new OCRP awards- Department of Defense
DFHCC investigators successfully compete for grants from the Ovarian Cancer Research Program, Department of Defense - December 2006
Daniel Cramer, MD, at the Brigham & Women’s Hospital, Luiz F Zerbini, PhD, at the BIDMC Genomic Center and Zak Mageek, PhD, at the Center for Engineering in Medicine, MGH successfully competed for and won grant awards from the Department of Defense. Dr. Cramer won the OCRP grant for the project titled “Mumps Parotitis and Ovarian Cancer: modern significance of an historic association”, specifically probing associations with mumps parotitis and immune mechanisms that reduce the risk of ovarian cancer in women affected with mumps. While Dr. Zerbini successfully competed for the DoD-OCRP Concept award for his project titled “Cell cycle based therapy for ovarian cancer” proposing to use NSAIDs to induce apoptosis in quiescent ovarian cancer cells, Dr. Mageek was funded for his project focused on elastin-based nanoparticles to target, image and kill the ovarian cancer cells. Brief abstracts for these projects are outlined below:
Mumps Parotitis and Ovarian Cancer: modern significance of an historic association- Daniel Cramer, MD
In a small epidemiologic study, West identified that women with ovarian cancer were less likely to report having had mumps parotitis compared to women with benign ovarian cysts, and concluded either that mumps parotitis conferred long-term protection against ovarian cancer or that females resistant to a mumps infection were more susceptible to ovarian cancer. Based on subsequent studies, it is estimated that the overall risk for ovarian cancer associated with history of mumps parotitis was 0.72 with 95% limits of 0.59-0.87, suggesting that mumps may indeed be inversely associated with ovarian cancer risk. Additionally, with the introduction of the mumps vaccine in the late 1970’s, the association between mumps parotitis and ovarian cancer was seemingly rendered irrelevant. Recently, however, a new theory for ovarian cancer was introduced involving immunity against ovarian cancer mediated through the surface glycoprotein and tumor marker Mucin 1 (MUC1).
Since circulating MUC1 and anti-MUC1 antibodies have also been found in healthy women, especially those pregnant or breastfeeding, it has been hypothesized that (pre-existing) immunity against MUC1 may help explain the long-term protective effects of pregnancy and lactation on ovarian and breast cancer risk.
Several traditional and new risk factors for ovarian cancer may be explained by their ability to induce MUC1 immunity through exposure of MUC1 to immune recognition in the context of inflammatory processes in various MUC1-expressing tissues. This mechanism may also explain the protective effect of mumps parotitis on ovarian cancer risk. It is likely that inflammation of salivary glands results in over-expression and spillage of an under-glycosylated form of MUC1 into the circulation, thereby triggering an immune response that could provide lasting protection against the development of MUC1-expressing ovarian (and perhaps other) tumors.
The proposed study plans to use unique banked specimens to assess the effects of mumps parotitis on MUC1 immunity, to compare anti-MUC1 antibody, IgG, and IgM titers in serum samples collected during acute and convalescent mumps parotitis infection to serial draws in individuals without mumps, and to look for the presence of under-glycosylated MUC1 antigen in sera of individuals diagnosed with mumps.
. Exploring the basis for this association through MUC1 immunity could point the way towards developing MUC1-based immune vaccines that could safely exploit the ability of natural and diverse events to induce immunity against ovarian and perhaps other cancers that express MUC1.
Cell-Cycle based Therapy for Ovarian Cancer - Luiz F Zerbini, Ph.D.
Background: Numerous studies demonstrate that non-steroidal anti-inflammatory drugs (NSAIDs) hold significant promise as anti-cancer therapeutics. Dr. Zerbini and Libermann have recently described the mechanisms by which structurally different NSAIDs induce programmed cell death in ovarian cancer. The biological effects of a comprehensive set of NSAIDs in proliferating ovarian cancer cells in vitro at physiologic concentration have been analyzed with selected NSAAID’s strong inducers of apoptosis.
It is hypothesized that by identifying the NSAIDs found to induce apoptosis of quiescent ovarian cancer cells, it will be possible to rationally design a combination of several drugs with distinct target specificities that should act synergistically against ovarian cancer. The goal of this project is to carry out a systematic survey of a panel of NSAIDs with regard to their ability to induce apoptosis in quiescent ovarian cancer. The use of NSAIDs or chemically modified NSAIDs which target specifically quiescent cancer cells in combination with other therapies that focus in the proliferative stage of the disease should enhance the apoptotic effect of NSAIDs on EOC.
Elastin Based Nanoparticles- Zak Mageek, PhD
“Polymeric micelles are 'core-shell' nanoparticles that can display bioactive and functional motifs on their surfaces, and encapsulate therapeutic or imaging agents. They have utility for the imaging and treatment of a variety of malignancies. Nanoparticles are typically assembled from chemically synthesized polymers. However, chemical synthesis has a limited ability to precisely control long-range polymer architecture, limiting the ability to produce supramolecular assemblies with precisely defined structures. By contrast, genetically engineered protein 'polymers' are amino acid-based, and produced by recombinant methods. These materials have very precise long-range structure that is encoded at the DNA level. This approach enables the design and formation of highly-ordered nanoparticles. Elastin-like polypeptides (ELPs) are biocompatible polymers composed of a pentamer repeat found in mammalian elastin. ELPs self-assemble and form nanoparticles. The aim of this concept award is to functionalize these nanoparticles with bioactive peptide motifs for specific targeting, imaging, and killing of ovarian cancer cells. The initial stage of this work involves the generation of large numbers of polymeric architectures and nanoparticle compositions, coupled with fluorescent microscopy-based high content screening assays, which will define probe specificity, bioactivity, and subcellular localization of the particles.”