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Pancreatic Cancer Action Network-AACR Research Acceleration Network Grants

The goal of the Pancreatic Cancer Action Network-AACR Research Acceleration Network (RAN) Grant is to provide funding and strategic assistance to a research project with the potential to double survival for pancreatic cancer by the year 2020. This project must be implemented by a multi-institutional team and include a clinical component with an endpoint relevant to improving the detection or treatment of pancreatic cancer.

2015 Grantees

Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant, supported by Celgene

Principal Investigator: Steven D. Leach, MD 
Director, Rubenstein Center for Pancreatic Cancer Research
Memorial Sloan Kettering Cancer Center
New York, New York

Co-Principal Investigator: Douglas T. Fearon, MD
Walter B. Wriston Professor of Pancreatic Cancer Research  
Weill Cornell Medical College
New York, New York

Eliminating T cell barriers in pancreatic cancer patients

New cancer treatment strategies utilizing the body's own immune system to target cancer cells have revolutionized the care of patients with melanoma and other select tumor types. However, these approaches have not yet achieved success in pancreatic cancer patients. Our combined Memorial Sloan Kettering/Weill Cornell Medical Center Research Acceleration Network proposes to accelerate already initiated collaborative immunotherapy research being conducted by a network of investigators at these institutions. Our network is dedicated to bringing seminal preclinical immunotherapy discoveries to the clinic, in a manner that will directly benefit pancreatic cancer patients. Among these exciting discoveries, Dr. Fearon's group recently discovered that pancreatic tumors secrete a protein known as CXCL12. This protein effectively eliminates immune cells from the local tumor environment, thereby protecting cancer cells from immune attack. Dr. Fearon's group has further demonstrated that a drug blocking CXCL12 sensitizes mouse pancreatic cancers to immune attack, leading to rapid tumor destruction. Based on these seminal findings, our group has obtained funding to initiate a clinical trial investigating the safety and efficacy of this drug (AMD3100) in pancreatic cancer patients. Using the resources of MSKCC's new Rubenstein Center for Pancreatic Cancer Research, including a new facility for the high volume production of pancreatic cancer mice, Drs. Leach and Fearon have now partnered with Bristol Myers Squibb to initiate preclinical studies of longer-lasting antibodies targeting CXCL12 and its receptor, known as CXCR4. At the same time, our clinical co-investigators Eileen O'Reilly, Jedd Wolchok, Manish Shah, and Peter Allen are preparing to launch two additional clinical trials evaluating this antibody-based approach in patients with either localized or metastatic pancreatic cancer. As a critical foundation for these trials, Dr. Leach and co-investigator Tim Chan will chart the neoepitope landscape of pancreatic cancer by determining the quantity and quality of effective T-cell neoepitopes in a series of patients with resected pancreatic cancer. Our team’s collaborative efforts have already generated significant shared funding, allowing us to initiate the work contained in the current proposal. By allowing pancreatic cancer patients to benefit from recent advances in immunotherapy, we believe that the studies enabled by this RAN grant will directly contribute to the Pancreatic Cancer Action Network's goal of doubling pancreatic cancer patient survival by 2020.

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Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant

Principal Investigator: Channing J. Der, PhD 
Sarah Graham Kenan Distinguished Professor of Pharmacology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Co-Principal Investigator: Jason B. Fleming, MD
Professor and Chief, Pancreas Surgery  
MD Anderson Cancer Center
Houston, Texas

Co-Principal Investigator: Krister Wennerberg, PhD
FIMM-EMBL Group Leader 
Institute for Molecular Medicine Finland, University of Helsinki  
Finland

