Research

SPORE in Pancreatic Cancer

Overview

Dr. Adetunji Toriola, Assistant Professor of Surgery and recipient of the Pancreas SPORE’s 2018 Developmental Research Program (DRP) in Disparities Research, has been selected to present his work at the 2019 meeting of the American Association for Cancer Research (AACR) 12th Annual Conference on the Science of Cancer Health Disparities in San Francisco, California September 20-23.  Dr. Toriola was awarded a DRP for his project “Metformin Use and Pancreatic Cancer Survival in African Americans.” The AACR is the oldest and largest scientific organization in the world focused on cancer research.


SPORE in Pancreatic Cancer Request for Applicants Pancreas SPORE Director: William Hawkins, MD, FACS The Specialized Programs of Research Excellence (SPORE) are the cornerstone of the National Cancer Institute’s effort to promote collaborative, interdisciplinary translational cancer research. Each SPORE is focused on a specific organ site and is designed to enable the rapid and efficient movement of basic scientific findings into clinical settings as well as to determine the biological basis for observations made in individuals with cancer.

5 Year Cancer Death Chart
Pancreas cancer is the most deadly of the top five causes of cancer death.

The Washington University SPORE in Pancreas Cancer is one of only four SPOREs in the nation. Pancreatic cancer is the 4th leading cause of cancer death in the United States. Washington University’s Pancreas SPORE is designed to address the deadliest form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), by collaborating with multiple departments, programs and other institutions in interdisciplinary translational research. The Pancreas SPORE investigators have expertise in basic and clinical sciences, and individual expertise in immunology, drug development, genomics and imaging to develop novel therapeutic approaches to PDAC. The Pancreas SPORE includes four research programs, an administrative core and two shared-resource cores, and research opportunities for collaboration including developmental research and career enhancement programs. Clinical trials are an important and active part of the Pancreas SPORE. The long-term goal of the Pancreas SPORE is to improve PDAC patient survival. To achieve this goal, our SPORE will collaborate both within Washington University and with external institutions. Our investigators expect no singular approach to solve PDAC and fully commit to supporting young investigators and evaluating new ideas. Our SPORE will provide access to pancreas cancer-specific resources to further this goal.

Projects

Project 1: Molecular determinants of decitabine responsiveness

David Linehan, MD, and David DeNardo, PhD

Pdac Image 3 Website
Depiction of the fibrosis present in the KPC mouse models of PDAC

Project 1 of the Pancreas SPORE will examine immune system responses and/or natural killer cells, which have been previously shown to restrain tumor development and progression. Unfortunately, immunotherapy attempts to date have struggled to achieve significant clinical benefits in pancreatic ductal adenocarcinoma (PDAC). Our investigators have previously found that blocking specific cell regulation results in slower tumor growth and improves responses to chemotherapy. Mouse models with PDAC have also shown the prevention of metastasized tumors. The end goal of our project will be to determine the effects, mechanism and possible future drug combinations to help enhance therapeutic outcomes in patients with PDAC. By engaging patients in clinical trials, we will be further able to understand the safety and efficacy of immunotherapy to treat PDAC. Research overview for of Project 1  

Project 2: Clinical development of the pancreatic cancer drug Conjugate SW V-49

William Hawkins, MD, FACS

Project 2 Photo
Pathology of human PDAC

Investigators in Project 2 of the Pancreas SPORE at Washington University hope to develop a drug for the treatment of pancreatic cancer to improve survival rates. In this research, our team will work towards developing a delivery platform for small-molecule drugs that sends a drug directly to tumors and avoids adverse side effects for patients. Through clinical trials, we will be able to test the success rates of such a drug specific to pancreatic cancer. Our project has tremendous potential to overcome drug resistance, improve success rates for patients, and minimize toxicity in patients. Research overview of Project 2  

Project 3: Combination inhibition of ERK for pancreatic cancer treatment

Andrea Wang-Gillam, MD, PhD, and Channing Der, PhD

Pdac Image 13 Website
PDAC stained for tumor cells (green) and stromal cells (red).

