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Last Updated: 02/21/17

SPORE in Gastrointestinal Cancer

University of Michigan

Principal Investigator:
Dean E. Brenner, M.D.

OVERALL ABSTRACT

A Specialized Program of Research Excellence (SPORE) entitled "Translational Research in Gl Cancer'' is proposed to tap the vast intellectual and physical resources of the University of Michigan to decrease the morbility and mortality from pancreatic and colorectal cancers. The SPORE will address the hypothesis that identifying and developing interventions to address molecular events that enhance cellular carcinogenesis or cellular transformed phenotype will reduce the morbidity and mortality associated with colorectal and pancreatic cancers through risk identification, preventive interventions, early detection, or improved treatment of invasive cancer. This integrated translational research program consists of four major projects that explore 1) fish oil intervention as a chemopreventive for colorectal cancer; 2) development and validation of biomarkers for the early detection of pancreatic and colorectal cancer using glycoproteomics methods; 3) targeted inhibition of Chk1 as a mechanism to reduce repair of radiation induced damage to pancreatic cancer; and 4) improved treatment of pancreatic cancer through targeted inhibition of ATDC to reduce DNA damage response. These major translational projects are complemented by Career Development and Developmental Research Programs that identify new risk assessment, preventive and treatment targets for colorectal and pancreatic cancers. All SPORE studies will be supported by three Core Resources (Administrative, Biostatistics and Informatics, and Biosample). The SPORE is a fully integrated component of the University of Michigan Comprehensive Cancer Center. The SPORE is also integrated into the University of Michigan's Institute for Clinical and Health Research, a new translational research resource for the Medical School and Health Sciences Campus. The SPORE integrates other SPORE programs and links the National SPORE program to other national cancer research resources such as the Early Detection Research Network and the Southwest Oncology Group. This GI SPORE places premiums on rigorous scientific review of its translational research programs, pairing of basic and clinical investigators, drawing on the expertise of diverse scientists, and utilizing flexibility to fund promising new research approaches. The interaction of our multidisciplinary group of investigators makes the GI SPORE at the University of Michigan Comprehensive Cancer Center greater than the sum of its individual parts.

PROJECT 1: OMEGA-3 FATTY ACIDS AND COLORECTAL CANCER PREVENTION

Project Co-Leaders:
Dean Brenner, M.D.
William Smith, Ph.D.

There is a need to identify and develop more favorable therapeutic index-based cancer preventive interventions. The overall goal of this project is to test the hypothesis that substituting w3 fatty acids for w6 fatty acids in colorectal mucosal membranes will sufficiently modify the ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) available to prostaglandin-H synthases (PGHS)-1 and 2 to reduce local prostaglandin (PG) E2 concentrations. Reduction of colonic mucosal PGE2 will reduce the carcinogenesis stress and ultimately reduce the development of neoplasia in the colonic epithelium. We also hypothesize that the dose of fish oil sufficient to reduce local PGE2 can be predicted by plasma EPA: AA ratio and thus be individualized. The reduction of PGE2 concentrations sufficient to reduce proliferation and enhance apoptosis of the colorectal mucosal crypt may be searched. Aim #1 will define the dose response to dietary fish oil in mice and the relationship between the plasma and colonic mucosal EPA:AA ratio upon reduction of PGE2 in colonic mucosa of PGHS-1 and -2 wild type mice will be fed diets formulated to match multiple human fatty acid intakes. The plasma and colonic mucosal EPA:AA ratios and PGE2 concentrations in colonic mucosa and urine will be assayed. Data in Aim 1 are necessary to define the design of a Phase I clinical trial proposed in Aim 2. The clinical trial will determine if fish oil supplementation in humans on a normal diet can produce a colorectal mucosal and plasma EPA: AA ratio defined in the mouse models that will reduce colorectal mucosal PGE2, reduce colorectal crypt proliferation index and enhance apoptosis indices. A Bayesian driven biomarker adaptive phase I design individualizes dose on the basis of individual biomarker response. The data obtained in this project will determine the feasibility, future design and biomarker endpoints of Phase II clinical trials of w3 fatty acids as potential preventives of colorectal adenocarcinoma.