Defining novel combination KRAS-targeted therapeutic strategies

The frequent mutation of the KRAS gene in pancreatic cancer (95 perceny), together with compelling evidence that "correction" of this gene defect can significantly halt pancreatic cancer growth, has made the development of anti-KRAS drugs one of the top four priorities identified by the NCI 2013 Pancreatic Cancer Working Group. The frequent mutational activation of two key KRAS effectors (BRAF and PIK3CA), and their well-validated roles as cancer drivers, has led to extensive ongoing clinical trials evaluating a large roster of inhibitors of these pathways. However, significant hurdles remain. First, although substantial cell culture and mouse model analyses indicate that combinations that concurrently block both pathways can have significant synergistic antitumor activity, the same antitumor activity has not been seen in patients, and normal tissue toxicity is also an issue. Second, even if an effective anti-KRAS therapy can be developed, experience with other successful targeted therapies is that resistance arises quickly. This proposal hypothesizes that novel additional combinations will be needed to overcome these limitations. However, the best combinations often cannot be found by logical deduction, largely because the knowledge of the full complexities of signaling dynamics and cross-talk remains very much incomplete. Instead, the identification of unexpected but successful combinations has often been fortuitous. In this proposal state-of-the-art innovative unbiased functional screens will be applied to identify combinations that will effectively suppress the RAF-MEK-ERK and PI3K-AKT-mTOR effector pathways. Finally, the best available preclinical models will be applied for prediction of therapies that will be most effective in pancreatic cancer patients. It is anticipated that distinct effector signaling-targeted combinations for specific molecularly-defined subsets of KRAS-mutant pancreatic cancer will be identified, to provide the first critical step in developing superior treatment options by the year 2020.

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Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant

Principal Investigator:  Jonathan R. Brody, PhD 
Associate Professor and Director of Surgical Research
Thomas Jefferson University
Philadelphia, Pennsylvania

Co-Principal Investigator: Christopher Albanese, PhD
Professor of Oncology and Pathology   
Georgetown University Medical Center  
Washington, D.C.  

Co-Principal Investigator: Subha Madhavan, PhD
Director, Innovation Center for Biomedical Informatics
Georgetown University Medical Center 
Washington, D.C.  

Co-Principal Investigator: Emanuel F. Petricoin, III, PhD
Professor and Co-Director, Center for Applied Proteomics and Molecular Medicine   
George Mason University  
Fairfax, Virginia  

Co-Principal Investigator: Michael J. Pishvaian, MD, PhD
Assistant Professor in Hematology/Oncology  
Lombardi Comprehensive Cancer Center  
Washington, D.C.  

Developing an algorithm for Molecular Tailored Therapy

The development for targeted therapeutics can take over a decade and cost over a billion dollars to take an agent from the bench to the bedside. Accordingly, the success of the various cytotoxic chemotherapy regimens is often diluted, and any success of targeted therapy is lost altogether when agents are tested in a large, unselected patient population. The inability to translate the significant benefits seen in some patients to the pancreatic cancer population at large is due to the fact that promising therapies are never administered to select patients who are most likely to respond based on their tumors' molecular profile. This work's mission is to immediately enhance patient outcomes by incorporating candidate and novel predictive biomarkers into therapeutic decision making, providing a realistic platform for physicians to precisely select from a shelf of currently available therapies for their patients.

The expected outcome of the clinical trial is that molecular tailored therapy will improve patient outcomes, as compared to standard of care selection. Recently, the use of multi-omic (proteo-genomic) profiling has been shown to increase survival of patients with metastatic breast cancer, which demonstrates functional feasibility of our approach. A successful trial could lead to direct adoption of commercially available molecular testing for patients with metastatic pancreatic cancer, and/or concurrently provide the justification for a definitive phase III trial to confirm the results of this phase II trial. Thus, the complementary in silico work described in will leverage our findings from the clinical trial to interrogate and define a set of network models representing major relevant changes in pancreatic cancer cells that associate significantly with response and/or resistance to standard therapies. This work will culminate in a version 2.0 (v2.0) molecular algorithm for the next, larger clinical trial. Finally, additional work will take an unprecedented approach at defining novel chemoresistance mechanisms and identifying targets to overcome such resistance in pancreatic cancer cells. The datasets will be loaded to G-DOC (an established Georgetown based network) as a mechanism for visualization and exploration by collaborators followed by immediate public availability upon publication.

