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Developmental Research Program
Nicole Urban, ScD
Principal Investigator
Approximately $100,000 is available annually from the POCRC to support developmental projects and pilot studies in translational ovarian cancer research. Priority for funding is given to proposals that have a clear translational objective, open substantial new approaches in translational ovarian cancer research, involve a multidisciplinary team of investigators, and compliment the ongoing work of the POCRC.
Investigators at research institutions, both inside and outside of the Pacific Ovarian Cancer Research Consortium, are encouraged to apply.
Currently funded pilot studies include:
Development of a marker panel for the prediction of oncolytic adenovirus performance in patient with ovarian cancer
André Lieber, MD, PhD
University of Washington
Dr. Lieber has generated a new type of capsid-modified, conditionally replicating, oncolytic adenovirus (Ad5/35.E1a/Trail) that is able to eliminate metastases in xenografts models after a single systemic application and that does not cause unspecific toxicity in mice or baboons. In preparation for a phase I clinical trial, Dr. Lieber plans to test his oncolytic vector on a representative number of primary tumor cell cultures derived from biopsies, ascites, or pleural fluid from patients with metastatic ovarian cancer. Dr. Lieber anticipates that Ad replication and viral oncolysis will vary across different tumor cultures. Using gene expression array technologies, Dr. Lieber will identify cellular factors that limit or support the replication of or oncolysis by his anti-tumor vector. Based on this information, Dr. Lieber will construct a panel of genes with high specificity for determining who would benefit from a therapy with the oncolytic vector. The specific aims are: 1) to assess the ability of the capsid modified Ad5/35 vectors, as compared to the traditional Ad5 vectors, to specifically transduce primary ovarian cancer cells; 2) to assess the oncolytic effect of Ad5/35.IR-E1a/Trail on primary ovarian cancer cell cultures; and 3) to use microarray expression data to identify alterations in gene expression associated with efficient oncolysis by Ad5/35.IR-E1a/Trail, and based on this, to construct a panel of marker genes that predict the performance of the oncolytic vector in patients.
Prioritization of genes for development based on quantification of protein in serum
Martin McIntosh, PhD, Fred Hutchinson Cancer Research Center
Michael Gelb, PhD, University of Washington
The purpose of this work is to use a new type of proteomic reagent developed in the Gelb lab for the quantification of proteins in serum that may serve as useful markers of ovarian cancer. Serum samples will be provided by collaborators in the POCRC.
Identification of ovarian carcinoma biomarkers using recombinant antibody arrays
Nathalie Scholler, MD, PhD, Fred Hutchinson Cancer Research Center
Dr. Scholler proposes to produce a recombinant antibody array to differentially screen ovarian cancer sera versus control sera for the purpose of early detection biomarker identification. After use first as a discovery tool, the recombinant antibody array will be evaluated as a diagnostic/prognostic tool to complement the ongoing work of POCRC investigators. The project will utilize single-chain Fragment variable (scFv, consisting of the epitope-binding, variable regions of the antibody heavy and light chain genes joined by a flexible linker) antibody arrays to examine protein expression differences in sera from carcinoma patients sera versus benign controls. The specific aims of the study are to 1) develop an array of scFv antibodies that react preferentially with epitopes present in human blood from carcinoma patients, and 2) screen normal and ovarian-carcinoma patient sera using the array to determine presence and abundance of ovarian-carcinoma specific antigens.
Gene expression in high-risk ovarian surface epithelium
Elizabeth Swisher, MD, University of Washington
Dr. Swisher hypothesizes the gene expression profile of cultured normal ovarian surface epithelium (NOSE) from women with mutations in the BRCA1 and BRCA2 gene differ in comparison to that from NOSE from control women. The specific aims of this study are:
Targeting mesothelin for cellular therapy of ovarian cancer
Cassian Yee, MD, Fred Hutchinson Cancer Research Center
Immune-based therapy of ovarian cancer represents and attractive strategy for the treatment of patients with refractory disease. However, a major obstacle to the application of immunotherapy has been the identification of only a handful of immunogenic ovarian tumor target antigens. Mesothelin is a tumor-associated self antigen that is overexpressed in more than 90% of epithelial ovarian cancers and represents a potential tumor rejection antigen. This project proposes to evaluate the feasibility of generating tumor-specific CD8+ and CD4+ T cells targeting mesothelin among patients with ovarian cancer. The project also proposes to identify immunogenic epitopes of mesothelin for eliciting antigen specific lymphocytes in vitro, and evaluating the endogenous in vivo cellular response to mesothelin.
