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Last Updated: 10/10/18

MAYO CLINIC SPORE IN PANCREATIC CANCER

Principal Investigator:
Gloria Petersen, Ph.D.
Daniel D. Billadeau, Ph.D.

Principal Investigator Contact Information

Gloria Petersen, PhD
Professor of Epidemiology
Mayo Clinic Rochester
Department of Health Sciences Research
200 First Street Southwest
Rochester, MN 55905
Tel: (507) 538-1563
Fax: (507) 266-2478
Email: petersen.gloria@mayo.edu

Daniel D. Billadeau, Ph.D.
Mayo Clinic Rochester
200 First Street Southwest
Rochester, MN 55905
Tel: (507) 284-4308
Fax: (507) 293-0107
Email: billadeau.daniel@mayo.edu

Overall Abstract

The Mayo Clinic SPORE in Pancreatic Cancer has built one of the best environments for translational researchers who are committed to the goal of reducing the incidence and mortality of this devastating malignancy. Tremendous progress has been made in creating an infrastructure that nurtures the conduct of innovative research and interdisciplinary interactions, and which has attracted committed scientists and clinicians. Four translational research projects focus on cutting edge approaches to facilitate early detection and treatment of pancreatic cancer. Four cores (Administrative Core, Biostatistics Core, Clinical Research Core, and Tissue Core) support research in the SPORE. Broad institutional support for investigators and the research infrastructure facilitate the translation of scientific discovery to the patient. Several innovative translational pilot projects are awarded annually through a Developmental Research Program with matching funds from the institution and a Career Development Program supports one junior faculty member each year.

PROJECT 1: NFAT Transcription Factors as Therapeutic Targets in Pancreatic Cancer

Co-Leaders:
Daniel D. Billadeau, Ph.D.
Steven Alberts, M.D.

Despite tremendous scientific efforts aimed at understanding the molecular biology of pancreatic cancer, conventional treatment approaches have had little impact on the course of the disease. Thus, studies identifying key determinants in pancreatic cancer and pancreatic cancer stem cell (CSCs) can provide both biomarkers of pancreatic ductal adenocarcinoma (PDAC) aggressiveness and potentially optimal targets to overcome chemoresistance. We have found that nuclear factor of activated T-cell (NFAT) transcription factors, NFATc1 and NFATc2 (NFATc1/c2) are ectopically expressed in PDAC samples, respectively and that pharmacologic inhibition or RNAi toward NFATc1/c2 reduces PDAC cell growth in vitro and in vivo. Interestingly, we show that expression of a constitutive nuclear NFATc1 in the developing mouse pancreas using p48-cre along with KRasG12D develop invasive PDAC by 16-20 weeks of age, thus demonstrating that NFATc1 is a potent oncogene in this disease. We performed NFATc1 ChIP-seq in order to gain insight into the transcriptional network driven by this oncogenic/inflammatory transcription factor. We identified nearly 1800 NFATc1-target genes, two-thirds of which are dependent on an interaction with STAT3. Significantly, most of the NFAT/STAT3-regulated gene networks are involved in inflammation, proliferation and metastasis. Moreover, we demonstrate for the first time that NFATc1 is enriched in pancreatic CSCs generated from PDAC cell lines and CSC self-renewal is inhibited by pharmacologically targeting NFAT nuclear activity through the use of cyclosporine A (CsA). However, the mechanisms by which NFATs regulate CSC self-renewal and or chemoresistance are unclear. Furthermore, we show that PDAC cell lines, which express NFATc1/c2 are sensitive to CsA and synergize with gemcitabine to kill tumor cells in vitro and limit tumor growth in vivo. Despite these preliminary observations, information regarding NFATc1/c2 target genes in human PDAC is lacking and mechanisms by which NFATc1/c2 regulate pancreatic cancer cell growth remain to be determined. Furthermore it is unknown whether ectopic expression of NFATc1/c2 correlates with specific clinical features of the disease, participates in pancreatic CSC biology, or represents a therapeutic target in the clinic. It is our central hypothesis that: NFATs are important transcriptional regulators in pancreatic cancer, whose expression correlates with high-grade tumors, facilitates tumor cell growth and contributes to pancreatic CSC characteristics.

