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SPORE IN BRAIN CANCER ABSTRACTS Mayo Clinic Foundation and Mayo Clinic Cancer Center Brian Patrick O'Neill, M.D., Principal Investigator General Summary This Specialized Program of Research Excellence (SPORE) in Brain Cancer at Mayo Clinic Cancer Center will support a multidisciplinary team of basic, clinical, and population science investigators to perform translational research directed at significantly reducing morbidity and mortality from brain cancer. Brian Patrick O’Neill, MD will serve as Overall Principal Investigator and Director of the Administrative Core. Robert B. Jenkins, MD, PhD, will serve as Overall Co-Principal Investigator and Administrative Core Co-Director. The SPORE will serve as the organizational nucleus for the research activities in these areas. The translational research objectives of the SPORE will be directed by 12 investigators from 8 departments with a demonstrable history of collaborative and translational research. The SPORE comprises four Mayo investigator-initiated research projects, and four core resources constructed around a theme of adult gliomas and consolidated by an Administrative Core. The SPORE also comprises Career Development and Developmental Research Programs. SPORE Research Projects:
SPORE Scientific Cores:
This SPORE structure provides the ideal mechanism to focus and integrate the discovery efforts of investigators and to optimally utilize the resources of the Mayo Clinic practice and the Mayo Clinic Cancer Center to conduct meaningful studies of brain cancer that will translate effectively Optimizing EGFR Inhibitor-based Therapies in GBM Amplification of EGFR, with or without mutation, occurs in 40% of primary GBM tumors, and at least in this subset of tumors, elevated signaling from EGFR presumably plays a central role in the malignant character of these radiation resistant tumors. However, it is not known whether the presence or absence of EGFR amplification is predictive of tumor sensitivity to EGFR-directed therapies. At Mayo Clinic, 2 Phase II clinical trials are being run through the North Central Cancer Treatment Group (NCCTG) to evaluate the efficacy of small molecule EGFR kinase inhibitors in GBM. Tissue specimens from these trials, which are evaluating radiation combined with sequential (N0074) or concomitant (N0177) EGFR inhibitor therapy, will be available for correlative studies, as will an extensive GBM tissue archive from patients treated with radiation alone. In addition, we have established a panel of serially transplantable GBM xenografts that maintain the original EGFR amplification status and the histopathologic and invasive features of their derivative GBM tumors. Using these resources, this project will identify molecular characteristics that predict for response to EGFR inhibitor therapy. We hypothesize that the anti-tumor effects of EGFR inhibitors result from suppression of a select subset of 1 or 2 essential pathways, and that resistance to EGFR inhibitor therapy results from compensatory signaling through these pathways caused by other GBM gene alterations (e.g. PTEN mutation). Thus, accurate prediction of sensitivity to EGFR inhibition may require information regarding the status of several molecular characteristics including EGFR amplification and mutation status. To succeed in identifying a predictive molecular fingerprint for sensitivity to EGFR inhibitor therapy in GBM, the following approach will be used. In Aim 1, we will examine tissue specimens collected from patients treated with a) radiation and concomitant OSI-774 on N0177, b) radiation followed by ZD1839 on N0074, and c) radiation alone. In Aim 2, we will examine serially transplantable orthotopic GBM xenografts to identify EGFR-dependent signaling pathways that are sensitive to OSI-774 therapy. In Aim 3, we will test whether the efficacy of EGFR inhibitor therapy can be enhanced by simultaneous inhibition of the mammalian target of rapamycin in orthotopic GBM xenografts. Collectively, the studies in this application will enhance our understanding of the molecular pharmacology of EGFR inhibitor therapy and will provide the scientific basis of customization of EGFR inhibitor therapies on the basis of molecular tumor characteristics. Targeted MV-CEA as a Potent Antitumor Agent against GBM Gliomas represent a promising target for gene transfer approaches given their limited ability to metastasize, but despite promising preclinical data, significant clinical benefit has not been materialized to date. Our group has developed