Investigators in Project 3 will examine screening combinations of drugs that may inhibit molecular pathways that support tumor survival in pancreatic cancer. A specific gene is found mutated in 95% of pancreatic ductal adenocarcinomas (PDACs), the deadliest form of pancreatic cancer. Our research and investigators hope to identify combination drug therapies that will overcome these gene mutations and, thus, help treat PDAC patients. Clinical trials based on this research will then begin in PDAC patients. Research overview of Project 3  

Project 4: Translation and preclinical studies of a personalized pancreas cancer vaccine

William Gillanders, MD, and Robert Schreiber, PhD

Pdac Image 1 Website
T-cell infiltration (pink) into PDAC

Project 4 aims to develop and test personalized vaccines for pancreatic ductal adenocarcinoma (PDAC) patients based on their genetic makeup. Our investigators’ previous research has shown that neoantigens are important tumor rejection toxins in the body and, thus, will help in the development of a personalized vaccine for PDAC patients. In the creation of this proposed vaccine, our investigators will test the success rate in clinical trials. Based on the results, the stage will be set for future clinical trials for personalized vaccines and/or combination therapies. Research overview for Project 4

SPORE Shared Resources (Cores)

Administrative Core

Directors: William Hawkins, MD, FACS, and David DeNardo, PhD Our Pancreas SPORE brings together a diverse group of talented investigators committed to understanding and treating pancreatic ductal adenocarcinoma. The goal of the Administrative Core is to provide executive oversight and administrative support for all of the Pancreatic Cancer SPORE projects and cores. The Administrative Core facilitates communication among the component activities of the SPORE, serves as the home for pancreatic cancer advocate activities, and provides an organizational portal for collaborations outside the SPORE. The Administrative Core also monitors the activities of all program components, ensures compliance with local and federal grant administration guidelines, and facilitates communication and collaboration among program members. The specific goals of the Administrative Core are outlined below:

  • Facilitate intra- and inter-SPORE communication and collaboration including development and maintenance of this website to provide real-time progress updates and contact information. In addition, the core plans and executes bi-monthly working group meetings, monthly Steering Committee meetings, and an annual retreat to facilitate the exchange of ideas and the use of shared resources.
  • Provide administrative and fiscal oversight and support for all SPORE components. The Administrative Core interacts with Washington University’s Grants and Contracts Office and the National Cancer Institute staff to prepare and submit annual progress reports and complete other projects as needed.
  • Coordinates all SPORE-related meetings. The Administrative Core coordinates the External Advisory Board and Internal Advisory Board meetings, attendance at the annual SPORE workshop, and monthly SPORE Steering Committee meetings.
  • Coordinates SPORE Developmental Research Program administrative activities through soliciting and coordinating the review of pilot project applications.
  • Coordinates the SPORE Career Enhancement Program. The Administrative Core assists with recruiting and monitoring candidates and awardees in this program.
  • Assists investigators with preparing scholarly presentations, publications, regulatory documents and all other SPORE-related products.
  • Enhances participation of underrepresented minorities in all SPORE activities.
  • Ensures that advocacy issues are properly addressed and included in all aspects of research with patient participants.

The Administrative Core is a shared resource within the pancreas SPORE and will provide the necessary administrative support for the translational projects and cores.

Biospecimen Core

Directors: Ryan Fields, MD, and Mark Watson, MD The controlled collection and processing of clinical specimens from patients with pancreatic ductal adenocarcinoma (PDAC) is a critical activity for an efficient and comprehensive program in translational research in the pancreas SPORE. Accordingly, the Biospecimen Core has one overarching aim: We will collect, store, process and distribute biospecimens from all patients with a diagnosis of PDAC seen at this institution to facilitate biospecimen-based translational research. Our investigators collect malignant cell populations from tumors (from pre-surgical and surgical biopsies) along with normal pancreas, pre-malignant pancreatic lesions and peripheral blood from PDAC patients. Serum and plasma are collected for correlative and future studies. Specimens are collected throughout each patient’s disease course (initial presentation, pre-treatment, post-treatment/follow-up), and, where appropriate, archival specimens from previous biopsies/etc. are retrieved. Specimens are processed to cellular RNA, genomic DNA, whole genome amplified DNA and protein extracts as required for each study. Cellular populations can also be frozen or immediately processed for patient-derived xenograft and/or cell line derivitization/creation.  A tissue microarray (TMA) has been created and will be expanded, creating an important resource for future studies. Importantly, all specimens used for research are extensively and accurately annotated with clinical (pre-treatment, treatment and follow-up) data utilizing the bioinformatics infrastructure at our institution. Expert pathologic review from a dedicated GI pathologist will ensure high-quality annotation. The aims of the Biospecimen Core are accomplished by expanding the scope of a well-established Cancer Center Tumor Bank and an on-going, funded effort to collect solid gastrointestinal malignancies at our institution.  Specifically, the Biospecimen Core will expand the number of PDAC patients from whom biospecimens will be collected, and serve as a conduit (through data and specimen sharing) to allow for a broader variety of translational research studies in PDAC malignancies, using new and previously banked biospecimens. The Biospecimen Core is responsible for the identification, enrollment and collection of specimens from adult patients referred to the Siteman Cancer Center (SCC) with newly diagnosed PDAC.  The pathologic material from these patients will be banked utilizing our existing collaboration with the SCC Tissue Procurement Core, drawing on caTissue and other informatics resources developed by the Center for Biomedical Informatics. Clinical data will be annotated and prospectively maintained in a robust clinical database. The Biospecimen Core is integrated with and extends the success of our existing Solid Tumor Tissue Bank and Registry, which was established by the Biospecimen Core (PI Fields) in 2011, to serve as a platform for the investigation of solid tumor pathogenesis. Available Resources: Tissue MicroArrays (TMAs) Pancreatic Tumors Bloods Animal Models Please contact Jacqueline Mudd for specimen requests at 314-362-2678 or jmudd@wustl.edu with the completed biospecimen request form. Request Form for Biospecimens *Please note requests are honored through a peer-review process.

