SPORE in Pancreatic Cancer
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.
The Washington University SPORE in Pancreas Cancer is one of only three SPOREs in the nation. Pancreatic cancer is the 3rd leading cause of cancer death in the United States. Only 24% of pancreatic cancer patients survive >1 year from diagnosis, and only 9% live for 5 years. Siteman Cancer Center physicians evaluate and treat greater than 3,000 pancreatic cancer patients per year.
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.
Pancreas SPORE Director: William Hawkins, MD, FACS
Our translational research program possesses both breadth and depth. Our team has repeatedly demonstrated its ability to translate basic science discoveries to therapeutic approaches. Recent examples of this ability include advances in our understanding of the tumor micro-environment (TME) or tumor-mediated immune suppression, which have successfully moved from discovery to preclinical models and ultimately into clinical trials. Our group has also successfully moved findings from the clinic back to the bench. For example, the rebound observed in other myeloid subsets when using CCR2 inhibitors led to testing of CCR2/5 inhibition in subsequent research efforts. The Washington University SPORE in Pancreas Cancer at Siteman Cancer Center includes patients with all disease stages, and its trials are led by many investigators representing multiple disciplines. The clinical program is well established, and our growing reputation for recruiting patients to clinical trials has facilitated academic and clinical partnerships, leading to numerous clinical trial opportunities. Over the last 4 years, pancreatic cancer patients have been enrolled in 103 studies, 41 of which are therapeutic clinical trials at Siteman.
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.
Project 1: Overcoming tumor-induced immune suppression to improve responses to immunotherapy.
Project 1 of the Pancreas SPORE examines the immune system responses and/or natural killer cells, which have been previously shown to restrain tumor development and progression. Unfortunately, immunotherapy attempts have struggled to achieve significant clinical benefits in pancreatic ductal adenocarcinoma (PDAC). Our investigators have discovered that blocking specific cell regulation results in slower tumor growth and improves responses to chemotherapy. Pre-clinicalmodels with PDAC have also shown the prevention of metastasized tumors. The goal of this project is to determine the effects, mechanism, and possible future drug combinations to help enhance therapeutic outcomes in patients with PDAC.
This project has successfully launched three clinical trials (NCT03496662, NCT04060342, NCT03184870). Pre-clinical data revealed that combining CCR2/5 inhibitors with both chemotherapy and PD1 checkpoint antagonists maximized tumor immunity and response. These studies resulted in openingof a new clinical trial testing a combination of a CCR2/5 inhibitor (BMS-813160), PD1 antagonist (nivolumab), and Gemcitabine and Abraxane. Highlights within this trial include verification of our pre-clinical data findings showing that the tested combinations resulted in increased T cell infiltration into patient pre-and post-treatment biopsies.
Dr. DeNardo recently published in the journal Immunity on how CCR2 inhibition in pre-clinical models improved our understanding of the diverse origins of PDAC-infiltrating macrophages. Additionally, our teams research discovered that PDAC tissue–residing macrophages may compensate for loss of monocyte recruitment into the tissue microenvironment.
This finding led us to pre-clinically test a second approach using a CD11b agonist, which like CCR2 inhibition, blocks monocyte recruitment but also directly activated interferon pathways in macrophages to support tumor immunity. In the Journal of Science Translational Medicine we reported how these unique properties of this CD11b-agonist approach showed very strong efficacy in combination with PD-1 antagonists in pre-clinical PDAC models. Research overview for of Project 1.
Project 2: Clinical development of the pancreatic cancer drug Conjugate SW V-49
Project 2 of the Pancreas SPORE at Washington University is working to develop a novel drug (SW V-49) for the treatment of pancreatic cancer. The overarching goal is to develop a delivery platform for small-molecule drugs that sends a drug directly to tumors and avoids adverse side effects for patients. Through clinical trials, this project has tremendous potential to overcome drug resistance, improve success rates for patients, and minimize toxicity in patients.Initial preclinical assessment of SW V-49, including assessment of its bioavailability, toxicity, efficacy, and pathway selectivity, demonstrated a narrower therapeutic window than expected.