PROJECT 2: MARKERS OF PANCREATIC CANCER USING A GLYCOPROTEOMIC APPROACH

Project Co-Leaders:
Mack Ruffin, M.D.
David Lubman, Ph.D.

Pancreatic cancer places a significant burden on society and has no effective early detection method. A glyco-microarray approach will be used to search for early detection biomarkers of pancreatic cancers in human plasma. We will use multi-dimensional liquid phase fractionation of intact N-linked plasma glyco­ proteins previously isolated by lectin affinity columns. The multi-dimensional fractionation will involve non-porous chromatography to separate the glycoproteins and liquid capillary isoelectric focusing to separate protein isoforms, thus providing a means to collect isolated glycoforms in liquid phase for further analysis. UV absorption detection will allow profiling of changes between cancer versus control. Proteins of interest will be identified by mass spectrometry. These fractions will be spotted on nitrocellulose-coated microscope slides to produce a natural glycoprotein microarray, and will be interrogated by various fluorescently-labeled lectins to probe each microarray spot for the presence of different glycan moieties. Patients with pancreatic adenocarcinoma, pancreatic mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neo­ plasms (IPMNs}, chronic pancreatitis, Type II diabetes for 10 or more year, and normal patients will serve as the disease categories of interest. Plasma from 30 participants per category will be analyzed to search for patterns that can discriminate patients with MCNs/IPMNS from the other disease categories. Glyco­ proteins that reveal such changes will be analyzed by QIT-TOF (MALDI-MSn) mass spectrometry to examine the detailed changes in glycan structure that may serve as biomarkers. Once the potential bio-markers are identified, high throughput antibody arrays will be used to establish information necessary to plan a validation study. This will include initial analytical validation to define the within and between individual variability using 30 participants per disease category. Next, preliminary decision analysis will be per-formed on an open label set of assays from 50 participants per disease category. Finally, a blinded set of assays will be done on 95 participants per disease category. This systematic approach to examining the analytic characteristics of the assay will provide information required to plan a validation of these early detection biomarkers for pancreatic cancer. It is envisioned that these biomarkers could be used for early detection among high risk groups such a smoker, patients with long term Type II diabetes or chronic pancreatitis.

PROJECT 3: MECHANISM-BASED USE OF Chk1 INHIBITORS IN PANCREAS CANCER

Project Co-Leaders:
Theodore Lawrence, M.D., Ph.D.
Jonathan Maybaum, Ph.D.

A strategy that shows great promise for treating pancreatic cancer is to combine cytotoxic treatments with agents that abrogate the already-tenuous checkpoint functionality exhibited by most tumor cells. Drugs that target the checkpoint protein Chk1 (such as AZD7762, currently in Phase-I clinical trials) are of particular interest in the context of pancreatic cancer because Chk1 has also been shown to have a critical role in mediating the activity of Rad51, a key protein in homologous recombination repair (HRR} that is associated with resistance to DNA damaging treatments, and is upregulated in human pancreatic tumors. The long­ term goal of our work is to improve the outcome of patients with pancreatic cancer by rationally adding Chk1 inhibitors to the combination of Gem and radiation.

Our preliminary data demonstrate that both chemo- and radiosensitization by AZD7762 vary substantially among human pancreatic tumor cell lines, and that under conditions of sensitization, AZD7762 affects several endpoints related to HRR. We also found that endpoints related to G2/M checkpoint abrogation reflected sensitization in some cases but not in others. Specific Aim 1 is to determine the mechanisms by which AZD7762 treatment affects HRR activity and sensitivity to Gem and IR in pancreatic cancer cell lines, in vitro. This work will allow us to identify mechanism-based molecular endpoints to be interrogated in future clinical studies, and to identify new targets for therapeutic intervention, related to HRR activity.