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2014 Grantees

Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant, in memory of Skip Viragh

Giulio Draetta, MD, PhDPrincipal Investigator: Giulio Draetta, MD, PhD 
Director, Institute for Applied Cancer Science
Professor, Molecular and Cellular Oncology
University of Texas MD Anderson Cancer Center
Houston, Texas
 
Lewis C. Cantley, PhDCo-Principal Investigator: Lewis C. Cantley, PhD
Director
Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College
New York, New York

 Developing a Novel Oxidative Phosphorylation Inhibitor in Pancreatic Cancer


Molecular characterization of pancreatic ductal adenocarcinoma (PDAC) has identified a handful of relatively common genetic lesions, the most significant of which is mutant KRAS (KRAS*) found in more than 90 percent of human tumors. While KRAS* has thus far proven an undruggable target, the medical community has invested heavily in finding inhibitors to quench the signaling cascade downstream of KRAS*. Despite this, clinical outcomes remain largely unchanged. Dr. Giulio Draetta and his laboratory at the MD Anderson Cancer Center (MDACC) used a genetically engineered mouse model of PDAC to develop a better understanding of the consequences of extinguishing KRAS* and why current therapies fail to eradicate disease. Despite visually complete regression of the tumor upon KRAS* extinction, they found that a subpopulation of cells survived and rapidly reformed tumors when KRAS* was re-expressed, thus emphasizing the need to identify molecular targets within the surviving cells to develop more powerful treatment strategies. To this end, they comprehensively characterized the oncogene extinction-resistant cells and identified a druggable metabolic pathway: these cells rely on oxidative phosphorylation (OXPHOS) for survival and cannot upregulate glycolysis in response to energetic stress. Based on these results, they hypothesize that combined treatment with inhibitors of RAS-mediated signaling and OXPHOS will eradicate PDAC tumors addicted to KRAS* and prevent tumor relapse. In this proposal, they will collaborate with Dr. Lew Cantley and his team of researchers at the Weill Cornell Medical College to further probe the mechanisms that drive sensitivity and adaptation/resistance to KRAS* extinction or signaling therapy in human tumors to characterize the mechanistic underpinnings of the OXPHOS dependency observed in oncogene extinction-resistant cells. They aim to rapidly progress the preclinical development of one or more signaling inhibitor treatments to use in combination with a novel inhibitor of OXPHOS developed at the MDACC Institute for Applied Cancer Science (IACS). These experiments will be conducted in parallel with early phase 1 studies of the IACS OXPHOS inhibitor compound. Together, these efforts are designed to accelerate clinical trials of combined targeted agents plus OXPHOS inhibitor treatment to rapidly determine the clinical relevance of a novel, potentially transformative approach to PDAC treatment.

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Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant, supported by the Fredman Family Foundation

Dung T. Le, MDPrincipal Investigator: Dung T. Le, MD  
Assistant Professor, Medical Oncology
Johns Hopkins University
Baltimore, Maryland
 

Co-Principal Investigator: Todd S. Crocenzi, MD
Director, Gastrointestinal Cancer Research
Providence Cancer Center, Earle A. Chiles Research Institute
Portland, Oregon

GVAX + CRS-207 Heterologous Prime Boost Vaccination with PD-1 Blockade

Barriers to effective immunotherapy strategies against pancreatic adenocarcinoma include a multitude of immune tolerance mechanisms both at the systemic level and in the tumor microenvironment. Unlike melanoma, there are very few tumor infiltrating lymphocytes at baseline in pancreatic tumors. Vaccines are necessary to prime and expand tumor specific T cells to infiltrate the tumor and agents designed to turn off the brakes on the T cells can then promote tumor regression. A heterologous prime boost strategy using GM-CSF-secreting tumor cells (GVAX vaccine) as a priming vaccine and Listeria monocytogenes expressing the tumor associated antigen mesothelin (CRS-207) as a boosting vaccine is a promising treatment strategy. Adding programmed death-1 (PD-1) antibody, which blocks negative signaling in T cells, to this vaccination strategy could significantly improve activity. The proposal aims to test this strategy in patients with previously treated metastatic cancer in the hopes to improve survival in this difficult to treat cancer. Correlative studies will be aimed at the assessment of immune responses and identification of therapeutic targets and biomarkers that may predict response and toxicity.