Thorough rigorous evaluation,Hawkins and colleagues identified a mesylate salt (ACXT-3102) as the optimal therapeutic candidate. ACXT-3102 is a two domain anti-cancer therapeutic providing three advantageous properties: cancer selectivity, targeting cell internalization, and metabolic stress and cell death by ROS. This promising new therapeutic candidate was selected for a new National Cancer Institute Stepping Stones Program to advance new therapeutic concepts toward clinical testing. Using an oral daily dosing strategy, we observed a significantly improved (over SW V-49) therapeutic window and more favorable toxicity profile. The new formulation (ACXT-3102) was evaluated in multiple pre-clinical models and we observed dramatic improvements in efficacy, as demonstrated by the >2-fold increase in median survival maintained with the new dosing plan. Final plans for a phase I clinical trial to be initiated in the early 2020’s is well underway. Research overview of Project 2
Project 3: Combination inhibition of ERK for pancreatic cancer treatment
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
Project 4 has developed and opened a phase 1 open-label study to evaluate the safety and immunogenicity of a neoantigen DNA vaccine strategy in pancreatic cancer patients following surgical resection and adjuvant chemotherapy. The neoantigen DNA vaccines incorporate prioritized neoantigens and personalized mesothelin epitopes that are administered with an electroporation device. The investigators of Project 4 hypothesize that neoantigen DNA vaccines will be safe and capable of generating measurable neoantigen-specific CD4 and CD8 T cell responses.
The trial (NCT03122106) is open at Siteman Cancer Center and Johns Hopkins. The trial is accruing rapidly and has more than 15 patients under evaluation. The majority of our ongoing efforts are focused on evaluation of the immune response to the vaccine using our tissue and human immune monitoring cores. Preliminary data demonstrate that patients are capable of responding to the vaccine. This project has been highly successful as it has accomplished its translational objective, is collaborative, spurred development of multiple spin off projects and an additional clinical trial (NCT03956056).
Drs. Gillanders and Schreiber have also been working to develop a more robust animal model and test enhancements to the vaccine strategy, respectively. To do so, they have utilized a cell line derived from a genetically engineered spontaneous pancreas tumor as the parental line from which to create our best model. We selected this particular line because it recapitulates many of the features of human pancreatic cancer. Like human PDAC, this line is resistant to immune checkpoint inhibitors. We treated this line in culture with oxaliplatin and a PARP inhibitor and isolated clones when approximately 30 mutations were acquired. We analyzed these mutations using the pVAC-seq antigen prediction model and subsequently created and tested personalized vaccines. These models have allowed us to test strategies to alter the tumor microenvironment in ways that may augment our vaccine strategy. Our goal is to select the best strategies to test in future clinical trials. Research overview for Project 4
SPORE Shared Resources (Cores)
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.
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 firstname.lastname@example.org with the completed biospecimen request form. Request Form for Biospecimens *Please note requests are honored through a peer-review process.
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:
- Provide ready access to statistical expertise and computing consultation to the Pancreatic Cancer SPORE.
- 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.
- 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.
- 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)
Program Application Information
The Pancreas SPORE will fund one to two investigators per year for the life of the SPORE. The 2020 deadline for applications is April 30, 2020. The award will be up to $75,000 per year for up to two years, beginning on July 1, 2020. Download the forms below to submit your project: Request for Applications and Instructions; Face Page.
SPORE CEP Overview
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.
CEP Past Awardee’s
The CEP has funded a total of four projects. These projects have led to two clinical trials in pancreatic cancer. CEP-funded investigators have published in top-tier journals, including Cancer Discover, Clinical Cancer Research, and Cancer Immunology Research. Thus, our CEP investments, in combination with our DRP awards, account for three out of four of the projects in this SPORE renewal application and a significant number of new trials for pancreatic ductal adenocarcinoma (PDAC) patients. These metrics highlight the quality of our applicants and the projects we foster with the developmental mechanisms. We aim to continue our success in this area. A summary of our CEP awardees and their collaborative, high-impact productivity is provided below.