Biostatistics Core

Directors: Graham Colditz, MD, DrPH, and Esther Lu, PhD The Biostatistics Core provides the statistical design, data management and computational support for all Pancreatic Cancer SPORE investigators and projects. The Biostatistics Core staff will support consultation and collaboration on all aspects of study design, database development and quality control, and analysis, interpretation and presentation of data. The statisticians, epidemiologist and the database manager participating in the Biostatistics Core have a strong record of collaboration, and have been specifically chosen for their broad range of expertise in and experience with clinical trials, laboratory experiments, genetics and genomics research, and epidemiology studies. Our members have participated regularly in planning meetings in which the scientific goals and research methods of the SPORE projects were discussed. The specific aims of the Biostatistics Core are to provide statistical input to the pancreas SPORE and, by so doing, to ensure a strong collaborative process. The Biostatistics Core will promote interaction among the projects and pilot studies. Through participation in specific projects and leadership activities, the interrelationships and synergy with the investigator team will accelerate the acquisition of knowledge beyond that which would be expected if these projects were implemented individually, or with research teams that were not interdisciplinary. The Biostatistics Core has the following specific aims: Aim 1: Provide ready access to statistical expertise and computing consultation to the Pancreatic Cancer SPORE. Aim 2: Provide biostatistical/epidemiological expertise for the planning, analysis and reporting of laboratory experiments, epidemiology studies, and clinical trials and links to the bioinformatics core resources for microarray data and high-throughput genomics data processing as needed. Aim 3: Advise and support pancreas SPORE investigators and their data collectors (technicians, nurses, data managers, etc.) in the areas of data form design, data collection, record abstraction, computerization, database designing and management, and data quality control. Aim 4: Provide the scientific computing expertise required to meet the data management and analytical needs of pancreas SPORE investigators, and support interpretation and presentation of data. The Biostatistics Core provides pancreas SPORE investigators with the ability to design and analyze studies that can then be linked to Shared Resources from the Siteman Cancer Center, Clinical Trials Office, Bioinformatics Solutions, and Genome Technology Access Center.  These resources can be leveraged for data form creation and uniform adverse event reporting, Tissue Procurement for sample storage and management (caTissue and related informatics), output from high-throughput genomic assays, and the expertise, tools, and analytic pipelines to streamline analyses and interpretation. The Biostatistics Core supports studies across the entire spectrum, from basic research to clinical translational trials.

Career Enhancement Program (CEP)

Directors: William Gillanders, MD, and Channing Der, PhD The Career Enhancement Program is a joint venture between the SPORE in Pancreatic Cancer, Washington University School of Medicine (WUSM), and Siteman Cancer Center (SCC). The primary objective of the Career Enhancement Program is to enhance pancreatic cancer research by providing financial support and mentoring for investigators who are new to the field to help build translational research careers in pancreatic cancer. The research initiatives that will be funded by the Career Enhancement Program are expected to have a major translational component, focusing on etiology, prevention, diagnosis, early detection, treatment or population science in pancreatic cancer. The Career Enhance Program’s goals are as follows:

  • Recruit and support new investigators to the field of pancreatic cancer research. The Career Enhancement Program is able to support a maximum of two investigators per year. Each investigator will be supported for up to two years, and the money can be used for salary support, laboratory supplies or tuition. The Career Enhancement Program will support both new investigators and established faculty members who are new to the field of pancreatic cancer research.
  • Provide mentoring to junior faculty members. Truly successful Career Enhancement Program awardees will be those who subsequently apply for and receive independent external funding to support their pancreatic cancer research careers. The Career Enhancement Program will foster this success by mentoring junior faculty members one-on-one, providing numerous opportunities for research training and didactic instruction, and assisting in the development and review of grant applications.
  • Promote participation of women and under-represented minorities in pancreatic cancer research. The Career Enhancement Program will specifically seek to increase the diversity of those participating in pancreatic cancer research through numerous outreach, recruitment, training and retention activities.