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2013 Grantees

Pancreatic Cancer Action Network-AACR Inaugural Research Acceleration Network Grant, in memory of Skip Viragh

Michael G. Goggins, MDPrincipal Investigator: Michael G. Goggins, MD
Professor of Pathology, Medicine, and Oncology
Johns Hopkins University
Baltimore, Maryland
 
Co-Principal Investigators: 
Marcia Irene Canto, MD
Professor of Medicine and Oncology
Johns Hopkins University
Baltimore, Maryland

Anil K. Rustgi, MDAnil K. Rustgi, MD
Chief, Division of Gastroenterology
University of Pennsylvania
Philadelphia, Pennsylvania
 
CAPS multicenter trial: Imaging and markers for pancreatic cancer screening

The Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant will provide much needed funding to enable our team to carry out a multicenter pancreatic screening trial. Since most patients with pancreatic cancer present with advanced disease, the best way to cure individuals who are likely to develop pancreatic cancer is to screen those at risk of developing pancreatic cancer while they are asymptomatic using the most accurate tests available. The goals of this trial are to evaluate clinical and research tests for their utility to identify precancerous and very early cancers in the pancreas that can be cured with appropriate therapy. We will screen individuals who have been identified as having a significantly increased risk of developing pancreatic cancer by virtue of having pancreatic cancer in multiple blood relatives. Generally, we will offer pancreatic screening to asymptomatic individuals who are over 55 whose family history indicates that their risk of pancreatic cancer may justify pancreatic screening. We will also offer screening to individuals who are carriers of mutations in pancreatic cancer susceptibility genes. The pancreatic screening tests we will perform include endoscopic evaluation of the pancreas with endoscopic ultrasound, pancreatic fluid collection and blood sampling to look for early signals of pancreatic cancer. We will compare our findings of screening individuals to patients who undergo pancreatic evaluation for other reasons, particularly those who have pancreatic cysts, but also those undergoing pancreatic evaluation for other reasons, such as suspected or known chronic pancreatitis.

There is a critical need to perform pancreatic screening trials to determine how effective pancreatic screening is, who can benefit most from screening, and which screening tests are most useful. This multicenter trial will enable pancreatic cancer screening to be offered at multiple centers throughout the US and allow us to enroll a large number of individuals who wish to undergo pancreatic screening. This multicenter screening trial would not be possible without the support of this PanCAN/AACR RAN grant.


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Pancreatic Cancer Action Network-AACR Inaugural Research Acceleration Network Grant, supported by Tempur-Pedic in memory of Tim Miller

Robert H. Vonderheide, MD, DPhilPrincipal Investigator: Robert H. Vonderheide, MD, DPhil
Associate Professor of Medicine
Associate Director for Translational Research
Abramson Cancer Center of University of Pennsylvania
Philadelphia, Pennsylvania

Dafna Bar-Sagi, PhDCo-Principal Investigator: Dafna Bar-Sagi, PhD
Vice dean for Science, Professor of Biochemistry and Molecular Pharmacology
New York University, Langone Medical Center
New York, New York

Accelerating Development of CD40 Therapy for Pancreatic Cancer

This project aims to develop novel immune therapies for pancreatic cancer that circumvent the highly immune suppressive nature of this tumor and its surrounding stroma. The focus of the investigational approach is based on the cell-surface molecule CD40, a key immunological activator. The hypothesis of the work is that therapeutic antibodies against CD40 can be used with standard-of-care for patients with pancreatic cancer to drive the immune system to destroy the tumor in robust and durable ways. This RAN proposal is designed to accelerate development of a clinical grade CD40 antibody for treatment of pancreatic cancer, and raise the prospect of using this antibody to improve survival by engaging our patient’s own immune systems. In parallel to clinical studies, we will also work in the laboratory to discover other CD40-based immune therapies, exploiting a number of clues and tools already in hand, and thereby pushing forward in a "bench to bedside" fashion. This Pancreatic Cancer Action Network-AACR Research Acceleration Network grant is an unprecedented and unique opportunity to achieve these goals.

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