Kian-Huat Lim, MD, PhD
Evaluation of IRAK4 as a Novel Immunotherapeutic in Pancreatic Ductal Adenocarcinoma. Immunotherapy using checkpoint inhibitors has revolutionized the outlook of several cancers, including melanoma, lung, and renal cancer, and yet has been largely unsuccessful in pancreatic cancer. Lim found that pancreatic cancer cells “armor” themselves by activating their own innate immune system, a self-defense mechanism that is usually summoned when cells are injured or invaded by microorganisms. Recent findings in his lab revealed that pancreatic cancer cells can utilize the same mechanism to invoke a fibrotic and inflamed tumor environment that renders immunotherapy ineffective. Lim found that deactivating this defense mechanism by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), the master switch that controls the innate immune pathway, caused pancreatic cancer cells to become greatly weakened and thus responsive to immunotherapy. His lab investigated the role of IRAK4 in other cell types within the pancreatic tumor, such as immune cells and fibroblasts, which will facilitate optimization of future clinical trial design. The results of Lim’s research were leveraged to obtain additional grants, including an American Cancer Society Award and a National Cancer Institute R37. He has published five articles in journals such as Clinical Cancer Research, Oncotarget, Molecular Cancer Therapeutics, Cancer Research, and Gut. CEP funding of Kian’s project led to development of a clinical trials (NCT03496662 & NCT03851237).
Role of Immunosuppressive B Cells in Pancreatic Cancer.
Understanding how cancer promotes immune suppression is vital to our ability to treat Pancreas Ductal Adenocarcinoma. The overall goal of Dr. Pylayeva-Gupta’s initial research revealed that B cells promote growth of pancreatic cancer, and the goal of her research was to identify new targets that can block immune suppression in pancreatic cancer. Her team has been testing strategies that block immune suppressive pathways in the tissue microenvironment and enhance the impact of T cell-reinvigorating therapies. She has published her research in top journals, including Cancer Discovery, Cancer Immunology Research, and Cytokine. The results of her work have led to multiple new grants in pancreatic cancer from the V Foundation for Cancer Research, Concern Foundation Conquer Cancer Now, Department of Defense, and the National Cancer Institute.
Aadel Ahmed Chaudhuri, MD, PhD
Circulating Tumor DNA for Early Treatment Response Assessment of Pancreatic Cancer. Pancreatic cancer is among the deadliest cancers worldwide, and surgical resection and stereotactic body radiotherapy (SBRT) play major roles in 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. In his research, Chaudhuri plans to address these issues by measuring circulating tumor DNA (ctDNA) in blood plasma using the CAPP-seq method to assess response to therapy at a molecular level. Chaudhuri’s research aims to provide key data to facilitate development of personalized response-adaptive therapy via dose escalation for patients with detectable MRD and avoid excess therapy for those with undetectable MRD. His research has led to publications in Gastroenterology and Molecular Diagnosis and Therapy. Based on Dr. Chaudhuri’s promising preliminary data this project has now evolved into a prospective longitudinal collaboration with Dr. Ryan Fields.
Carl DeSelm, MD PhD
Care Modified Innate Immune Cells for Pancreatic Ductal Adenocarcinoma. Pancreatic cancer remains one of the deadliest cancers and is characterized by a rich infiltration of innate immune cells that are programmed by the tumor to facilitate its own survival, growth, and spread. In other contexts, these same innate immune cells can be potent killers of bacteria, viruses, or even tumor cells. Why they become strong tumor-supportive cells rather than tumor-killing cells and how to reverse this role remain key gaps in knowledge. Using genetic techniques, DeSelm is modifying these innate immune cells with chimeric receptors that, upon tumor binding, initiate a program of anti-tumor activity. These anti-tumor responses range from direct tumor phagocytosis or killing to modulation of the tumor microenvironment to lead to its eventual death. This genetic programming impedes the tumor’s manipulation of innate immune cells. This strategy may become an effective treatment option for pancreatic cancer at all stages. Dr. DeSelm is currently developing a new clinical trial with Dr. David DeNardo of Project 2 that is planned to open in the early 2020’s.