The Career Enhancement Program will select awardees from the collaborating SPORE institutions and from other appropriately qualified institutions. Financial support (salary, research supplies and tuition) will be provided for awardees for up to two years. The Career Enhancement Program will facilitate interactions between awardees and all members of the SPORE, emphasizing the basic and clinical science cross-fertilization that is essential to translational research. The SCC, WUSM, and our collaborating SPORE institutions provide outstanding opportunities for career development in translational pancreatic cancer research. We have the broad research base, existing and continually evolving new collaborations, basic science and clinical programs in pancreatic cancer that make the Career Enhancement Program a success. We have established intra-SPORE collaborations with the University of North Carolina, University of Rochester and Johns Hopkins University, broadening the Career Enhancement Program applicant pool and helping to match the interests of junior investigators with local expertise and need. The Career Enhancement Program will be open to all institutions participating in the SPORE.

Program Application Information

The Pancreas SPORE will fund one to two investigators per year for the life of the SPORE. The 2019 deadline for applications is April 30, 2019. The award will be up to $75,000 per year for up to two years, beginning on July 1, 2019.

Download the forms below to submit your project: Request for Applications and Instructions Face Page (PDF Document)

2018 Awardee

Chaudhuri Aadelpic1 CropAadel Ahmed Chaudhuri, MD, PhD Washington University School of Medicine Project Title:  Circulating Tumor DNA for Early Treatment Response Assessment of Pancreatic Cancer Lay Abstract:  Pancreatic cancer is among the deadliest cancers worldwide, and surgical resection and stereotactic body radiotherapy (SBRT) play major roles the treatment of localized disease. Unfortunately, there is no modality in clinical practice that can reliably detect molecular residual disease (MRD) after surgery, or distinguish between post-treatment inflammation/fibrosis and residual disease after SBRT. Here we will attempt to address these issues by measuring circulating tumor DNA (ctDNA) in the blood plasma using the CAPP-Seq method to assess response to therapy at a molecular level. Our goal is to show that this method can reliably detect MRD shortly after treatment completion. If successful, this would pave the way for personalized response-adapted therapy via dose escalation for patients with detectable MRD and avoid excess therapy for those with undetectable MRD. Our aim is that this research will improve pancreatic cancer survival through the application of precision medicine.

2017 Awardee

Pylayeva Pic1 Cropped WebsiteYuliya Pylayeva-Gupta, PhD University of North Carolina at Chapel Hill Project Title: Role of Immunosuppressive B Cells in Pancreatic Cancer Lay abstract: Pancreatic cancer is a very aggressive disease. It is the 4th leading cause of cancer deaths in the USA. Only 6% of patients who can undergo surgery will survive past five years. Late diagnosis and lack of good treatment options are some of the reasons for this outcome. Recent progress in cancer immune therapy showed effect in cancers such as relapsed leukemia and metastatic melanoma. Unfortunately, immune therapy was not effective in patients with pancreatic cancer. One explanation for this result is that pancreatic cancer blocks immune responses against cancer. Thus, understanding how cancer promotes immune suppression is vital to our ability to treat this deadly disease. Our initial work has revealed that B cells promote growth of pancreatic cancer. However, it is not clear how B cells promote cancer growth, and how targeting these cells can benefit patients. We propose to understand how B cells function in pancreatic cancer. The goal of this research project is to find new targets that can block immune suppression in pancreatic cancer. Using both mouse models of pancreatic cancer and patient samples, we hope to identify B cell based targets in pancreatic cancer. We ultimately hope to translate our findings into effective therapies that may also work with existing immune therapy treatments.

