Rationale: Breast cancers are marked by a property called "genomic instability," which means their DNA is changing much faster than non-cancer cells. This gives them the ability to evolve faster and to rewire their growth instructions that makes them both harder to kill and faster growing. Unfortunately, there are many ways to accomplish this rewiring so 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. Unfortunately, this has yielded only modest progress. 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 turn off 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 many genes in cancer cells and ask whether they would make a good potential drug target.

Objective: In this grant, we propose to focus on genomic instability as a target. Breast cancer cells change their DNA rapidly because they do not replicate and repair it properly so they always have spontaneous DNA damage that leads to mutations. Many current therapies take advantage of these problems and kill breast cancer cells by adding even more damage, which overwhelms them. However, this standard chemotherapy is toxic to patients as well because it hurts normal cells. Because of their spontaneous damage, cancer cells depend upon support DNA repair pathways to fix this DNA damage to keep them alive, more so than normal cells that can tolerate turning off some DNA repair genes because they have less spontaneous DNA damage to fix. We will turn off their DNA repair genes one at a time to find which DNA repair genes they depend upon for survival. We have developed new methods to turn these genes off very efficiently. This allows us to find non-oncogenes that might be good targets for cancer drug development. We will then look for new chemicals/drugs that can inhibit those repair pathways and kill breast cancer cells by making them very sick because they will not be able to repair the damage they spontaneously generate. These drugs that act to block DNA repair will be much less toxic to patients than current chemotherapies, and some drugs against repair pathways already are working in the clinic. 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.

Impact: The ability to interfere with the pathways that allow breast cancers with genomic instability to survive will be a very important step forward in breast cancer therapeutics. Breast cancer patients with both sporadic and familial disease will benefit from these studies both from a basic knowledge point of view as well as from the identification of new avenues for drug discovery for pathways critical for cancer. Furthermore, since genomic instability is a hallmark of many different kinds of cancer, these studies are likely to have a broad impact on cancers of many types.