Patrick Grierson, MD PhD
Evaluation of MK2 as a novel Immunomodulatory Target in Pancreatic Cancer. Pancreatic cancer remains among the deadliest cancers, and is presently unresponsive to targeted or immunotherapies, leaving combination chemotherapies as the primary treatment for advanced disease. However, treatment responses to chemotherapy are neither universal nor durable, largely due to intrinsic signaling events that drive resistance as well as a protective extrinsic tumor microenvironment that limits the delivery of chemotherapy and neutralizes anti-tumor immunity. In preclinical models, near-complete stromal depletion reverts pancreatic cancer cells into a primitive and more aggressive tumor type and clinically, stromal depletion via addition of hyaluronidase fails to potentiate chemotherapy and may increase toxicity. These findings underscore the need to identify novel therapeutic targets in pancreatic cancer. Grierson has found that adaptive activation of the MK2/Hsp27 pathway is a novel and major resistance mechanism to genotoxic stress in pancreatic cancer, and that treatment with a novel oral MK2 inhibitor concurrent with chemotherapy greatly augments the efficacy of chemotherapy in preclinical models. Furthermore, targeting MK2 causes marked reduction in stromal density and shifts tumor-infiltrating T cells and myeloid cells to an activated anti-tumor phenotype. Beyond the CEP award, his work has also led to grant support from the Emerson Collective Cancer Research Fund to further study pancreatic cancer. Dr. Grierson is currently developing a new clinical trial based on this work.
Calvin L. Cole, PhD
Role of CCR2 and CXCR1/2 inhibition on the attenuation of PDAC-related cachexia. Pancreatic cancer is a leader in cancer-related deaths due to the aggressive nature of the disease, treatment intolerance, and/or discontinuation related to cancer-related skeletal muscle wasting (SMW) and decreased quality of life. The Cole laboratory is focused on elucidating the mechanisms of SMW uniquely associated with pancreatic cancer and developing interventions. Importantly, a large percentage of patients with pancreatic cancer experience cancer-related SMW, and have reduced physical function and response to treatment, increased postoperative morbidity, and shorter life expectancy. Thus, treatments that attenuate muscle wasting may also improve treatment tolerance, quality of life, and survival. Recently, Dr. Cole obtained NIH P30 pilot grant funding to evaluate sarcopenia in the KCKO murine model of PDAC developed in Dr. David Linehan’s laboratory via standard histology and novel longitudinal dual-energy X-ray absorptiometry (DEXA) outcomes. The results of this research revealed several remarkable innovations that were published in PLOS ONE. Most notable was our discovery that PDAC bearing mice faithfully recapitulate the pathophysiology of cancer-related SMW, upregulated systemic and local inflammation (TNF-α, IL-1, and IL-6), and increased tissue-associated cellularity, which are known to be upregulated in animal models of cancer cachexia. Upregulation of these cytokines have been linked to high levels of the chemokine receptor genes CCR2 and CXCR1/2, which attract myeloid cells to the tumor microenvironment (TME). The goal of Dr. Cole’s current research is to understand the relationship between secretions from the TME and SMW in a murine model of PDAC and translate these findings into clinically relevant treatments.
Developmental Research Program (DRP)
Program Application Information
The Pancreas SPORE will fund up to three investigators per year in the Developmental Research Program. The 2020 deadline for applications is April 30, 2020. The award will be up to $75,000 for one year (July 1, 2020 through June 30, 2021). Download the forms below to submit your project: Request for Applications and Instructions; Face Page
SPORE DRP Overview
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, epidemiological 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 and to support 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.