We will address this hypothesis through the following three specific aims: Aim 1 will identify NFATs and NFAT-dependent target genes in pancreatic cancer. We will analyze the expression of NFATc1/c2 by IHC using PDAC tissue microarrays (TMAs) and correlate with clinical data (e.g. survival, stage, grade, metastasis) and timing of expression in pancreatic intraepithelial neoplasia (PanIN); determine how NFATc1 and STAT3 cooperate to regulate target gene expression; and identify NFATc2-regulated target genes. Aim 2 will determine the role of NFATs in the acquisition of pancreatic CSC properties. We will examine the role of NFATs in pancreatic CSCs using in vitro and in vivo assays measuring CSC growth, survival, de-differentiation and self-renewal; define the regulation of Sox2 expression by NFATc1 in CSCs and impact on de-differentiation; and determine whether pharmacological (CsA) inhibition of NFATs sensitizes pancreatic CSCs to gemcitabine- nab-paclitaxel (abraxane) in vivo. In Aim 3, we will conduct a Phase I study with an expansion cohort for CsA and gemcitabine-abraxane in untreated, metastatic pancreatic cancer (MPC) patients with metastases amenable to biopsy.

PROJECT 2: Targeting NAD catabolism in Pancreatic Cancer Cells: Role of small molecule SIRT1 activating compounds (STACs) in the Therapy of Pancreatic Cancer

Co-Leaders:
Eduardo N. Chini, M.D., Ph.D.
Amit Mahipal, M.B.B.S., M.P.H.

It has been known since the seminal discoveries of Otto Warburg in the early 1900’s that cancer cells have unique metabolic features. However, it was not until recently that cancer cell metabolism became the focus of intense investigation. In particular, tumor cells undergo metabolic adaptations and have highly active glycolytic, pentose and fatty acid synthesis pathways. All of these metabolic changes contribute to increased tumor cell survival, proliferation and metastasis. Nicotinamide adenine dinucleotide (NAD) is central for these metabolic changes and cellular levels of NAD must be balanced to modulate these processes. A systematic analysis of the metabolism of NAD has not been performed in pancreatic cancer cells. NAD metabolism is regulated at the level of synthesis and degradation, and a decrease in cellular NAD levels leads to metabolic collapse and cell death. Recently, unique features of NAD metabolism have been described in cancer cells, opening the possibility that targeting NAD synthesis and/or degradation may lead to cancer specific metabolic collapse and serve as new therapy for a variety of human tumors including pancraeric cancer. Hence, we propose that activation of NAD degradation or inhibition of its synthesis will lead to a decrease in pancreatic cancer cell NAD levels and metabolic collapse, with subsequent tumor cell growth arrest and cell death. The central hypothesis is that increasing NAD degradation (by activation of the enzyme SIRT1 with small molecules) or inhibiting its synthesis (using inhibitors of the enzyme Nampt) will cause metabolic collapse resulting in antitumor activity by itself and may also increase the antitumor activity of other chemotherapeutic agents. The hypothesis will be tested by the following aims: Aim 1 will perform mechanistic studies on the effect of STACs in pancreatic cancer cells. We will characterize the mechanisms causing SIRT1 susceptibility to increased activation by STACs in pancreatic cancer cells; and characterize the mechanisms that lead to STACs induced cell death: Role of NAD catabolism and energy metabolism in cell fate. Aim 2 will perform pre-clinical studies with STACs and current chemotherapeutic agents (gemcitabine and paclitaxel) used in pancreatic cancer and define potential mechanisms of resistance. We will: determine the effect of STACs in animal models of pancreatic cancer; and define the impact of STACs on the response to chemotherapeutic agents (gemcitabine and taxol) both in vitro and in animal models of pancreatic cancer. Aim 3 will perform a phase I trial with an expansion cohort using the SIRT1 activator SRT3025 combined with gemcitabine and nab-paclitaxel (Taxol) in patients with pancreatic cancer. We will define the recommended phase 2 dose of SRT3205 combined with gemcitabine and nab-paclitaxel using a bivariate continual reassessment method, and analyze in biopsies SIRTUINs, CD38, Nampt, and markers of metabolic collapse such as phospho-AMPK, p21, and activated caspase 3.

