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MAYO CLINIC SPORE IN PANCREATIC CANCERGloria Petersen, Ph.D., Principal Investigator 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: REGULATION OF PANCREATIC CANCER CELL PROLIFERATION AND SURVIVAL BY GSK-3BDaniel D. Billadeau, Ph.D. Pancreatic adenocarcinoma is the most lethal solid tumor challenging Americans today. Although 11th in prevalence, it ranks fifth in cancer mortality. Therefore, urgency is needed to understand the molecular mechanisms underlying the development of pancreatic cancer with the hope that this will lead to preventative and treatment strategies to improve the outcome of the disease. Although the underlying etiology and pathophysiology of pancreatic ductal cancer is poorly understood, there is an increasing body of published work, suggesting that signaling pathways that control cell proliferation, differentiation, and apoptosis are dysregulated in pancreatic cancer. The mechanistic experiments test the central hypothesis that overexpression of GSK-3β contributes to pancreatic cancer cell proliferation and survival and is thus a viable therapeutic target. We hypothesize that: (a) the GSK-3β gene is gained or amplified in a subset of patients with pancreatic cancer; (b) oncogenic K-Ras signaling regulates the expression of the GSK-3β promoter through its effects on Ets-1, Ets-2 and AP-1 transcription factors; (c) c-Src is a regulator of GSK-3β protein overexpression; (d) GSK-3 is required for the development of PDA in the LSL-KRasG12D mouse model of pancreatic cancer; (e) enzastaurin will inhibit GSK-3 function in vivo. In order to test these hypotheses we will (1) determine the mechanism regulating the expression of GSK-3β in pancreatic adenocarcinoma; (2) determine the requirement for GSK-3β in pancreatic cancer pathogenesis; (3) perform a phase II study of enzastaurin and gemcitabine in untreated, metastatic pancreatic cancer patients with metastases amenable to biopsy. Together, our studies will provide invaluable information on the mechanisms regulating the expression of GSK-3β in pancreatic cancer, the role of GSK-3β in pancreatic cancer development and the effect of GSK-3 inhibition in the treatment of pancreatic cancer. Additionally, there is increasing evidence that GSK-3β participates in many human malignancies, thus, information obtained in our studies might advance our understanding of this kinase in other human neoplasms.
PROJECT 2: PANCREATIC CANCER-ASSOCIATED DIABETES: PATHOGENESIS AND BIOMARKERSSuresh T. Chari, M.D. Our long-term goal is to develop screening strategies to diagnose asymptomatic pancreatic cancer (PaC). Up to 80% of PaCs have hyperglycemia and diabetes (DM), which is evident many months prior to the cancer diagnosis and improves following resection of PaC. Conversely, older subjects with new-onset DM have a ~8 fold higher risk of having PaC compared to the general population. Recognition of new-onset DM as an early manifestation of PaC could lead to diagnosis of asymptomatic early stage PaC. We will take our strong and consistent clinical and epidemiological observations to the laboratory to understand the pathogenesis of PaC-associated DM (PaCDM) and identify its biomarkers. Specific Aim 1: To determine if β-cell dysfunction is an early and key defect in PaCDM: DM occurs in insulin resistant states when β-cells fail to compensate for impaired insulin action. The very high prevalence of DM in PaC implies high rate of β-cell failure. We have developed a technique in humans to simultaneously assess β-cell function, insulin sensitivity, and hepatic insulin extraction using 3 radiolabeled glucose tracers. We have used this technique to study subjects with type 2 DM, impaired glucose tolerance and normal glucose tolerance. We will perform similar studies in PaC to determine if β-cell dysfunction is an early and key defect in glucose metabolism in PaCDM. Specific Aim 2: To determine if adrenomedullin (AM) is the mediator of PaCDM: AM is a 52 amino acid peptide hormone expressed in normal human islets that inhibits insulin exocytosis from β-cells. It is markedly overexpressed in PaC and its plasma levels are increased in PaCDM. We hypothesize that AM is the mediator of β-cell dysfunction in PaC. In preliminary studies we have been able to “transmit” DM from a human to SCID mice using a xenograft of PaC from a patient with PaCDM, while a xenograft of PaC from a patient with normal fasting glucose had no effect on glucose levels. In in vitro studies using INS-1, an insulinoma cell line, we have observed that PaC cell lines inhibit glucose-mediated insulin release. Using genetic and pharmacological methods to modulate the expression and action of AM in these in vivo and in vitro models, we will investigate the role of AM in causing PaCDM. Specific Aim 3: To develop a predictive model for PaC among new-onset diabetics: PaCDM is associated not only with high plasma AM levels, but also with older age, obesity and family history of DM. We will measure plasma AM, insulin and glucose levels as well as CA 19-9, the best known tumor marker of PaC, in a large cohort (n=420) of subjects with PaC with and without new-onset DM, new-onset type 2 DM, and healthy and disease controls. We will determine the performance characteristics of AM as a biomarker of PaCDM and develop a predictive model for PaC using laboratory, clinical and demographic predictive factors. If a biomarker of PaC-induced DM is identified, it will have immediate clinical impact as it will allow us to start screening for asymptomatic PaC in the subjects with new-onset DM.
