Grants and Contracts Details
It is estimated that 203,500 women and 1,500 men will be diagnosed in the United States with breast cancer this year alone (2002). Tragically, approximately 39,600 women and 400 men will die this year due to this particularly pernicious disease. Clearly, new and more effective medical strategies for combating cancer are needed, both before and after the onset of symptoms. Perhaps surprisingly, the root cause of many heritable cancers are known. Two particularly relevant examples are the breast cancer susceptibility genes called BRCAI and p53. These genes, through a relatively simple biochemical pathway, are converted into specialized proteins whose purpose is to suppress tumor initiation and development within individual cells. As long as these proteins are made correctly, cellular growth is held in check, and tumor formation (cancer) is prevented. If something deleterious happens to them, however, their ability to suppress tumor formation can be critically compromised, leading to the onset of breast cancer. This often occurs because the BRCAI or p53 genes themselves become mutated, and the genes are ultimately converted into defective tumor suppressors. Fortunately, technologies for the identification and early detection of such mutations are progressing relatively rapidly. Unfortunately, technologies to combat these mutations, especially at the causative gene level, are lagging far behind. BRCAI and p53 gene mutations are often the result of aberrant genetic material being inserted within the normal genes. Therefore, one possible therapeutic strategy entails removing this aberrant genetic material from the genes. The corrected genes would then result in restored tumor suppressor protein activity, which likely would stop, and perhaps reverse, tumor growth. Due to the inaccessibility of the genes themselves, however, an intermediate in the pathway between the genes and the resultant proteins, called RNA, is the target for which we are most likely able to intercept and repair the gene product. We propose to design, engineer, and test a biomolecule, called a ribozyme, that can remove known cancer-causing insertion mutations from the RNA of mutant BRCAI and p53 genes, thus restoring the coding potential of the gene back to normal. Such technology currently does not exist. Initial tests of new experimental strategies usually involve the development of a cell-free model system for which the number of variables, which are very numerous and complex in a cell, can be controlled. Initially we will follow this time-tested course of action by using small subsets of mutant BRCAI and p53 RNAs for analyzing the ability of our engineered ribozymes to remove the designated mutations. Success in this initial stage will lead to assay development and testing in increasing complex systems, first involving entire mutant BRCAI and p53 RNAs and then involving cellular systems. In this way, we can more fundamentally understand how the variables at each stage influence the effectiveness of this potential therapeutic strategy. My laboratory has developed a new class ofribozymes that we think could be engineered to perform this admirable feat We feel that the potential benefits could be tremendous, both for cancer research in general and for patients who will (or have) come face to face with this disease, and could far outweigh the inherent risk of attempting to put into practice this novel idea. In addition, success in this endeavor will initiate a potentially new kind of therapeutic strategy that could ultimately be useful for aiding individuals with other genetic diseases, including Parkinson's disease, Cystic Fibrosis, ovarian cancer, etc. Carrying out the research in this proposal will also have the much desired affect of allowing my graduate students and I to embark on a program of research on cancer.
|Effective start/end date||5/1/03 → 8/30/05|
- Department of Defense: $155,125.00
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