PROJECT 3: Optimal Pairing of Chemotherapy with Immunotherapy for Pancreatic Cancer

Co-Leaders:
Peter A. Cohen, M.D.
Sandra Gendler, Ph.D.

The overarching goal of this project is to implement and validate an effective immunotherapeutic treatment for advanced pancreatic ductal adenocarcinoma (PDAC).Recent evidence indicates that human PDAC is vulnerable to immune recognition and rejection. This raises the challenge of identifying immunotherapy strategies for PDAC that are not excessively labor intensive, that consistently prolong survival, and that ideally are curative. In our effort to develop effective off-the-shelf immunotherapy against PDAC, we discovered that repetitive administration of cyclophosphamide (CY) alternating with TLR agonists (TLRa) is therapeutically as or more effective than the classically synergistic combination of CY and T cell adoptive therapy. Off-the-shelf CY+TLRa treatment is much less labor intensive than adoptive therapy, is well tolerated, and is often sufficient to cure syngeneic wildtype mice of advanced PDAC tumors. Remarkably, CY+TLRa’s therapeutic efficacy is fully abrogated by depleting host CD4+ and CD8+ T cells and NK cells, indicating that CY+TLRa successfully maintains an endogenous anti-tumor immune response even in the absence of adoptive therapy or vaccine maneuvers. An additional unique therapeutic feature is CY+TLRa's ability to convert rebounding myeloid progenitors into tumoricidal macrophages, thereby preventing tumors from differentiating them into myeloid-derived suppressor cells. In Aim 1, we will fully delineate the mechanism by which CY+TLRa treatment is therapeutically effective against mouse PDA models, thereby maximizing translatability. We hypothesize that repetitive contraction and homeostatic proliferation promotes and sustains the natural endogenous anti-tumor T cell response, while rebounding myeloid progenitors are induced to become surprisingly effective TM1 by the combination of stimuli from endogenous T cells and exogenous TLRa. In Aim 2, we will perform integrated Phase I/II trials designed to elicit maximal therapeutic synergy when patients with advanced PDA receive a novel TLR8 agonist, VentiRx-2337, with CY as 2nd line therapy. In Aim 3 we will complete development of a “chemo+TLRa friendly” vaccine strategy capable of priming T cell responses to tumor-associated (hypoglycosylated) MUC1, which is hyperexpressed by >90% of human PDA tumors. We hypothesize that incorporation of vaccine into the CY+TLRa strategy will therapeutically potentiate future clinical trials in advanced unresectable PDA.

PROJECT 4: TARGETING DNA REPAIR IN SELECTED PATIENTS WITH PANCREATIC CANCER: AN APPROACH TO INDIVIDUALIZED TREATMENT

Co-Leaders:
Fergus J. Couch, Ph.D.
Robert R. McWilliams, M.D.