2016 Awardee

Cep Kian Lim PhotoKian-Huat Lim, MD, PhD Washington University Project Title: Evaluation of IRAK4 as a Novel Immunotherapeutic Target in Pancreatic Cancer Lay Abstract: To date, the prognosis for pancreatic cancer remains dismal. To improve patient outcome, novel and effective therapeutic strategies must be developed. Immunotherapy using checkpoint inhibitors has revolutionized the outlook of other cancer types including melanoma, lung and renal cancer, and yet is largely unsuccessful in pancreatic cancer. Our lab recently found that pancreatic cancer cells “armored” themselves by activating their own innate immune system, a self-defense mechanism that is usually summoned when cells are injured or invaded by microorganisms. We now believe, based on recent findings in our lab, that pancreatic cancer cells can utilize the same mechanism to invoke a fibrotic and inflamed tumor environment that renders immunotherapy ineffective. Our approach is to “deactivate” such defense mechanism by inhibiting Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), the master switch that controls the innate immune pathway. By doing so we found that pancreatic cancer cells become greatly weakened and are now responsive to immunotherapy. In this proposal, we will further investigate the role of IRAK4 in other cell types such as immune cells and fibroblasts within the pancreatic tumor, which will yield valuable knowledge to optimize future clinical trial design. In addition, we will test two new, highly potent IRAK4 inhibitors in combination with immunotherapy in mouse models with the goal of advancing a promising regimen that can be tested for pancreatic cancer patients.

Developmental Research Program

Directors: Lee Ratner, MD, PhD, and David Linehan, MD The goal of the SPORE in Pancreatic Cancer Developmental Research Program is to recruit and support developmental research projects in pancreatic cancer, for future incorporation as full SPORE projects or as the basis for applications for other major peer-reviewed funding. The types of research projects to be supported include basic research, clinical research, epidemiologic studies, and cancer prevention and control in pancreatic cancer. Projects will expand the scope of translational research and increase the number of investigators committed to pancreatic cancer research. The Developmental Research Program is responsible for: Recruiting research projects that will promote pancreatic cancer research to help define the new treatment directions of pancreatic cancer research. Supporting early-stage pancreatic cancer research projects so that they may achieve independent funding through competitive applications including R01, SPORE, foundations and other mechanisms. This program is open to all of the institutions participating in the SPORE, and any of their collaborators to maximize the number of innovative and high-quality projects. In addition, plans call for development of new projects with other SPOREs. This program, along with the Career Enhancement Program, is consistent with the Siteman Cancer Center’s overall commitment to the recruitment of minority and underrepresented investigators. New research projects are solicited and funded through developmental funds. Two to three developmental projects will be funded each year throughout the life of the SPORE. Requests for Applications for developmental projects in pancreatic cancer research will be requested annually. All developmental project applications will be reviewed by a Research Development Advisory Committee consisting of scientists (representing basic and applied science) with expertise in pancreatic cancer, a biostatistician, a patient advocate and ad hoc members, as necessary (special expertise, no conflict of interest). This committee will make recommendations to the Pancreatic Cancer SPORE Steering Committee, which will make final funding decisions.

Program Application Information

The Pancreas SPORE will fund up to three investigators per year in the Developmental Research Program. The 2019 deadline for applications is April 30, 2019.  The award will be up to $75,000 for one year (July 1, 2019 through June 30, 2020). Download the forms below to submit your project: Request for Applications and Instructions Face Page (PDF Document)

