Each year, MOCA funds research which advances the treatments and cure for ovarian cancer. All of the money dedicated to research stays in the state of Minnesota. In 2005, we are proud to announce that through our combined hard work and dedication to this cause, MOCA funded almost $300,000 to four ovarian cancer research projects. After reviewing 15 proposals submitted to MOCA, our grant review panel, composed of three national experts in ovarian cancer research and four consumer representatives, made the funding recommendations which were accepted by the MOCA Board of Directors. A summary of this research is listed below.

Summary Abstracts of 2005 Research

“Genetic variation in Inflammation Genes and Associations with Ovarian Cancer Risk and Prognosis” submitted by Ellen Goode, Ph.D., M.P.H., Department of Health Services Research, Mayo Clinic.
Dollars Funded $58,000.

Although it is clear that inherited genetic susceptibility plays a role in ovarian cancer, much remains unknown about the etiology and progression of this deadly disease. One promising area of research is the role of inflammation pathways in ovarian cancer. It is thought that the NFk B pathway (nuclear factor of kappa light polypeptide gene enhancer in B-cells) is a central mediator between inflammatory and carcinogenic processes.

We hypothesize that inherited variation in genes inhibiting or activating NFk B may modify risk of ovarian cancer and may also play a role in prognosis. We intend to examine these hypotheses in a population study using a comprehensive approach for evaluation of inherited variation in ~ 90 NFk B-related genes. Over 320 women with ovarian cancer and 395 healthy controls have been previously recruited into an ongoing case-control study at the Mayo Clinic and have provided risk factor information and genomic DNA; clinical follow-up data is available on the vast majority of cases.

To evaluate variation in approximately 90 candidate genes, we will take advantage of the recently-announced, new generation of genetic maps to identify the single nucleotide polymorphisms (SNPs) which are most informative for identifying or "tagging" underlying genetic differences across individuals. We expect ~ 480 "tagSNPs" to be identified through a bioinformatics screen of publicly-available databases and in-house statistical analysis. We will utilize cutting-edge technologies at the Mayo Clinic Advanced Genomic Technology Center for efficient and robust genotyping of each of these tagSNPs in our case-control study population.

These genotyping data from 328 cases and 395 controls will be statistically analyzed to assess whether any particular tagSNP is associated with increased or decreased risk of ovarian cancer. We will also consider joint effects of multiple tagSNPs within each candidate gene in a haplotype-based analysis. Among cases only, these genotype data will also be used to assess whether any particular tagSNP, or tagSNPs combination, is associated with longer or shorter time to disease recurrence. Our hope is that this comprehensive, yet efficient, approach to analysis of genetic variation in the NFk B pathway will highlight particular genes worthy of follow-up with additional molecular and population studies.

To our knowledge, this project will be the first to apply the novel genetic tagSNP approach in a comprehensive pathway-specific manner in ovarian cancer research. We will capitalize upon a vast amount of existing resources including previously-recruited ovarian cancer cases and controls with attendant biospecimens, state-of-the-art laboratory technology, and an active, multidisciplinary team of basic, clinical, and population scientists with proven expertise relevant to the discovery of genetic components for ovarian cancer. Increased understanding of the genetics of this disease at the population level will hopefully lead to targeted, more effective, prevention and therapeutic strategies.

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“Folate-Receptor Targeted Measles Virotherapy for Ovarian Cancer” submitted by Kah-Whye Peng, Ph.D., Molecular Medicine Program, Mayo Clinic.
Dollars Funded $86,000.

A phase I clinical trial using live attenuated measles virus as a novel therapeutic for recurrent ovarian cancer is in progress at Mayo Clinic Rochester. This study will develop a new generation of targeted measles virus that exclusively infects ovarian cancer cells, thereby enhancing anti-tumor efficacy and minimizing toxicity.

Our goal is to develop replication-competent attenuated measles virus (MV) for targeted therapy of ovarian cancer (virotherapy). Attenuated MV is potently oncolytic for ovarian cancer cells and human tumor xenografts in mice. The virus uses its hemagglutinin (H) attachment protein to bind to CD46 receptors on ovarian cancer cells and enters cells using its fusion (F) protein. The virus then exploits the host cell machinery to express the viral proteins and for production of viral progeny. Subsequently, expression of MV-H and F proteins on surfaces of infected cancer cells results in extensive fusion with CD46 positive neighboring cells, leading to tumor cell destruction.

Encouraged by the promising anti-tumor activity of MV, we are currently testing intraperitoneal delivery of a recombinant MV (MV-CEA) in a phase I clinical trial for patients with recurrent ovarian cancer. The MV-CEA virus has been genetically engineered to express an inert soluble marker peptide to facilitate noninvasive monitoring of the profile of viral gene expression in patients. Ovarian cancer is highly amenable to intraperitoneal measles virotherapy because the cancer is localized mainly in the peritoneal cavity. Direct delivery of the virus into the peritoneal space maximizes contact with tumor cells and minimizes potential neutralization by anti-measles antibodies in the blood. We are now designing the next generation of MV with enhanced performance for clinical testing. We hypothesize that the therapeutic index (efficacy versus toxicity) of oncolytic MV will be enhanced by developing viruses that infect exclusively ovarian cancer cells. To test this hypothesis, we will generate targeted measles viruses ablated for binding to its two native cellular receptors, CD46, that is ubiquitously expressed on all human cells (except for erythrocytes) and SLAM (signaling lymphocyte activation molecule), which is expressed on activated B cells, T cells and monocyts/macrophages. To confer specificity, we will redirect MV binding and cell fusion exclusively to the alpha-folate receptor (aFR) via display of an anti-folate receptor single-chain antibody (scFv). Alpha-folate receptor is a highly desirable target in ovarian cancer therapy as it is overexpressed in more than 90% of epithelial carcinomas and the Mov18 antibody from which the scFv is derived has been tested in various clinical trials.