Blocking of the CA125-Mesothelin Interaction with Recombinant Antibodies to Prevent the Implantations of Ovarian Carcinoma Metastasis
Nathalie Scholler, MD, PhD, Fred Hutchinson Cancer Research Center
This project proposes the development of therapeutic agents that have the potential for treating metastatic disease in mesothelin-dependent cancers. One example would be the prevention of relapse in ovarian cancer patients that responded to initial therapy but are at risk for regrowth of the tumors. This project will use a yeast-display library of single chain Fragment variable (scFv) antibodies to identify the scFv recombinant antibodies able to block the attachment of CA125-expresser ovarian cancer cells to mesothelin-expresser cells in an in vitro model system that was recently developed by the investigator.
Identification of a Transcriptional Signature of AKT Activation in Ovarian Cancer Cells
Charles Drescher, MD, Fred Hutchinson Cancer Research Center
The PI3-kinase/AKT signaling pathway plays a critical role in regulating cell proliferation, survival, invasion and metastasis and is emerging as an important therapeutic target for many cancers including ovarian. Robust assays capable of detecting pathway activation and measuring pathway related gene transcription in clinical samples would facilitate the development of clinically useful pathway inhibitors and the recognition of treatment-responsive cancers. The primary objective of this proposal is to identify a gene expression signature of PI3-kinase/AKT pathway activation in ovarian cancer cells. To begin, a comprehensive list of genes will be generated whose expression correlates with experimentally induced AKT activation in immortalized HOSE cells. In these primary cells the pathway can be selectively activated and the system is free of artifacts of prolonged culture in-vitro. To identify additional genes whose correlation with AKT activation is limited to transformed cells, gene expression profiles of ovarian cancer cells will be characterized with and without activated AKT. From gene expression datasets generated by multiple complementary strategies of AKT pathway activation, a profile will be derived that correlates with activation of the AKT pathway and the profile will be tested to see if it can be used to classify ovarian cancer cell lines and patient cancer tissues according to the status of activation of the AKT pathway.
A Model System for Identifying, Developing, and Validating Markers of Early Detection for High-Grade Ovarian Serous Carcinoma
Beatrice Knudsen, MD, PhD, Fred Hutchinson Cancer Research Center
The goal of this project is to identify and measure gene expression profiles that are associated with early events in ovarian carcinogenesis and to develop protein-based screening assays for ovarian carcinoma. Normal ovaries from individuals with a genetic predisposition to ovarian cancer have been examined for early lesions leading to high-grade ovarian serous carcinomas. These ovaries contain inclusion cysts that demonstrate changes in the epithelial lining indicative of conversion to Mullerian epithelium as it exists in the fallopian tube and uterus. Some inclusion cysts contain clusters of benign epithelial cells with features of Mullerian metaplasia and with detectable expression of p53 protein. Based on these observations, mutationally inactivated p53 has been implicated as an early mechanism of cellular transformation in ovarian cancer. Thus, the central hypothesis motivating the proposed project is that high-grade ovarian serous carcinomas develop in epithelial cells of Mullerian differentiation through loss of p53 function. In addition, we postulate that a gene expression profile specific for loss of p53 inactivation exists and is detectable in cells that are destined to become cancerous. If this were true, the corresponding proteins may be useful as early markers of ovarian cancer. The specific aims of the study are to 1) determine unique gene expression profiles of ovarian surface epithelium and Mullerian epithelium and to compare these to genes overexpressed in ovarian cancer, and 2) identify a gene expression profile that is associated with the loss of p53.
Identification of Markers Specific for Ovarian Cancer Stem Cells
Pavel Sova
Dr. Sova is using his career development support to work with hi
s mentors, Drs. Andre Lieber, David Haynor, and Thalia Papayannopoulou on a research study entitled Identification of Markers Specific for Ovarian Cancer Stem Cells. The specific aim of Dr. Sova’s study is to identify new surface markers for further enrichment of ovarian cancer stem cells. Dr. Sova's experiments will test the hypothesis that comparing the gene expression profiles of ovarian cancer cell subpopulations displaying ovarian cancer stem cell properties will lead to identification of new surface markers allowing for better enrichment/isolation of ovarian cancer stem cells. Dr. Pavel Sova is an Acting Assistant Professor in the Department of Pathology at the University of Washington (UW).