a novel potent antitumor approach to attack recurrent gliomas, by utilizing an Edmonston’s vaccine strain of measles virus, which we have engineered to produce the marker peptide CEA (MV-CEA). CEA serves as a trackable marker of viral gene expression and can be used to monitor viral therapy in vivo. Using MV-CEA we have demonstrated significant antitumor activity in vitro against several glioma lines and in vivo in subcutaneous and orthotopic U87 xenografts. We now propose to perform additional preclinical work in order to optimize MV-CEA-based therapy for the treatment of recurrent gliomas. In order to overcome challenges associated with the variability of expression of the measles virus receptor CD46 in gliomas and the ubiquitous, although low level, expression of CD46 in normal brain, we propose to exploit alterations of the EGFR pathway, possibly in combination with ablation of the natural binding to the CD46 and SLAM receptors to construct retargeted MV-CEA derivatives. These will be comparatively tested in vitro and in vivo in order to decide on the optimal candidate for clinical translation. This proposal brings forward two novel concepts: exploring the use of an attenuated measles virus of the Edmonston vaccine lineage to treat recurrent gliomas and use of a novel tracking system that could significantly improve our ability to monitor virotherapy trials in brain tumors. Our hypothesis is that targeted MV-CEA derivatives will be potent antitumor agents against glioblastoma multiforme with a superior efficacy/toxicity profile as compared to MV-CEA. Therefore, our proposal has the following specific aims: 1) To generate and characterize derivative attenuated vaccine strains of measles virus, expressing the marker peptide CEA by expanding the MV-CEA tropism in order to facilitate entry in glioma cells overexpressing EGFR and/or the EGFRvIII mutant with or without ablation of the tropism to the natural receptors CD46 and SLAM; 2) To compare the efficacy of MV-CEA with the EGFR targeted derivative viruses in vitro and in vivo in four different orthotopic glioblastoma models that exhibit distinct alterations of the EGFR pathway and to assess the value of serum CEA as a correlate of viral gene expression, viral replication, and antitumor activity in this setting; 3) To compare toxicity of the different engineered strains, in a susceptible primate model, and to assess the impact of preexisting measles virus immunity and steroid induced immunosuppression on the safety of the treatment; 4) To use the viral strain with the optimal safety/efficacy profile in a phase I clinical trial in patients with recurrent glioblastoma multiforme. Association of Chromosome 19 q-arm polymorphisms with Glioma Development,
Survival and Response to Therapy Deletions of the chromosome 1p and 19q arms have been associated with gliomas, especially oligodendrogliomas. Oligodendrogliomas with these alterations have been observed to have a better survival and a better response to chemo- and/or radiation-therapy. Recent evidence suggests that, in addition to acquired alterations, germline polymorphisms mapped to19q13.3 are associated with cancer development (e.g. basal cell carcinoma, breast cancer, adenocarcinoma of the lung, and glioma) and with cancer aggressiveness (e.g. prostate cancer). Our main hypothesis is that there is a gene (or genes) on 19q13.3 that increases the risk of glioma and predict progression. We propose to employ two fundamental study designs to achieve three aims: a case-control study design to identify single nucleotide polymorphisms (SNPs) associated with glioma risk, and a patient cohort study design to identify SNPs associated with survival and response to therapy. Aim 1 will evaluate the association of 19q SNPs with the risk of oligodendroglioma, mixed oligodendroglioma, and astrocytoma; will stratify the association analysis by glioma 19q deletion status; and will determine which alleles are lost in gliomas. Aim 2 will evaluate the association of 19q SNPs with glioma survival and response to therapy for each of the three morphologic subtypes; will stratify by glioma 19q deletion status; and will determine which alleles are lost. Aim 3 will focus the investigation on the narrow regions surrounding the significant SNPs identified by Aim 1; these regions most likely contain the gene(s)/SNP(s) associated with glioma risk. All three Aims have two evaluation tiers using two independent yet complementary study samples: the first to screen SNPs for associations, the second to replicate and validate these