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Pancreatic SPORE ProjectsThe 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.
In addition to these research projects, the SPORE grant provides funding for a developmental research program for pilot grants to explore innovative research ideas, and a career development program to nurture the next generation of pancreatic cancer scientists. The SPORE grant also provides core resources for the pancreatic cancer scientists, including administrative support, tissue and serums, a comprehensive patient registry, and biostatistics support. Project 1: Regulation of Pancreatic Cancer Cell Proliferation and Survival by GSK-3βPrincipal Investigators: Daniel D. Billadeau, Ph.D. and George Kim, M.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:
In order to test these hypotheses we will:
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. Back to topProject 2: Pancreatic Cancer-associated Diabetes: Pathogenesis and BiomarkersPrincipal Investigators: Suresh T. Chari, M.D. and George Klee, M.D., Ph.D. Our long-term goal is to develop screening strategies to diagnose asymptomatic pancreatic cancer (PaC). Up to 80 percent 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. Back to topProject 3: Hedgehog and EGF Pathway Interaction: A Novel Approach for a Multi-Target Therapy in Pancreatic CancerPrincipal Investigators: Martin E. Fernandez-Zapico, M.D. and Charles Erlichman, 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: Specific Aim 1:
Specific Aim 2: To examine whether 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 a mouse allograft model. We will use genetically manipulated cell lines deficient in pancreatic cancer specific tumor suppressor gene. Specific 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. Back to topProject 4: Optimal Immunotargeting of MUC1 for Pancreatic CancerPrincipal Investigators: Peter A. Cohen, M.D. and Sandra J. Gendler, Ph.D. Cancer of the pancreas carries an overall dismal prognosis regardless of its stage at diagnosis, and improved therapeutic outcomes are urgently needed for this type of cancer. The nearly global aberrant hyperexpression of MUC1 in human pancreatic cancer affords a ready opportunity to target this disease immunologically. While mouse data demonstrate the potential value of reversing tolerance to this self-Ag, therapeutic responses to MUC1-directed immunotherapy remain disappointing. This appears to be due to the natural thymic deletion of high avidity responses to self-Ags such as HER2neu and MUC1, and the persistence of only low avidity responses in the residual tolerized state. It is now possible routinely to reverse such tolerance to self-Ag by exposing T cells to Ag-pulsed dendritic cells (DCs). We have also demonstrated that IL-12 producing DCs can not only reverse tolerance, but can also up-modulate T cell avidity to enable much enhanced targeting of tumor-associated self-Ags. Such reversal of tolerance, however, must occur within an integrated approach to immunotherapy. We and others have demonstrated that immunotherapy is most successful when:
We hypothesize that all three components can be achieved for pancreatic cancer through an intregrated immunotargeting of MUC1. We will employ previously validated algorithms to identify MUC1-derived "promiscuous 15mers" which can stimulate both CD4+ and CD8+ high avidity T cell responses to MUC1 when presented in the context of IL-12 producing DCs. The nearly ubiquitous expression of MUC1 in pancreatic cancer, the broad immunogenicity of promiscuous 15mers regardless of patient HLA-DR haplotype, and the synergizing potential of gemcitabine constitute a promising immunotherapy strategy applicable to most patients with pancreatic cancer. Aim 1 will optimize these components of therapy in a valid tolerized mouse model of MUC1-expressing pancreatic cancer. Aim 2 will identify the critical MUC1-derived immunogenic peptides essential to implement this integrated strategy in clinical trials. Back to top |
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