PROJECT 3: HEDGEHOG AND EGF PATHWAY INTERACTION: A NOVEL APPROACH FOR A MULTI-TARGET THERAPY IN PANCREATIC CANCERMartin E. Fernandez-Zapico, M.D. Pancreatic cancer is a deadly disease in which the dismal outcome is primarily attributed to the lack of an effective treatment. Therefore, the need of translational researchers, such as our laboratory, to develop therapies targeting novel biochemical pathways relevant to the pathobiology of pancreatic cancer has never been greater. Our goal is to design studies that are both mechanistic and translational, taking advantage of the knowledge recently generated in our laboratory. These data show a novel pathway that identifies the transcription factor GLI1 as a shared effector for both pancreatic oncogenic pathways, Hedgehog (HH) and Epidermal Growth Factor (EGF), engendering a prosurvival/anti-apoptotic function in pancreatic cancer cells. Thus, we will utilize a comprehensive translational approach (from molecules-to-cells-to animals-to-human) for the molecular and cellular characterization of this pathway as well as the preclinical and clinical testing of its targeted inhibition. Our central hypothesis is that a novel functional interaction between the HH and EGF pathways regulates cell survival via a GLI 1-mediated anti-apoptotic response and targeting of this pathway by a combination therapy will positively impact on the treatment of pancreatic cancer. To address this hypothesis we propose the following aims: AIM 1: (a) To characterize the role of the Hedgehog (HH)-EGF-PI3-AKT-GLI pathway on pancreatic cancer cellular survival using luciferase and chromatin immunprecipitation assays as well as expression of the apoptotic regulators BCL-2, BFL-1/A1 and 4-1BB by PCR and western blot and (b) We will complement these studies with apoptosis assays so as to determine the biological relevance of the PI3K-AKT pathway in HH-EGF-GLI1 survival; AIM 2: To examine that targeted inhibition of the HH-EGF-GLI1 pathway results in specific molecular changes indicative of tumor response by assessing the effect of this combination therapy using the experimental technique Magnetic Resonance Elastography (MRE) in mouse allograft model. We will use genetically manipulated cell lines deficient in pancreatic cancer specific tumor suppressor gene. The added value of this aim is the mechanistic component, which is the evaluation of treatment in the context of specific inactivation of tumor suppressors, a known modulator of therapy response; and AIM 3: To perform a Phase I Trial of the combination Erlotinib (Genentech EGFR inhibitor) and GDC-0449 (Genentech Hedgehog inhibitor) to define the maximum tolerated dose, dose-limiting toxicity, and effects on molecular endpoints in pancreatic cancer subjects. Thus, the knowledge derived from these studies will further our understanding of the complex network implicated in pancreatic carcinogenesis, as well as serve as a foundation for the development of new therapeutic approaches for pancreatic cancer.
PROJECT 4: TO BE ANNOUNCED.
CORE A: ADMINISTRATIVE COREGloria M. Petersen, Ph.D. Core A, the Administrative Core, will continue to 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. 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 the annual 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 resources, such as PACGENE, PANC4, PanCAN, the Phase II Consortium, and the North Central Cancer Treatment Group; 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 COREMariza de Andrade, Ph.D. The Biostatistics Core (BC) provides statistical collaboration and data management support for each of the SPORE projects, the Developmental Research Program projects, the Career Development Program, and the other Cores. In the past funding period, the BC supported research, and established the infrastructure to link the Tissue and Patient Registry Cores. For this competitive renewal, the BC prepared the statistical plans for each of the four Projects, will provide data management for each of the projects, and will prepare data summaries for manuscript preparation. These projects span a wide range of approaches and analyses required. The BC 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 more than 10,000 clinical and basic science research studies since 1966. The BC has capability to provide statistical support across different fields, including molecular epidemiologic studies, basic science with translational, immunologic, and correlative studies, gene microarray and imaging, clinical trials, gene and mutation discovery, and information management. The comprehensive nature of the BC 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 BC also provides a mechanism for the management and integration of both existing and newly collected data through consistent and compatible data handling. Areas of support include 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 BC are our collaboration with each of the projects and cores, the ability to utilize the established centralized research database, the operational and statistical infrastructure already in place in the SPORE, and the breadth of expertise provided by BC personnel.