2018 Awardees

Chen Photo CropDelphine L. Chen, MD Washington University School of Medicine Project Title:  Imaging PARP Expression in Pancreatic Cancer Lay Abstract: Poly(ADP-ribose)polymerase (PARP) inhibitors are a promising new class of anticancer drugs. However, identifying the patients who will best respond to these drugs is challenging, especially in light of the side effects associated with PARPi therapy. We have developed a new positron emission tomography (PET) technique to image PARP expression in tumors. The goal of this project is to test whether we can use this new PET technique to identify patients who will best respond to PARP inhibitors and spare patients from side effects of ineffective treatment. Liu Photo CropYongjian Liu, PhD Washington University School of Medicine Project Title:  PET Imaging Guided Drug Delivery for Pancreatic Adenocarcinoma Therapy Lay Abstract:  Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of human cancer and is a rising major health problem in the US. By the year 2020, PDAC is projected to be the second-leading cause of cancer death in the United States. Because of the lack of early diagnosis tools and ineffective drug delivery for treatment, the median survival of patients with advanced-stage disease is less than one year, and the five-year overall mortality rate approaches 100%, demonstrating the urgent need for new therapies to improve treatment outcomes. A nanoparticle is a microscopic-sized vehicle that improves cancer imaging and drug delivery efficiency. Nanoparticles have been used successfully to improve the treatment outcome of cancer patients, but not in PDAC. In this study, we plan to develop an ultrasmall nanoparticle to enhance chemotherapy drug delivery to pancreatic tumors. To improve the delivery efficiency and treatment accuracy, we propose a targeted mechanism using a peptide binding to a protein called CCR2, which is highly expressed on monocytes/macrophages, which are important components of tumor microenvironment and a barrier for PDAC treatment. Through the incorporation of a radioactive atom of copper-64, we propose that the targeted nanoparticle can serve as a platform to deliver chemotherapy drugs more efficiently to PDAC tumors following the real-time imaging guidance. The results obtained from this pilot study will serve as solid foundation for future translation to treatment therapy. Toriolaadetunji267x400Adetunji Toriola, MD, PhD, MPH Washington University School of Medicine Project Title:  Metformin Use and Pancreatic Cancer Survival in African Americans Lay Abstract:  Pancreatic cancer is the 4th leading cause of cancer death in the US. African Americans have a higher incidence of pancreatic cancer, present with more advanced stages at diagnosis, and are less likely to receive surgery than any other racial group. Reducing these disparities will involve ascertaining factors that improve clinical outcomes in African Americans. Type II Diabetes Mellitus (DM) is one of the few modifiable factors that impacts pancreatic cancer survival. Notably, African Americans are nearly twice as likely as non-Hispanic Whites to have Type II DM. On the basis of the growing evidence that metformin, an anti-diabetic drug, is associated with better survival in pancreatic cancer patients, metformin has been considered a useful adjunctive therapy for pancreatic cancer. Nevertheless, well-designed prospective studies investigating the associations of metformin use with pancreatic cancer survival in African Americans are lacking. Thus, it is impossible to determine whether African Americans with pancreatic cancer will benefit from any survival advantage conferred by metformin, further exacerbating the disparities. Our proposal will begin to address this gap in current knowledge by investigating the associations of metformin use, including duration of use, with survival and other clinical outcomes in African American pancreatic cancer patients with pre-existing type II DM.

2017 Awardees

Dr Julie Schwarz WebsiteJulie K. Schwarz, MD, PhD Washington University School of Medicine Project Title: Targeting the Tumor Stroma to Improve Neoadjuvant Approaches in Pancreatic Cancer Lay Abstract: Chemo-radiation strategies currently used for pancreatic cancer are disappointingly effective at generating significant tumor regression. This is likely due to our poor understanding of how these therapies impact of the fibrotic and immunologic components of the unique pancreas cancer stroma. Our goal is to understand how to best integrate stromal disrupting therapies to improve responses to radiation therapy in the neoadjuvant setting and to move these therapies into a new clinical approach aimed at directly impacting pancreatic cancer patients. Ryan C Fields Md WebsiteRyan Fields, MD, FACS Washington University School of Medicine Project Title: An Autologous Humanized Mouse Model to Evaluate Immune Modulating Therapeutics in Pancreatic Cancer Lay Abstract: Progress in the early detection and treatment of cancer requires accurate model systems to further evaluate new, promising discoveries.  Small animal, and in particular mouse, model systems are attractive to researchers for numerous reasons, including their ease of use and well-described platforms.  Immunotherapy has revolutionized clinical oncology, but lacks pre-clinical models of the human immune system and human cancer to investigate new modalities and limitations/toxicities of treatment regimens.  The ability to grow human tumors in immunodeficient mice (so-called patient-derived xenografts, or PDXs) allows researchers to work directly with human cancer tissue in a controlled setting.  However, PDX models are limited by their lack of an intact immune system.  The broad objective of this proposal is to validate an in vivo model to evaluate human tumors in the context of a complete and intact human immune system in a completely personalized and autologous fashion.  Herein, we propose to validate the ability to establish humanized mice from patients with pancreatic cancer. Aram Hezel 1 Mb Jpeg WebsiteAram F. Hezel, MD University of Rochester Project Title: Arid1a in Pancreatic Cancer; Transcription Control Therapeutic & Clinical Impact Lay Abstract: The gene Arid1a is mutated in a significant number of pancreatic cancers.  We have created new models and systems to study this gene and the effect of its mutation in this disease. Here we will use these systems to understand how cancers with Arid1a mutations may be specifically treated more effectively.