Attempts to improve therapy for pancreatic adenocarcinoma patients have largely failed to meaningfully improve survival. Therefore, there is a critical need for identification of specific molecular changes that define prognosis and guide therapy decisions. Mutations in the BRCA1 and BRCA2 cancer susceptibility genes, which are associated with defects in homologous recombination repair (HRR) of DNA double strand breaks, are prime examples of such predictive and prognostic biomarkers. Specifically, BRCA1 and BRCA2 mutations are associated with hypersensitivity to PARP inhibitors, which accentuate the formation of DNA double strand breaks in HRR deficient cells. While mutations in BRCA1, BRCA2, PALB2 and ATM are associated with 5% to 8% of pancreatic cancer patients, alterations in other genes that also confer sensitivity to PARP inhibitors, may be present in 15% to 20% of pancreatic tumors. We hypothesize that PARP inhibitor therapy will improve survival for pancreatic cancer patients, when patients are selected for defects in the HRR machinery. We propose to investigate the impact of rucaparib (CO-338) on HRR deficient pancreatic cancer cells based on preclinical studies showing that rucaparib is cytotoxic to BRCA2 deficient cells and has greater effects on HRR deficient pancreatic cancer cells than other PARP inhibitors. In Aim 1 we will characterize the influence of mediators of HRR activity on response to PARP inhibitors in pancreatic cancer. In particular, we will assess whether defects in cancer susceptibility genes and somatic alterations in genes implicated in HRR deficiency influence rucaparib response in pancreatic cancer cells. In Aim 2 we will investigate the ability of DNA instability and gene expression-based models that identify DNA damage response deficient tumors, to predict response to chemotherapy in pancreatic tumors. In Aim 3 we will conduct a Phase II study of rucaparib in chemotherapy refractory HRR deficient pancreatic cancer. We will select participants by rapidly screening patients for defects in HRR associated genes using a rapid throughput DNA repair gene sequencing test. In vitro cell line models and patient materials from the phase II trial will then be used to explore mechanisms of resistance to rucaparib.

CORE A: ADMINISTRATIVE CORE

Co-Director:
Gloria M. Petersen, Ph.D.

The Administrative Core will provide organizational support for the leadership of the SPORE, facilitate communication among the component activities of the SPORE, serve as the home for pancreatic cancer SPORE advocate activities, and provide an organizational portal for collaborations outside the SPORE. The Administrative Core will work across all three Mayo Clinic campuses using the institutional infrastructure for communications to ensure that investigators are seamlessly integrated as a SPORE organization. Core A’s functions are to: 1) Provide leadership and coordination between the Research Projects and Cores of the SPORE; 2) Assure ongoing integration and participation of the Pancreatic Cancer SPORE in the activities of Mayo Clinic Cancer Center; 3) Organize monthly meetings of the SPORE investigators; 4) Organize yearly research retreats and meetings of the External Advisory Committee; 5) Organize meetings of the SPORE Scientific Advisory Committee as needed; 6) Organize monthly meetings of the SPORE Steering Committee; 7) Provide administrative support to the Developmental Research Program; 8) Provide administrative support to the Career Development Program; 9) Facilitate investigator trips to relevant SPORE meetings in the mid-Atlantic region; 10) Facilitate activities of the pancreatic cancer SPORE advocates; 11) Prepare the yearly non-competing SPORE application; 12) Serve as the administrative liaison between the Mayo Clinic SPORE and the NCI SPORE Program, other SPOREs, and collateral organizations; 13) Maintain the Mayo Pancreatic Cancer SPORE websites that will be useful to investigators inside and outside the SPORE, as well as patients; 14) Coordinate information and communication about SPORE-related research developments to and among the Mayo Clinic SPORE investigators, to the scientific community at large, and to the public.

CORE B: BIOSTATISTICS CORE

Co-Director:
Ann Oberg, Ph.D.