DRP Past Awardee’s
The DRP has funded a total of 10 projects to-date. Our DRP-funded investigators have published their research in high-impact journals including Nature Medicine, Cancer Cell, and Nature Communications. Additionally research funded through the DRP has led to the development of multiple new clinical trials for patients with pancreatic cancer. A summary of our DRP awardees and their collaborative, high-impact work is provided below.
Scott Gerber, PhD
Revisiting neoadjuvant therapy for pancreatic cancer: Incorporation of new strategies. This project investigated whether radiation therapy augmented immune responses to pancreatic tumor in the neoadjuvant setting. The team developed a mouse model to test whether radiation therapy generated a locally potent immune response at the primary pancreatic tumor, and hypothesized that this neoadjuvant therapy would induce systemic antitumor immunity. Thus, this DRP aimed to determine whether neoadjuvant radiation therapy generated an antitumor immune response that reduced local recurrence/metastases in PDAC. The results of this study have been published in multiple top tear journals including Oncotarget, Radiation Research, Cell Reports, and Cancer Immunology Research. Additional Gerber’s team has translated these findings to into the development of multiple planned Clinical Trials and additional grants from the National Cancer Institute, Wilmot Cancer Institute, and the University of Rochester Technology Development Award.
Christopher Maher, PhD
Understanding the role of long non-coding RNAs in pancreatic cancer. This project aimed to determine how primary tumors invade and metastasize secondary sites, with an overall goal of identifying novel targets and strategies to improve pancreatic cancer diagnostics and therapeutics. The results of this study were leveraged to obtain grants from the American Cancer Society and the National Cancer Institute.
Ryan Fields, MD
An autologous humanized mouse model to evaluate immune modulating therapeutics in pancreatic cancer. This proposal aimed to validate a recently described “MSTRG” HuMo model, which enables development of a human immune system encompassing both innate and adaptive cell populations, and apply this model to pancreatic adenocarcinoma. The results of Dr. Fields work have been published in the journals such as Oncotarget, Immunity, and Journal of Immunology. Additionally, the results of this DRP award were leveraged to obtain additional awards from the National Cancer Institute and National Institutes of Health.
Julie Schwarz, MD PhD
Targeting the tumor stroma to improve neoadjuvant approaches in pancreatic cancer.
This project investigated why current chemoradiation strategies for pancreatic cancer are disappointingly ineffective in significant tumor regression. This is likely due to our poor understanding of how these therapies impact the fibrotic and immunologic components of the unique pancreatic cancer stroma. The project goal was to optimize the integration of stromal disrupting therapies to improve responses to radiation therapy in the neoadjuvant setting, and to integrate these therapies into a new clinical approach that will directly benefit pancreatic cancer patients. The exciting results of Schwarz’s study have been recently published in Science Translational Medicine with another paper accepted at Cancer Cell. Dr. Schwarz and team are in the final phases of developing a clinical trial based on the findings for patients at Siteman Cancer Center.
Aram Hezel, MD
Arid1a in pancreatic cancer: Transcription control therapeutic and clinical impact. This project investigated Arid1a gene mutation, which occurs in a significant number of pancreatic cancers. We created new models and systems to study this gene and the effects of its mutation in pancreatic cancers. These newly developed systems were used in this study to determine how cancers with Arid1a mutations can be more specifically and effectively treated. Data from this study was recently published in Gut, and a second manuscript is under review.
Delphine Chen, MD
Imaging PARP expression in pancreatic cancer. This project investigates poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), a promising new class of anticancer drugs. However, identifying patients who best respond to these drugs is challenging, especially because of side effects associated with PARPi therapy. Chen’s team developed a new positron emission tomography (PET) technique to image PARP expression in tumors. The goal of the project was to test whether this new PET technique could be used to identify patients who best respond to PARPi and spare non-responding patients from the side effects of ineffective treatment. Data from this study was leveraged to obtain additional funding from a Multi-PI Siteman Investment Program Award which is being used to support a clinical trial (NCT02469129) that is currently enrolling patients.