Although the mechanistic basis for therapeutic effects of Chk1 inhibitors is not yet completely understood, our data in vitro and in vivo already provide strong motivation for conducting an initial clinical trial. Specific Aim 2 is to use xenograft models to establish the basis for conducting a clinical trial combining AZD7762 with Gem and radiation. The results of Aim 2 will help to define the design of our subsequent clinical trial.

Specific Aim 3 is to carry out a clinical trial using AZD7762 in combination with Gem and radiation in patients with resected pancreatic cancer. We will use a combination of Gem and radiation followed by Gem alone, combined with dose-escalating AZD7762, based on the schedule suggested in Aim 2. We hypothesize that the MTD for AZD7762 will be similar to that determined in the current phase I trials using Gem alone (i.e. that adding conformal radiation will have a minimal impact on the MTD of AZD7762 in combination with Gem). Also, we hypothesize that AZD7762 will inhibit Chk1 activity in surrogate normal tissues when administered at the MTD, and, possibly, at lower doses.

PROJECT 4: ATDC AS A THERAPEUTIC TARGET IN PANCREATIC CANCER

Project Co-Leaders:
Diane Simeone, M.D.
Mats Ljungman, Ph.D.

Pancreatic cancer is a deadly disease characterized by late diagnosis, aggressive invasion of surrounding tissues, early metastasis, and resistance to therapy. The molecular basis of pancreatic cancer is incompletely understood. We have recently found that the majority of human pancreatic adenocarcinomas specifically over-express the gene for Ataxia-Telangiectasia Group D Complemented (ATDC). The ATDC gene was initially described in association with the genetic disorder ataxia-telangiectasia (AT) but was later found not to be the gene responsible for that disorder, and its function remained unknown. We have found that high levels of expression of endogenous ATDC confer a growth advantage of pancreatic cancer cells both in vitro and in vivo by stabilization of beta-catenin. We have also identified ATDC as a novel DNA damage response gene that confers a survival advantage to pancreatic cancer cells exposed to irradiation therapy (RT) or the chemotherapeutic drug gemcitabine which are agents used for standard care of pancreatic cancer patients. We show that ATDC traffics to the nucleus and that loss of ATDC results in radioresistant DNA synthesis and a defect in downstream cell cycle checkpoint activation signaling. In this proposal, we will investigate the molecular mechanisms by which ATDC functions in the response to the combination of ionizing gemcitabine and RT. The experiments will test the hypothesis that ATDC is an important stress response regulator in both ATM- and ATR-mediated signaling cascades. Furthermore, we will analyze the effect of targeting ATDC in combination with gemcitabine and RT as a therapeutic modality in pancreatic cancer using a xenograft mouse model and immunoliposomes carrying ATDC-targeting shRNA. The results from these preclinical animal studies will be used as a guide in the development of a clinical trial where ATDC will be targeted in pancreatic cancer cells prior to standard treatment with gemcitabine and RT. We propose that ATDC is a promising novel therapeutic target for both slowing the growth of pancreatic tumors as well as making them more susceptible to treatment with the combination of gemcitabine and RT.

CORE A: ADMINISTRATIVE CORE

Core Director:
Dean Brenner, M.D.

Core Co-Director:
Diane Simeone, M.D.