The Biostatistics Core provides statistical collaboration and data management support for each of the SPORE projects, the developmental projects, and the other Cores. In this competitive renewal, the Biostatistics Core has been very active in preparing the statistical plan for each Project. In addition, the Biostatistics Core continues to provide data management for each of the projects, adverse event monitoring for the clinical trials, and prepares data summaries for manuscript preparation. These projects span a wide range of approaches and analyses. The Biostatistics Core builds upon the innovative and time-tested procedures and systems developed by Mayo Clinic, one of the largest statistical groups in the country whose members have collaborated on clinical and basic science research studies since 1932. The Biostatistics Core will provide statistical support across different fields, including epidemiological studies, basic sciences including translational and immunologic correlative studies, gene expression and imaging, clinical trials, gene and mutation discovery, next generation sequencing and information management. The comprehensive nature of the Biostatistics Core assures each SPORE investigator access to statistical expertise that includes collaborative development of study designs and analysis plans, state of the art data analysis and interpretation, data management resources, and abstract and manuscript preparation. The Biostatistics Core also provides a mechanism for the management and integration of both existing and newly collected data through consistent and compatible data handling, database development, data form development and processing, data collection and entry, data archiving, quality control, and management of information relating to the projects and cores. This Core complements and assists the efforts of the Clinical Research and Tissue Cores by providing superior data management and experience with tissue registries. The strengths of the Biostatistics Core are our collaboration with each of the projects and cores, the ability to utilize the established centralized research database as well as the operational and statistical infrastructure already in place in the SPORE, and the breadth of expertise provided by Biostatistics Core personnel.

CORE C: CLINICAL RESEARCH CORE

Co-Directors:
Gloria M. Petersen, Ph.D.
Wen Wee Ma, M.B.B.S.

The Clinical Research Core combines the ongoing Patient Registry activities with the new clinical trial activities in all four translational research projects in the proposed funding period. The aims of the Clinical Research Core are to: 1) perform the necessary clinical trial management support activities; 2) centrally coordinate all activities with the infrastructure of the Cancer Center CRO to ensure smooth execution of the SPORE’s early-phase clinical trials; 3) perform all patient recruitment activities for the clinical trials in the SPORE projects; 4) maintain the ultra-rapid case recruitment and registry of pancreatic cancer patients; and 6) serve as a resource to future Developmental Research Program and Career Developmental Program research projects. The directors of this Core have extensive experience in studies of human subjects and recruitment of patients to research protocols, both for observational studies and clinical trials. Mayo Clinic diagnoses and/or treats an estimated 650 pancreatic cancer patients per year across its three campuses. To date, the pancreatic cancer SPORE’s Patient Registry activities have been very productive, with accrual of 5,395 consented subjects, using ultra-rapid case finding, a necessary method for this rapidly fatal cancer. There are 3,121 pancreatic adenocarcinoma cancer patients in the Registry. In addition, the Registry includes data on over 2,500 age, sex, race, and region-matched healthy controls. It will coordinate its activities very closely with the Biostatistics Core and the Tissue Core to ensure the highest quality annotated biospecimens and pancreatic cancer database for research. The close coordination and oversight of the most senior leaders of the SPORE will ensure that all clinical research activities are performed with the highest level of research integrity and adherence to all human subjects regulations.

CORE D: TISSUE CORE

Co-Directors:
Thomas Smyrk, M.D.
Lizhi Zhang, M.D.

The Tissue Core of the SPORE is responsible for accessioning and processing new biospecimens and to make them available for use in the four SPORE translational research projects and as needed for the Developmental Research and Career Developmental Programs. The Tissue Core will provide sample accessioning and pathology support for the early phase clinical trials as needed in these projects. The Tissue Core Director and Co-Director are highly experienced pancreatic pathologists. Biospecimens will also be made available to other intra- and extra-mural investigators engaged in pancreatic cancer translational research. Requests for biospecimens will be reviewed by the Biospecimen Access Committee for Pancreatic Cancer (BACPaC), with consideration given primarily to scientific merit and availability of specimens and their associated data needed for analysis. Input from the Biostatistics and Clinical Research Core is included in the evaluation of requests for tissues. The pathologists in the Tissue Core will provide detailed annotations in the SPORE's pancreatic cancer tissue database for frozen and formalin-fixed paraffin-embedded tissues of all available patients who have been resected for pancreatic cancer at Mayo Clinic. The pathologists will also interpret IHC staining and provide other pathology support such as evaluating pancreas samples from transgenic or knockout mouse models. The Tissue Core will coordinate with the Mayo Clinic Cancer Center Biospecimen Accessioning and Processing (BAP) Shared Resource to process blood samples to provide genomic DNA and serum aliquots, and with the Pathology Research Core (PRC) Shared Resource to provide histology and other tissue-based services, including paraffin and frozen sectioning, immunohistochemistry, tissue microarray construction, and digital imaging. Working closely with existing infrastructure such as these shared resources minimizes redundancy of services and utilizes existing experience and state of the art equipment.