CORE C: CLINICAL RESEARCH COREGloria M. Petersen, Ph.D. The Clinical Research Core is a newly created resource for the SPORE. It combines the Patient Registry activities that have been ongoing and supported by the SPORE in the previous funding period with the new activities in the proposed funding period related to support for clinical studies in all four translational 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. To date, the pancreatic cancer SPORE’s Patient Registry activities have been very productive, with accrual of over 2,500 consented subjects (~325/year), using ultra-rapid case finding, a necessary method for this rapidly fatal cancer. Mayo Clinic diagnoses and/or treats an estimated 570 pancreatic cancer patients per year across its three campuses. In addition, the Registry includes data on 1513 age, sex, race, and region-matched healthy controls. It coordinates 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 Clinical Research Core will perform the necessary clinical trial management support activities; centrally coordinate all activities with the infrastructure of the Cancer Center CRO to ensure smooth execution of the SPORE’s clinical trials; maintain the ultra-rapid case recruitment and registry of pancreatic cancer patients at all three Mayo campuses; and serve as a resource to future developmental research and career development research projects. 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 COREWilma Lingle, Ph.D. The goal of the Tissue Core is to provide investigators in the Pancreas SPORE with high quality patient data, DNA, RNA, serum, circulating tumor cells, and pancreas tissues from pancreatic cancer patients, and to make these resources available for future studies. The activities of the Tissue Core will be overseen under the combined leadership of Dr. W. Lingle, Director of the TACMA and Co-Director of the BAP Shared Resources of the Mayo Clinic Cancer Center, and Dr. T. Smyrk, anatomic pathologist. The activities of the Tissue Core will be conducted in a way that does not compromise patient confidentiality, yet will be as comprehensive as possible in the materials that are provided. The acquisition of human tissue and subsequent cellular/molecular analysis of that tissue within the context of pathology and patient data are key to many laboratory-based studies of cancer. The Mayo Clinic has a strong tradition of ethically sound support of research that links tissue acquisition and patient data records. Paraffin embedded tissues, histological slides, and associated patient charts from surgeries performed since the first decade of the 1900's are maintained in Mayo’s Tissue Registry and the Mayo Archives. The Tissue and Cell Molecular Analysis (TACMA) Shared Resource of the Mayo Clinic Cancer Center is a resource of expertise and service for immunohistochemistry, laser capture microdissection, tissue microarray preparation, and digital imaging. Likewise, the Biospecimen Accessioning and Processing (BAP) Shared Resource of the Mayo Clinic Cancer Center is the primary site of accessioning and standardized processing of blood, frozen tissue, and other non-paraffin embedded specimens collected explicitly for research. New methodologies for biospecimen collection, processing, and analysis will be developed in the Tissue Core. These methodologies will be shared with other Mayo SPORE Tissue Cores and integrated with services offered by the BAP and TACMA Shared Resources. Tissue Core activities will be closely coordinated with the newly formed Clinical Research Core and with the Biostatistics Core to provide seamless linkage of clinical annotations with research biospecimens. Core D will be integrated with the existing tissue-oriented Cancer Center shared resources and the other scientific Cores in this SPORE in order to provide a coordinated, centralized, dedicated program for standardized collection, accessioning, processing, and evaluation of biospecimens and patient data from pancreatic cancer patients. Furthermore, the Tissue Core will make biospecimens collected for this SPORE available to the pancreas cancer research community in order to stimulate translational research with the goal of improving prevention and treatment of pancreatic cancer.
DEVELOPMENTAL RESEARCH PROGRAMDebabrata Mukhopadhyay, Ph.D. The Mayo Clinic SPORE in Pancreatic Cancer Research makes 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. The DRP will: (1) encourage and solicit innovative translationally-relevant laboratory, population and clinical study proposals; (2) encourage and support interdisciplinary collaboration in translational research in pancreatic cancer; and (3) 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 3 to 5 projects annually. A process has been successfully established to call for applications on an annual basis and to formally peer review submissions utilizing the expertise of the Scientific Advisory Committee and other experienced investigators. Criteria will be based upon scientific merit, originality, qualifications of the key personnel and interactions, and translational potential. It is our experience, and will continue to be anticipated, that support of developmental research projects will result in the generation of new hypotheses that can potentially be addressed in existing SPORE-sponsored projects, or through peer reviewed external grant support. 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 Program Project Grant proposals in the next funding period.
Career Development ProgramDirector: Fergus J. Couch, Ph.D. The Career Development Program of the Mayo Clinic SPORE in Pancreatic Cancer is targeted to junior faculty career development early mid-career faculty who will commit to mentored career development in translational pancreatic cancer research. One of the starkest realities facing the contemporary research community is the paucity of experienced investigators involved in translational pancreatic cancer research. We have recognized the importance of attracting and nurturing individuals who would be committed to a pancreatic cancer research career. The core of senior pancreatic cancer researchers at Mayo Clinic, combined with highly productive investigators in other areas of cancer research, will form mentoring teams. 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. Mayo Clinic also has very competitive recruitment to faculty positions. There thus exists a continuous pool of outstanding scientists and clinicians (including talented female and minority investigators) who are early in their careers and who need exactly an impetus such as that offered by our SPORE’s proposed Career Development Program 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 Career Development Program will build upon the resources allocated to them to develop independent funding in pancreatic cancer research. |
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