Yongjian Liu, PhD
PET imaging guided drug delivery for pancreatic adenocarcinoma therapy. This project developed an ultrasmall nanoparticle to improve chemotherapy drug delivery efficiency and treatment accuracy to pancreatic tumors. They investigated a targeted mechanism that used peptide binding to a CCR2 protein, which is highly expressed on monocytes/macrophages that are important components of the tumor microenvironment and a barrier for PDAC treatment. A radioactive copper-64 atom was incorporated into the nanoparticle to investigate whether it could serve as a platform for real-time PET imaging and efficient chemotherapy drug delivery to PDAC tumors. Data from this study was leveraged to obtain a National Cancer Institute grant and led to a clinical trial (NCT03851237) that is currently enrolling patients.
Adetunji Toriola, MD, PhD
Metformin use and pancreatic cancer survival in African Americans. This project investigated African American disparities in pancreatic cancer compared with other racial groups. Type II diabetes mellitus (DM) is one of the few modifiable factors that impacts pancreatic cancer survival. Notably, African Americans are approximately twice as likely as non-Hispanic Whites to have type II DM. Evidence is emerging that metformin (an anti-diabetic drug) is associated with better survival in pancreatic cancer patients. Metformin has been proposed as a useful adjunctive therapy for pancreatic cancer, although well-designed prospective studies investigating the associations of metformin use with pancreatic cancer survival are lacking. Thus, it is impossible to determine whether metformin will enhance the survival of African Americans with pancreatic cancer, further exacerbating the disparities. This project investigated associations between metformin use and duration of metformin use with survival and other clinical outcomes in African American pancreatic cancer patients with pre-existing type II DM. Toriola recently had a manuscript published in Cancer Epidemiology, Biomarkers & Prevention.
Mark Meacham, PhD
A novel high-throughput, ex vivo, vascularized tumor model for pancreatic cancer. This project leveraged an ex vivo, 3D microphysiological device created by their team of oncologists, cell biologists, immunologists, and biomedical engineers to study vascularized tumor biology. The current device consists of a central chamber in which fibroblasts (FB) and endothelial cells (EC) can form vasculature, and connected upper and lower chambers for tumor/non-tumor cells. Newly proposed model systems will recapitulate cancer biology, immunobiology, tumor-induced vasculature formation, and multiple aspects of the tumor microenvironment (TME) in a high-throughput format. The ability to precisely model the complex TME in vitro is crucial for the development of novel diagnostics and therapeutics. This project is developing a platform that recapitulates major features of the pancreatic cancer and robustly mimics human tumor biology and immunobiology for screening treatment combinations.
Kristen Bryant, PhD
Exploiting autophagy for pancreatic cancer treatment. This project builds on Bryant’s preliminary research, which demonstrated that pharmacological inhibition of the MAPK cascade promotes KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) addiction to autophagy; therefore, combining MEK-ERK and autophagy inhibitors could provide a new therapeutic strategy. This project aims to develop additional therapies to exploit the dependency of PDAC on autophagy.