DEVELOPMENTAL RESEARCH PROGRAM

Director:
Daniel Billadeau, Ph.D.

The Mayo Clinic SPORE in Pancreatic Cancer Research will make every effort to maximize the number of innovative and high-quality projects in the Developmental Research Program (DRP). The goal of the DRP is to support innovative, scientifically sound research projects from which findings can be translated into clinically relevant applications that will impact screening, diagnosis, and management of pancreatic cancer. Awards in the past 5 years have resulted in support for 26 of 64 (41%) DRP applications. These meritorious projects have yielded important new insights about pancreatic cancer and have led to extramural funding, including contributions to the full translational research projects in this current SPORE application. The Specific Aims of the DRP are to: (1) Encourage and solicit innovative translationally-relevant laboratory, population and clinical study proposals and support interdisciplinary collaboration in translational research in pancreatic cancer; (2) Conduct a thorough evaluation of all applications for the DRP award; (3) Evaluate and monitor progress of DRP awardees; and (4) Facilitate opportunities for extramural funding and integration into future SPORE projects. These projects will generate new hypotheses that can be tested in larger-scale research projects or clinical trials that can impact pancreatic cancer. The DRP will provide up to $50,000 (utilizing funds from both the SPORE grant and institutional resources) to 2 to 3 projects annually. There will be the possibility of a second year of support based on progress. A successfully established process will call for applications on an annual basis and to formally peer review submissions utilizing the expertise of the Scientific Advisory Committee and others as needed, including our Advocates. Criteria will be based upon scientific merit, originality, qualifications of the key personnel and interactions, and translational potential. It is the intent of the SPORE leadership to encourage and help the investigators to use the data generated by these projects to design either R01-type grants or similar extramural proposals in the next funding period.

Career Enhancement Program

Director:
Debabrata Mukhopadhyay, Ph.D.

One of the starkest realities facing the contemporary research community is the paucity of experienced investigators involved in translational pancreatic cancer research. The goal of the Career Enhancement Program (CEP) is to attract, develop, and monitor the most promising investigators for translational research in pancreatic cancer. The CEP is targeted to both junior faculty and early mid-career faculty at any Mayo Clinic campus who will commit to mentored career development. We have attracted and nurtured individuals who are now committed to a pancreatic cancer research career. The corps of senior pancreatic cancer researchers at Mayo Clinic, combined with highly productive investigators in other areas of cancer research, form mentoring teams. Mentoring is accompanied by close oversight by the SPORE leadership team. The Director of the CEP will report to the SPORE Director and the SPORE Steering Committee. Mayo Clinic has, by its seamless blend of patient care and basic and applied research facilities, an environment conducive to this type of mentored translational research. Because Mayo Clinic is competitive in recruiting faculty, there is a continuous pool of early but outstanding scientists and clinicians (including talented female and minority investigators) who need an impetus such as that offered by our SPORE’s proposed CEP to engage in translational research with a focus on pancreatic cancer. We will continue to implement our formal mechanisms for recruiting, selecting and evaluating awardees, and will ensure that awardees are integrated into the SPORE research environment. In all cases, we expect that recipients in the CEP will build upon the resources allocated to them to develop independent funding in pancreatic cancer research. The explicit expectation is that the awardees will utilize the resources made available to them for the development of independent research programs and acquisition of independent funding in breast cancer research. One annual award for up to $100,000 will be made.