2016 Awardees

Scott Gerber, PhD University of Rochester Medical Center Project Title: Revisiting Neoadjuvant Therapy for Pancreatic Cancer: Incorporation of New Strategies Lay Abstract: Pancreatic ductal adenocarcinoma (PDAC) continues to have dismal prognosis with surgical resection offering the only real potential for cure. However, even in patients undergoing surgery, the prognosis remains poor due to a high rate of local recurrence and metastases. Therefore, there is a vital need to develop new therapies that will increase the survival rate of patients with PDAC. To that end, our preclinical research project will examine a novel multimodal approach that will not only facilitate surgical removal of the primary malignancy, but may also stimulate a systemic immune response capable of preventing metastases. This approach will combine both radiotherapy and immunotherapy delivered in a neoadjuvant setting, which is defined as treatment that occurs before surgical excision of the tumor. The immunotherapy arm of this treatment is designed to enhance the efficacy of radiotherapy, resulting in a potent systemic anti-tumor immune response. Ultimately, we hope to demonstrate that this novel approach reduces both local recurrence and metastases in patients with pancreatic cancer. Christopher Maher, PhD Washington University Project Title: Understanding the Role of IncRNAs in Pancreatic Cancer Lay Abstract: Currently, our limited understanding of how the original pancreatic tumor spreads throughout the body (also known as metastases) is a critical barrier to improve the current inadequate treatments. Although early-stage pancreatic ductal adenocarcinoma (PDAC) is curable with surgery and adjuvant therapy, metastatic pancreatic cancer is usually lethal. To date, PDAC research has primarily focused on protein-coding genes, thereby missing the emerging class of long non-coding RNAs (lncRNAs), which do not generate proteins. While our understanding of how lncRNAs function to promote metastasis is still in its infancy, initial studies suggest that lncRNAs can function by binding with proteins and guiding them throughout the genome to regulate genes involved in cancer. Therefore, the focus of this proposal is to understand how lncRNAs act as a master regulator by interacting with a protein complex known to promote tumor spread/metastases. To accomplish this, we will perform the first analysis that includes normal, primary and multiple distant metastatic tumors from the same patients to discover lncRNAs altered during metastasis. Next, we will identify which lncRNAs confer metastatic properties in cells through their interaction with a protein complex known to promote aggressive disease. Overall, successful completion of these aims will significantly advance our understanding of lncRNA tumor biology and pancreatic cancer metastasis. A better understanding of how lncRNAs enable primary tumors to invade and metastasize could lead to the development of specific treatments to improve patient outcomes.

Clinical Trials in Pancreas Cancer

Clinical trials are research studies that provide hope for patients with cancer. These trials give patients access to new treatment therapies including new drugs or new ways to use existing drugs. They also include new radiation therapies, new surgical procedures, and new ways to combine different cancer treatments. The ultimate goal of each clinical trial is to find new and improved ways to safely and effectively treat cancer. Clinical trials are important to patients because they give access to treatment that would not be provided otherwise. In addition, they are important because they help get drugs approved and more easily accessible for future patients. If you are interested in learning more about the Pancreas SPORE clinical trials, you should ask your doctor or nurse if a clinical trial is available and appropriate for you. Below are current clinical trials the Pancreas SPORE investigators are researching.

NeoAdjuvant

NCT03122106: Neoantigen DNA Vaccine in Pancreatic Cancer Patients Following Surgical Resection and Adjuvant Chemotherapy The purpose of this research study is to learn more about the safety and feasibility of injecting a personalized DNA vaccine into people with pancreatic cancer. Injection of this DNA vaccine may be a way to generate an immune response to tumor cells and help fight cancer.

Locally Advanced

NCT03496662: BMS-813160 With Nivolumab and Gemcitabine and Nab-paclitaxel in Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma (PDAC) The purpose of this research study is to learn what the best dose is of the investigational drugs nivolumab and BMS-813160 when combining them with the currently approved drugs for pancreatic cancer, gemcitabine and nab-paclitaxel. NCT02283372: Nab-Paclitaxel Plus Gemcitabine With Concurrent MR-Guided IMRT in Patients With Locally Advanced Pancreatic Cancer The purpose of this research study is to find the highest dose of radiation that can be safely given during chemoradiotherapy with modern chemotherapy agents to treat pancreas cancer. In addition, the machine being used to administer the radiation therapy uses a technique called magnetic resonance imaging (MRI)-guided adaptive radiation therapy. MRI-guided adaptive radiation therapy involves the adjustment or re-planning of treatment day by day while you are receiving treatment.

