With advances in early detection and treatment, more women are surviving breast cancer. However, this disease remains the second leading cause of cancer death in women in Canada and the United States, exceeded only by lung cancer. Breast cancer comes in many different forms with very different treatment options. The most successful drugs block cancer cell growth fueled by the female hormones estrogen or progesterone, or by a substance called human epidermal growth factor. Tumors that don't rely on any of these three for growth are termed triple-negative breast cancer (TNBC). For this, and other aggressive forms of breast cancer, treatment options are limited and even when chemotherapy works, relapse and rapid progression commonly follow.
The Stand Up To Cancer Canada-Canadian Breast Cancer Foundation Breast Cancer Dream Team brings together a group of outstanding laboratory researchers, clinical experts, and breast cancer patient advocates from across Canada to address this problem by accelerating the development of three promising agents as new drugs for TNBC and other aggressive forms of breast cancer. The Dream Team's approach, called "targeted therapy," is to identify differences in the cancer cells that distinguish them from normal body cells, find out how those differences make the cancer cells vulnerable, and then target drugs to those points of vulnerability in order to kill the cancer cells. Their studies have identified three new approaches to target such vulnerabilities in aggressive breast cancer. The first blocks a molecule called polo-like kinase 4 (PLK4), an enzyme that drives tumor growth by helping cancer cells divide and proliferate. The second approach also blocks cell division, this time by inhibiting a molecule known as the dual specificity protein kinase TTK. Since normal cells, unlike cancer cells, do not seem to rely on PLK4 and TTK for cell division, drugs that inhibit these enzymes could be efficient and precise in killing the cancer cells, the essence of targeted therapy. The third approach that the team will follow interferes with the process of DNA replication, in which the cell makes copies of its DNA to pass on to newly divided cells. The drug being developed is believed to work by binding to the replicating DNA, stopping the cell's copying machinery in its tracks. Normal noncancerous cells can overcome this interference through a mechanism called DNA repair. In many cancer cells, however, DNA repair doesn't work properly, so the interference with DNA replication results in cancer cell death.
The hope is that by exploiting differences that separate cancer cells from the body's normal noncancerous cells, these targeted therapies will be more effective and have fewer side effects than conventional chemotherapy. Two of the compounds that the team has developed are already in early clinical trials and the third is expected to enter clinical testing during 2015. This Dream Team will accelerate development of all three potential treatments first by using state-of-the-art laboratory approaches to understand how the agents can be used most effectively against breast cancer, and then testing them in clinical trials of patients with advanced breast cancer across Canada. In the laboratory phase of drug development they will study how breast cancer cells and tumors respond to the drug. Further, they will identify specific changes in genes (mutations) or other biological molecules in the cancer cells or in the tumor microenvironment (the cells and substances that surround and support the tumors) that predict which tumors are more or less likely to respond positively during treatment. The mutations and other biological molecules that best predict response, termed biomarkers, will be measured in patients involved in clinical trials to help identify those women most likely to respond to the new drugs.
The Dream Team's goal is to pave the way for larger trials that will establish these targeted agents as new standard breast cancer treatments and to help women with TNBC and other aggressive breast cancers in the near future. By developing not only effective cancer cell-targeted therapies, but also the biomarkers that can be used to identify patients most likely to respond, the team hopes to improve survival while avoiding unnecessary toxicities, ensuring that each woman receives the best treatment possible.