Linda Peterson, MD
Joseph Ippolito, MD, PhD
Targeting pancreatic cancer with sodium glucose transporter 2 (SGLT2) inhibition. The goal of this project is to re-purpose sodium glucose cotransporter 2 inhibitors (SGLT2i) for the treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). SGLT2i are FDA-approved and are an appealing new, class of glucose-lowering therapies that have been shown to improve all-cause survival and decrease major cardiovascular events in patients with type 2 diabetes and in those with heart failure. Normally, SGLT2i block glucose re-uptake in the kidneys resulting in glucosuria that effectively lowers serum glucose. However, exciting new preclinical data show that there may be direct effects on PDAC tumors themselves, as: 1) functional SGLT2 is expressed in human PDAC tumors; 2) glucose uptake through SGLT2 plays a role in PDAC growth and survival in animals with human PDAC xenografts; and 3) treatment with the SGLT2i, dapagliflozin, significantly inhibits PDAC tumor growth and increases tumor necrosis. Thus, SGLT2i may be able to rob PDAC tumors of glucose necessary for growth and function. In addition, SGLT2i have other protective effects including inducing a mild ketonemia (which has anti-tumor effects) as well as reducing visceral obesity, which is associated with worse outcomes in subsets of PDAC patients. Our primary hypothesis is that dapagliflozin is well-tolerated and safe to use in patients with metastatic PDAC. We also hypothesize that dapagliflozin will be efficacious as an adjunct to PDAC front-line chemotherapy assessed by decreased tumor markers mediated by its pleiotropic metabolic effects. To evaluate their hypothesis this project is conducting a phase Ib clinical trial of the SGLT2i, dapaglifilozin, added to standard of care front-line chemotherapy for metastatic PDAC patients.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
SPORE in the News
Recent SPORE Publications
- Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy. Nature Medicine.
- Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nature Medicine.
- KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. Cancer Cell.
- Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression. Immunity.
- Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut.
Investigators and Staff
|Maxim Artyomov, PhD
Project 4 Co-Investigator
Associate Professor of Pathology & Immunology
|Deyali Chatterjee, MD
Biospecimen Core Co-Investigator
Assistant Professor of Pathology & Immunology
|Graham Colditz, MD, DrPH
Biostatistics Core Director & Administrative Core Associate Director
Niess-Gain Professor of Surgery
|David DeNardo, PhD
Project 1 Co-Leader & Administrative Core Associate Core Director
Associate Professor of Medicine, Pathology & Immunology.
|Channing Der, PhD
Project 3 Co-Leader & Career Enhancement Program Co-Director
Sarah Graham Kenan Distinguished Professor of Pharmacology
|Bettina Drake, PhD, MPH
Administrative Core Co-Investigator
Professor of Surgery
|Ryan Fields, MD
Biospecimen Core Director
Professor of Surgery
|Feng Gao, MD, PhD, MPH
Biostatistics Core Biostatistician
Associate Professor of Surgery
|Andrea Wang-Gillam, MD, PhD
Project 3 Co-Leader
Associate Professor of Medical Oncology
|William Gillanders, MD
Project 4 Co-Leader & Career Enhancement Program Director
Mary Culver Professor of Surgery
|Peter Goedegebuure, PhD
Biospecimen Core; Projects 1, 2, & 3 Co-InvestigatorAssociate Professor of Surgery
|William Hawkins, MD, FACS
SPORE Director; Project 2 Co-Leader; Administrative
Neidorff Family and Robert C Packman Professor of Surgery
|Aram Hezel, MD
Project 1 Clinical Trial Co-Leader
Associate Professor of Medical Oncology
|Elizabeth Jaffee, MD
Project 4 Translational Co-Leader
Professor of Oncology
|Daniel Laheru, MD
Project 4 Co-Investigator
Professor of Oncology
|Kian-Huat Lim, MD, PhD
Project 3 & 4 Co-Investigator
Assistant Professor of Medical Oncology
|David Linehan, MD
Project 1 Co-Leader; Developmental Research Program
Seymour I Schwartz Professor of Surgery
|Esther Lu, PhD
Biostatistics Core Biostatistician
Associate Professor of Surgery
|Lee Ratner, MD, PhD
Developmental Research Program Co-Director
Alan A. & Edith Wolff Professor of Oncology
|Maranna Ruzinova, MD, PhD
Biospecimen Core Co-Investigator
Assistant Professor of Pathology & Immunology
|Robert Schreiber, PhD
Project 4 Co-Leader
AM & JM Bursky Distinguished Professor of Pathology & Immunology
|Dirk Spitzer, PhD
Project 2 Co-Investigator
Assistant Professor of Surgery
|Mark Watson, MD
Biospecimen Core Co-Leader
Associate Professor of Pathology & Immunology
|Greg Williams, MA
SPORE Administrative Core