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“Mullerian Inhibiting Substance Type II Receptor: A Novel Ovarian Cancer Target” submitted by William Cliby, M.D., Division of Gynecologic Surgery, Mayo Clinic.
Dollars Funded $86,000.

Hypothesis, Rationale and Specific Aims: A major obstacle in the management of ovarian cancer is the inability to specifically distinguish the ovarian cancer cells, which would allow targeted therapy. Treatment strategies rely on a therapeutic ratio derived primarily from subtle differences between most cancers and normal cells in the ability to respond to DNA damage caused by anti-cancer agents. Current imaging strategies rely on nonspecific characteristics to differentiate tumor from normal tissues: recent advances such as PET-scanning have improved for some malignancies. The identification of tumor-specific characteristics would greatly enhance our ability to target ovarian cancer for therapy and imaging.

The regulation controlling the growth of the male or female reproductive structures during embryologic development is complex and depends upon tissue specific regulation of receptors. MISIIR is a receptor specifically expressed in the progenitor tissues of the female reproductive tract during embryology. In a male fetus the testis expresses MIS, the ligand for MISII and this signals for regression of the mullerian tissues. In the female fetus, MIS is not expressed and the structures persist and develop further. MISIIR remains expressed in adult tissues apparently in a tissue-specific manner. Expression of MISIIR in a mullerian-specific manner may represent a great opportunity to selectively target ovarian cancer. We hypothesize that MISIIR expression is specific to the female reproductive tract and therefore an attractive target for therapy. We propose:

1. To determine the tissue pattern of expression of MISIIR in adult females
2. To analyze the expression of MISIIR in a stage-and histology-specific manner in primary and recurrent ovarian cancers
3. To determine the fetal and adult patterns of MISIIR expression in mouse to explore the suitability of such a model for future development of MISIIR
4. To improve the specificity of viral-mediated therapy for ovarian cancer using MISIIR as a target

The information obtained from this Minnesota Ovarian Cancer Alliance grant will provide preliminary data to a) determine the feasibility of pursuing MISIIR as an ovarian-specific target, and b) support an independent NIH grant application.

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“Novel Effect of a Mutant Endostatin in Inhibiting Peritoneal Dissemination of Ovarian Cancer” submitted by Sundaram Ramakrishnan, Ph.D., Department of Pharmacology, University of Minnesota.
Dollars Funded $69,000.

Cancer patients are currently treated by surgery and chemotherapy. While Taxol and platinum based drugs are the front line treatment choices, newer combinations with drugs such as Gemcitabine, 17-AAG, proteosome inhibitors are being introduced to aggressively eliminate the tumor cells. The ultimate goal of these combination regimens is to selectively inhibit the growth of cancer cells, and if possible, minimize toxicity. By understanding the biology of cancer cells it is possible to rationally design novel drugs in the future. But we have almost reached the threshold of chemotherapy beyond which the quality of life of cancer patients will be compromised.

In this context it is important to investigate alternate targets, especially outside the tumor cells to complement existing methods of treatment. Four potential targets are amenable for therapeutic intervention in addition to the tumor cells.

1. Vascular endothelium that provides nutrients and oxygen to the growing tumor,
2. Tumor infiltrating lymphocytes,
3. Stromal cells and
4. Extracellular matrix that provides the scaffold for tumor cells to attach and remodel. Extracellular matrix also sequesters growth factors and provides them to cells.

Our work focuses on the vascular endothelium since it is the lifeline for the tumor tissue. Each endothelial cell in a blood vessel supports the growth of about 500 cancer cells. Therefore, inhibition of angiogenesis should profoundly affect cancer growth... We have recently identified and characterized a mutant endostatin which was genetically modified to target tumor vasculature. The mutant endostatin bound to not only the endothelium but also ovarian cancer cells. Other antiangiogenic molecules such as angiostatin did not bind ovarian cancer cells. Based on this observation, we investigated whether the mutant endostatin can be used to block peritoneal dissemination of ovarian cancer cells. Ovarian cancer cells when shed into the peritoneum needs to seek out preexisting vasculature and co-opt with the vessels for survival. Attachment of cancer cells to a proximal site near a blood vessel is the first step in metastasis. Seeding is followed by angiogenic response which results in tumor growth. Our preliminary studies show that the mutant endostatin can indeed block the attachment of ovarian cancer cells to the peritoneal wall and prevent peritoneal dissemination. Ovarian cancer is a unique target for the mutant endostatin which can be used to prevent cell attachment to the peritoneal wall in addition to inhibiting angiogenesis. We would like to expand on this novel effect of mutant endostatin so that we can develop a secondary prevention strategy to reduce recurrence rate of ovarian cancer.