associations. Aims 1 and 3 use cases and controls enrolled retrospectively (tier-1) and prospectively (tier-2) at the Mayo Clinic; Aim 2 uses Mayo Clinic retrospective cases (tier-1) and the RTOG trial 9402 cohort (tier-2). The overall study design is efficient and internally controlled. The Mayo Clinic retrospective cases and controls and the RTOG 9402 cases are already enrolled and will be available for analysis; the prospective cases and controls will be enrolled using established research infrastructure at the Mayo Clinic at Rochester, Minnesota. Our translational goal is to find 19q SNP markers that are useful and feasible in glioma risk assessment and survival prediction. Administrative Core The Mayo Clinic Cancer Center SPORE in Brain Cancer comprises four Mayo investigator-initiated research projects, and four core resources constructed around a theme of adult gliomas and consolidated by an Administrative Core. The SPORE also contains Career Development and Developmental Research Programs. The Administrative Core supports the operational structure of this SPORE. It will provide coordination of the research projects, scientific cores, and developmental programs (Developmental Research Program, Career Development Program) of the SPORE. It will also serve to enhance communication between SPORE investigators and facilitate all SPORE operations and interactions . The Administrative Core will be responsible for coordinating the SPORE Executive Committee and the Advisory Council. Dr. Brian Patrick O’Neill will serve as Director of the Administrative Core, and Dr. Robert Jenkins will serve as Co-Director. The Administrative Core will support SPORE activities by: (1) providing leadership, organizational support, and financial management for SPORE investigators; (2) coordinating monthly scientific meetings of SPORE investigators, and the ongoing scientific review of SPORE research projects and cores; (3) reviewing progress of the SPORE full and developmental projects; (4) providing for information transfer to the scientific community via professional and public means; (5) providing the structure for nurturing collaborations to facilitate and expand glioma research; and, (6) acting as liaison with leadership of the other Brain SPOREs and the NCI SPORE Program. Biostatistics Core The Biostatistics Core provides statistical collaboration and/or data management for each of the SPORE projects, developmental projects, and cores. Each project in this application reflects input from members of the Biostatistics Core on study design and analysis plans. Statistical collaboration and analysis will involve many different fields, including epidemiologic studies, basic sciences, and clinical trials. These studies will be conducted across different platforms with different data management needs, from in vitro experiments to in vivo murine models to phase I/II cancer clinical trials. The Biostatistics Core will provide each investigator access to statistical expertise that includes collaborative development of study designs, data collection tools, analysis plans, state of the art statistical modeling, analysis and interpretation of complex data, data management resources, and abstract and manuscript preparation. The core will also provide statistical collaboration and resources for the developmental projects as well as for pilot projects initiated through the career development component of this grant. In this sense, the Biostatistics Core not only collaborates on and supports the projects presented in this grant application but also will serve as a resource for future investigators interested in participating through this SPORE. In addition to providing statistical collaboration on current and future projects, the Biostatistics Core will work closely with the Clinical Research Core and the Xenograft Core to develop data quality control processes and to assist with the development of new databases or to add database functionality. The Biostatistics core will also develop and help manage project-specific databases as well as to perform necessary data quality control checks. The strengths of the Biostatistics Core are our collaboration with each of the projects, our close integration with the Clinical Research Core and Xenograft Core and the diverse experience or our members. The Biostatistics Core builds upon the innovative and time-tested procedures and systems developed by one of the largest statistical groups in the country whose members have collaborated on more than 8,000 clinical and basic science research studies since 1932.
