.
 

Modulation of the Pancreatic Tumor Microenvironment by SBRT and Cell Death
George Miller, MD, New York University School of Medicine, New York, New York, United States

Pancreatic ductal carcinoma is the 4th most common cause of cancer death in the United States and is lethal in more than 95% of caes. Unlike most adenocarcinomas, pancreatic cancer is composed mainly of stromal and desmoplastic elements interspersed with islands of neoplastic epithelium. Recent evidence suggests that far from being a passive observer, pancreatic tumor stroma has impact both on cancer progression and clinical outcome. In particular, by releasing nutrient growth factors into the tumor microenvironment, such as insulin-like growth factor and platelet-derived growth factor (PDGF), the stromal component of pancreatic cancer has been closely linked to both tumor growth and invasiveness. In addition, chemotherapy resistance has been correlated with the extent of tumor desmoplasia as the stroma is thought to be a physical barrier to cytotoxic agents reaching the neoplastic epithelial cells. Hence the delineation of the regulatory circuitry responsible for the activation of pancreatic cancer stroma has the potential to greatly expand our capabilities for therapeutic intervention.  Various elements of the tumor microenvironment induce immune suppression enabling tumor progression. For example, myeloid derived suppressor cells veto cytotoxic CD8 T cells tumoricidal activity. Conversely, Th2-deviated T cells can generate tumor-promoting inflammation. Similarly, selected subsets of tumor associated macrophages promote tumor growth by facilitating immune suppression. In the current work we investigate the collateral effects of tumor-directed radiation on changes to the inflammatory microenvironment in pancreatic cancer. We also focus on the effect of radiation-induced cell death on the surround inflammatory milieu and tumor progression.
 
Coauthors: Lena Tomkötter, Susanna Nguy, Elliot Levie, Rocky Barilla, Andrew Eisenthal, Matthew Pergamo, Nina Avanzi, Atsuo Ochi, Donnele Daley, Alejandro Torres-Hernandez, Mauricio Rendon, Sara Alothman, Dalia Qunaibit, Daniel Tippens, Mridul Pansari, Atif Salyana, Kevin Du
New York University School of Medicine, New York, New York, United States
 

Targeting the Inflammatory Aspect of Pancreatic Cancer through PI3Kδ Inhibition
Michael O. Ports1

Inflammation in pancreatic ductal adenocarcinoma (PDA) is apparent at the earliest stages of neoplastic development and contributes to a microenvironment that is conducive for disease progression.  PDA-mediated inflammation extends its reach systemically, contributing to the emergence of paraneoplastic syndromes like cachexia that increase morbidity, while decreasing opportunity for aggressive therapeutic intervention.  Zydelig® (idelalisib), a potent and selective PI3Kδ inhibitor, was recently approved for treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic leukemia.  The PI3Kδ isoform, generally expressed by leukocytes, is an attractive target for hematologic malignancies or inflammatory disorders with pathologic activation of the PI3K pathway; however, little is known regarding the utility of targeting PI3Kδ for the treatment of solid tumors.  To this end, we evaluated a potent and selective PI3Kδ inhibitor (GS-9820), with similar properties to Zydelig, on primary PDA patient immune cells and KrasLSL-G12D/+; Trp53LSL‑R172H/+; Pdx-Cre (KPC) mice with advanced disease.  Peripheral myeloid cells from patients and KPC mice displayed enhanced PI3Kδ signaling relative to myeloid cells isolated from healthy donors or control mice.  PI3K signaling in myeloid cells was inhibited by GS-9820, resulting in decreased inflammatory cytokine expression.  GS-9820 treatment of KPC mice with detectable tumor, improved median survival to 30.5 days relative to gemcitabine (17 days) and vehicle controls (13.5 days) (p<0.001).  PI3Kδ inhibitor decreased tumor burden by more than 50% (p<0.05), and decreased fibrillar collagen organization. In depth histologic evaluation of KPC tumors revealed no effect on CD11b, CD8 and T-regulatory numbers in the primary tumor.  Systemically, PI3Kδ inhibition altered inflammatory gene expression in PDA-associated myeloid cells.  Additionally, a systemic response to treatment was observed through increased KPC mice quadriceps weight and a normalization of increased glycolysis and oxidative damage metabolites in skeletal muscle predicted to be associated with cachexia.  Our results provide proof-of-concept for PI3Kδ inhibition as a target for pancreatic cancer, normalizing deregulated systemic inflammatory and metabolic pathologies associated with the etiology of PDA.
 
Coauthors: Maryam Jangani2a, Essam Ghazaly2b, Juliana Candido2a, Jun Wang2c, Ai Nagano2c, Andrew Campbell3, Terry Gentzler1, Adam Kashishian1, Owen Sansom3, Nicholas R Lemoine2c, Christophe Quéva1, Thorsten Hagemann2a
1. Gilead Sciences, Seattle, WA 98102, USA
2. Centre for Cancer and Inflammationa, Centre for Hemato-Oncologyb, Centre for Molecular Oncologyc, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, United Kingdom
3. Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, Scotland

 

Enzymatic Remodeling of the Pancreatic Ductal Adenocarcinoma Tumor Microenvironment to Improve Chemotherapeutic Efficacy
Curtis B. Thompson, PhD1

Pancreatic ductal adenocarcinoma (PDA) is characterized by a tumor microenvironment (TME) with high stromal desmoplasia, a reduction in vessel density, and poor perfusion, all instrumental in PDAs observed resistance to chemotherapeutic intervention. Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been shown to accumulate to high levels in approximately 90% of PDA tumors, and is thought to be a key component of this desmoplastic response. In preclinical mouse models, including tumor xenografts, patient-derived tumor xenografts, and genetically engineered mouse models of pancreatic cancer (KPC), depletion of HA from the TME with a pegylated recombinant human hyaluronidase PH20 (PEGPH20) is associated with remodeling of the tumor stroma, reduction of tumor interstitial fluid pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy. Tumor remodeling following HA depletion appears to be sustained. Studies in the KPC model have shown that increased tumor perfusion following PEGPH20 treatment in combination with gemcitabine persists for weeks after therapy cessation. In other mouse models, PEGPH20-mediated HA removal also induces a partial reversal of the classical epithelial-mesenchymal transition process associated with the progression of malignancy. In view of these findings, a Phase 1b/2 clinical trial to evaluate PEGPH20 in combination with gemcitabine in patients with stage IV metastatic pancreatic cancer was conducted. PEGPH20 plus gemcitabine was well tolerated and showed promising efficacy in patients with high tumor HA, leading to the current clinical phase 2 study of PEGPH20 in combination with nab-paclitaxel and gemcitabine for the treatment of stage IV PDA.
 
Coauthors: H. Michael Shepard, PhD1 and Daniel C. Maneval, PhD1
1. Halozyme Therapeutics, Inc., San Diego, CA
 

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