Using Genetics and Genomics for the Detection and Treatment of Breast Cancer

Principal Investigator: ELLEDGE, STEPHEN J
Institution Receiving Award: BRIGHAM AND WOMEN'S HOSPITAL, INC.
Program: BCRP
Proposal Number: BC076053
Award Number: W81XWH-08-1-0638
Funding Mechanism: Innovator Research Project Award
Partnering Awards:
Award Amount: $3,498,246.00


The key to the successful treatment of breast cancer is early detection and specific killing of tumor cells without killing normal tissues. We propose to approach both of these aspects using novel methods. Cancer cells have genetic alterations that rewire how they function so that they can grow inappropriately. Unfortunately, there are many ways to accomplish this rewiring, as breast cancer is not one but several diseases. For the last 25 years, scientists have been identifying cancer-causing genetic changes in breast cancer and then trying to use that information to treat it, without much success. This is in part because the tumors can change and circumvent treatments and in part because the scientists are taking educated guesses as to what genes are the most important to interfere with to treat the disease. They are educated guesses, but they are still guesses. Cancer researchers have focused on a concept called "oncogene addiction" in their search for cancer gene targets. The idea behind this is that mutations that activate certain genes called oncogenes drive cancer development and are also required for the maintenance of the tumors, i.e., the cancers are addicted to the oncogene. If you make a drug to the protein encoded by that gene, it will kill the cancer cells. This makes sense, and several therapies, particularly for lung cancer, have been successfully developed around this idea. However, we feel that cancer researchers are ignoring a larger body of potential cancer drug targets that are not oncogenes and might not be mutated in cancers. We call this "non-oncogene addiction." These genes are needed for tumors to survive, but they are not oncogenes; they support but do not cause the tumor state. The problem has been how to find these important drug targets since they are not changed in cancer cells. We have developed a way to do this using a new technological development called RNA interference, or RNAi. What RNAi allows us to do is to turn off each gene in a cancer cells one gene at a time. We then measure whether the cancer cell can grow and survive. If it can, then the gene is not needed for the cancer. If the cancer cell cannot grow without the gene, that gene is a potential cancer drug target. We do the same thing for normal cells. We are most interested in the genes that normal cells do not need but that cancer cells do need. In this unbiased, one-at-a-time, leave-no-stone-unturned analysis, we search through all the genes in cancer cells and ask whether they would make a good potential drug target. This allows us to find both oncogenes and non-oncogenes that might be good targets for cancer drug development. Drugs take time to make, but finding the right protein targets is key to making it happen fast. Any drugs made to these proteins could affect the outcomes of breast cancer patients from all walks of life. For early detection, we are exploring whether the immune system can act as an early warning system to indicate the presence of tumorigenic activity. If so, this could be employed as an early cancer diagnostic method. A second approach is to develop ultrasensitive protein detection methods that can detect breast cancer-specific proteins that are present in the blood in minute amounts. If we can find either auto-antibodies that are present early in cancer development or the correct cancer-specific proteins that might spill out of cancer cells and be present in the blood and detected with new ultrasensitive methods, this could lead to a quick blood test for early detection and increase the effectiveness of anti-breast cancer therapies. The fewer tumor cells present when we start treatment, the greater the chance we will be able to cure the cancer.