Pathology Core The Pathology Core of the Mayo Clinic Cancer Center SPORE in Brain Cancer will provide a coordinated and centralized resource dedicated to procurement and processing of tissues obtained from patients with gliomas. The Goal of the Pathology Core is to procure tissue and specimens from nearly every newly diagnosed or relapsed glioma patient seen at the Mayo Clinic and from all patients entered onto SPORE protocols The Pathology Core will coordinate acquisition of both normal and neoplastic brain tissues for translational research and ensure appropriate diagnosis and quality of tissue. A portion of normal and tumoral brain tissue from each patient will be obtained fresh, processed for culture/xenograft and/or stored frozen to provide investigators with DNA and RNA. The remainder of the tissue will be available in paraffin blocks stored at the Mayo Clinic Tissue Registry. Oversight will be by the Administrative Core The Pathology Core will also serve as a resource of expertise, collaborative effort and service for the pathology needs of the individual projects. The Core will interface with and be electronically integrated with the Neuro-Oncology Database and the Biostatistics Core to provide investigators with clinically annotated tissues. The collection, banking, and use of tissue will be performed with appropriate patient consent and institutional approval. The Pathology Core will interact and collaborate with other Brain Tumor SPOREs to promote resource sharing, and integrate scientific projects of mutual interest. Xenograft Core Through the development and maintenance of several serially transplantable GBM tumor lines, each of which has been or will be characterized for GBM signature lesions, the Xenograft Core will provide to SPORE investigators robust animal models that recapitulate the invasiveness seen in the human phenotype. The serially passaged xenografts provide a more clinically relevant model than established cell lines grown as xenografts. This determination has many implications for neuro-oncology research, but is likely to be of greatest importance to the testing of experimental therapeutics. It is our contention that results from testing anti-tumor therapeutics with serially-transplanted GBM xenografts will show improved consistency with clinical trial results in humans. Specifically, the Xenograft Core will:
All specimens will be collected and processed under tight quality control, and will be distributed
to SPORE researchers or banked for future SPORE research projects. The SPORE Pathology Core will
assure that specimens are properly fixed, stained, and histologically evaluated. All activities will
be traced in the Biostatistics Core using a sophisticated database essential to the SPORE. This database
merges the activities at Mayo, and allows integration with clinical and other data collected in research
projects. Clinical Research Core The goal of the Clinical Research Core is to provide investigators in the SPORE high quality biospecimens as well as patient data from consented patients with glioma and to make these resources available for future studies. The services provided are: 1) to coordinate the collection, processing, storage, distribution and tracking of biospecimens including blood, throat swabs, urine and cerebrospinal fluid; 2) A: To extract clinical data from patient records and collect epidemiologic research information, with entry into the Neuro-Oncology Database for all newly-diagnosed glioma patients not on interventional clinical trials and B: to enroll controls who are age- gender- and race-matched to cases for Project 4; 3) to provide protocol-specific clinical data from patients enrolled in interventional clinical trials; and 4) to provide coordination and oversight of compliance with regulatory issues involving human subjects. This core will also serve as the interface with Mayo Clinic Cancer Center’s shared resources including the Biospecimens Acquisition and Processing shared resource, the Clinical Research Office, and the Protocol Review and Monitoring System. In addition, this core will interact with the other cores of this SPORE application, including the Administrative Core by participating as a member of the Executive Committee, with the Biostatistics Core by joint development of data entry forms and quality assurance of clinical data, and with the Pathology Core by sharing the responsibilities for biospecimens review and utilization. These essential services provide support for specific aim 1 of project 1, specific aim 4 for project 2, essential biospecimens and data for all of the aims in projects 3 and 4, and one developmental project. Core utilization will include assisting in the recruitment of patients to studies, ensuring eligibility, informed consent, scheduling appropriate protocol tests and follow-up, obtaining clinical data and biospecimens from approximately 200 patients and 125 controls per year, entry of clinical trials data information according to Mayo Clinic Cancer Center policy set forth by the Clinical Research Office and Protocol Review and Monitoring System, and compliance with human subjects protection in keeping with the policies of the Mayo Clinic Cancer Center. Finally, this core will interface with the clinical research components of other Brain Tumor SPORE grantees, cancer centers and cooperative groups to facilitate multi-institutional clinical research arising out of national brain tumor research efforts |
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