The University of Michigan Cancer Center GI SPORE Administrative Core is responsible for leadership, guidance, and management. The Administrative Core oversees all aspects and performs numerous duties across the expansive scope of the SPORE. These duties are to: 1. Provide scientific leadership, oversee scientific progress, ensures integration and asserts translational focus of all components of the Gl SPORE. 2. Provide logistical and coordinating support for all GI SPORE operations; 3. Manage and oversee the budgets of all SPORE components; 4. Administer developmental research projects and career development awards; 5. Facilitate interactions between the GI SPORE, other SPOREs, and the NCI; 6. Communicate with NCI program staff and coordinate submission of required reports; 7. Ensure recruitment of underserved minorities to all GI SPORE projects and research support opportunities; 8. Assure compliance with regulations regarding animals in research; 9. Coordinate with the Biostatistics and Bioinformatics Core, the Cancer Center's Clinical Trials Office, and support GI SPORE translational research in humans, and to ensure compliance Good Clinical Practice. Dean E. Brenner, M.D. will serve as principal investigator of the Administrative Core. Dr. Brenner will oversee the day to day operations including all SPORE functions, budget, scientific and administrative decisions. He will serve as Chair of the SPORE Operations Committee and signs off on all Operations Committee decisions. Diane Simeone, M.D. will serve as co-principal investigator of the Administrative Core. A co-program director of the Cancer Center GI Program, she serves as a critical link to the GI Program. She will oversee the Career Development and Developmental Research Programs and she will oversee the use of SPORE discretionary funds. She will organize the joint SPORE and GI Program retreats. Ms. Mary Rexer-Biuhm will serve as interim SPORE administrator until a permanent administrator is appointed. Ms. Rexer-Biuhm has provided administrative support for 10 SPORE submissions over the last 13 years for the University of Michigan Cancer Center and serves as the administrative supervisor for the SPORE Program Managers. This Core provides the framework to support the success and the mission of the UMCCC SPORE as a cohesive group of investigators committed to the development of translational research in GI cancers.

CORE B: BIOSAMPLE CORE

Core Director:
Thomas Giordano, M.D. Ph.D.

The overarching mission of the GI SPORE Biosample Core is to collect, catalogue and distribute human biological samples with associated pertinent clinical data to the projects to facilitate translation research and help them accomplish their specific aims. The Biosample Core will be housed and administered within the Department of Pathology to ensure uncompromised patient care and confidentiality. The explicit goals of the Biosample Core include: (1) Uncompromised pathology diagnosis and patient care. Tissues will collected with informed consent under IRB-approved protocols and patient confidentiality will be protected. (2) Prospective procurement and processing of colonic and pancreatic tissues from resection specimens. The Biosample Core with work closely with and enhance the existing Tissue Procurement Service to obtain high­ quality tissue samples not needed for diagnosis. (3) Prospective collection of blood and serum from patients with colorectal and pancreatic cancer, both pre-operative and post-operative. (4) Expert pathology review of colonic and pancreatic tissues. Internationally recognized colonic and pancreatic pathologists will review all collected tissues and assist with selection of tissues for tissue array construction and interpretation of immunohistochemically-stained slides. (4) Data management. Pertinent pathologic and clinical information will be collected and managed in conjunction with GI SPORE Biostatistics and Bioinformatics Core and the Bioinformatics Group at Dartmouth Medical College. (5) Tissue array construction for validation studies. In conjunction with the UMCCC Tissue Core, the Biosample Core will construct colonic and pancreatic tissue arrays from archival pathology material. (6) Assist in tissue-based gene expression and biomarker validation studies, such as immunohistochemistry and automated in situ protein detection. Collectively, the many services of the GI SPORE Biosample Core will facilitate translational research and enhance the resources of other NCI-supported networks and groups.

CORE C: BIOSTATISTICS AND INFORMATICS CORE

Core Director:
Daniel Normolle, Ph.D.

The Specific Aims of the Biostatistics and Informatics Core are:

  1. To provide expertise in hypothesis formulation, experimental design, project monitoring, data analysis and data presentation and reporting to the primary projects, developmental research projects, career development projects and cores of the GI SPORE.

  2. To ensure that data collected in clinical, pre-clinical and translational research is promptly, reliably and securely acquired, stored, recovered and distributed, and to support the sample management needs of translational researchers engaged in multi-center research.

To these ends, the GI SPORE has recruited experienced biostatistical investigators who are familiar with advanced data analysis techniques, oncology and translational research, and an experienced data management team at Dartmouth Medical School, with whom the biostatisticians have considerable experience and in whom they have confidence. The biostatistical investigators keep abreast of contemporary data analysis methods in relevant fields such as machine learning and clinical trial design. Informatics personnel participate heavily in national informatics initiatives such as CaBIG.