Metastatic

NCT02546531: Defactinib Combined With Pembrolizumab and Gemcitabine in Patients With Advanced Cancer The purpose of this research study is to test the combination of three drugs called defactinib, pembrolizumab, and gemcitabine for the treatment of  pancreatic cancer.  The study will help us discover what the best dose of each drug is and how well the combination treats pancreatic cancer. NCT02608229: BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer The purpose of this research study is to learn more about the combination of three drugs – BVD-523, gemcitabine, and nab-paclitaxel – for the treatment of metastatic pancreatic cancer. We will be looking at how well these drugs are able to control pancreatic cancer growth. NCT03184870: A Phase 1b/2 Study of BMS-813160 in Combination with Chemotherapy or Nivolumab in Patients with Advanced Solid Tumors The purpose of this research study is to discover if patient are treated with an immunotherapy drug, called BMS-813160, alone or together with another immunotherapy drug, called nivolumab or chemotherapy have better control of their cancer than patients who do not receive the immunotherapy drugs. NCT02993731: A Phase III Study of BBI-608 plus nab-Paclitaxel with Gemcitabine in Adult Patients with Metastatic Pancreatic Adenocarcinoma The purpose of this research study is to find out whether participants with pancreatic cancer live longer when receiving an experiment treatment with an investigational drug, BBI-608, in combination with standard chemotherapy (nab-Paclitaxel and Gemcitabine) compared to patients who are treated with standard chemotherapy alone. 201611106 The purpose of this research study is to create a patient registry and tissue bank in order to identify early biomarkers for pancreatic disease, and to develop better tests and treatments for pancreatic disease. NCT03336216: A Phase 2 Study of Cabiralizumab (BMS-986227, FPA008) Administered in Combination with Nivolumab (BMS-936558) with and without Chemotherapy in Patients with Advanced Pancreatic Cancer The purpose of this research study is to test the effectiveness of the combination of cabiralizumab (BMS-986227) and nivolumab with and without chemotherapy for the treatment of advanced/metastatic pancreatic cancer. NCT03512756:  A Phase II Multi-Center Study of SM-88 in Subjects with Pancreatic Cancer Whose Disease Has Progressed or Recurred after/on First Line Chemotherapy The purpose of this research study is to find the appropriate dose of SM-88, an experimental drug regimen, and see how well it works to treat pancreatic cancer.

Investigators and Staff

Maxim Artyomov, PhD Project 4 Co-Investigator Graham Colditz, MD, DrPH Biostatistics Core Director; Administrative Core Associate Core Director David DeNardo, PhD Project 1 Co-Leader; Administrative Core Associate Core Director Channing Der, PhD Project 3 Co-Leader; Career Enhancement Program Co-Director Delphine L. Chen, MD Project 2 Collbaorator Bettina Drake, PhD, MPH Administrative Core Co-Investigator Ryan Fields, MD Biospecimen Core Co-Director Timothy Fleming, PhD Project 4 Co-Investigator; Biospecimen Core Co-Investigator Feng Gao, MD, PhD, MPH Biostatistics Core Biostatistician Andrea Wang-Gillam, MD, PhD Project 3 Co-Leader; Project 1 Co-Investigator William Gillanders, MD Project 4 Co-Leader; Career Enhancement Program Co-Director S. Peter Goedegebuure, PhD Project 1 Co-Investigator; Project 3 Co-Investigator; Project 4 Co-Investigator; Biospecimen Core Co-Investigator William Hawkins, MD, FACS SPORE Director; Project 2 Co-Leader; Administrative Core Co-Director; Project 4 Co-Investigator Aram Hezel, MD Project 1 Clinical Trials Co-Leader Elizabeth Jaffee, MD Project 4 Translational Co-Leader Daniel Laheru, MD Project 4 Co-Investigator Kian-Huat Lim, MD, PhD Project 3 Co-Investigator; Project 4 Co-Investigator David Linehan, MD Project 1 Co-Leader; Developmental Research Program Co-Director Ta-Chiang Liu, MD, PhD Biospecimen Core Co-Investigator Esther Lu, PhD Biostatistics Core Biostatistician Robert Mach, PhD Project 2 Collaborator Lee Ratner, MD, PhD Developmental Research Program Co-Director Maranna Ruzinova, MD, PhD Biospecimen Core Co-Investigator Robert Schreiber, PhD Project 4 Co-Leader Dirk Spitzer, PhD Project 2 Co-Investigator Mark Watson, MD Biospecimen Core Co-Leader Krister Wennerberg, PhD Project 3 Co-Investigator