A woman diagnosed with triple-negative breast cancer (TNBC) often receives the recommendation to start chemotherapy right away and wait up to 3 months for surgery (neoadjuvant chemotherapy). Neoadjuvant chemotherapy serves two purposes: (1) to eliminate any tumor cells that might have left the tumor and are circulating through the body (called micro-metastases) and (2) to shrink the primary tumor so that breast-conserving surgery can be performed. This approach is often effective: after treatment, about 3 in 10 patients will have no primary tumor remaining at the time of their surgery and these patients are often cured of their disease. However, for the other 70%, the future is uncertain. The presence of living tumor cells in the primary tumor that has been surgically resected suggest that there are also other tumor cells alive that may be scattered throughout the body and may later develop into metastases. Most doctors take a "watch and wait" approach, with no other treatment given until the population of cancer cells left in the body grows large enough to be detected in the clinic. This is primarily because the tumor cells that have persisted throughout neoadjuvant chemotherapy and surgery are unlikely to respond to more chemo. Also, many patients cannot tolerate (or are unwilling to undergo) additional chemo. Tragically, many of these patients will eventually die from metastatic breast cancer, primarily because we do not yet know how to kill these micro-metastatic tumor cells. The main goals of the work in this proposal are to address two of the overarching challenges identified by the Department of Defense: identify why some TNBC cancers metastasize to other parts of the body and how we can target the causes of metastasis to end mortality in breast cancer.

In cancer cells, the DNA sequence of important genes has changed, allowing the cells to survive and divide continually, which contrasts with normal cells. In TNBC, more DNA changes occur than in any other breast cancer subtype. We examined the DNA sequences of the TNBC tumors of 68 patients that endured neoadjuvant chemotherapy and found that some treated TNBCs that did not respond completely to neoadjuvant chemotherapy had many DNA copies of the JAK2 gene. These increases, called "amplifications," often lead to high tumor expression of the JAK2 protein, which is encoded by the JAK2 gene. Other amplified genes in breast cancer include HER2, which has been a highly successful target of therapy, and the development of Herceptin (which targets HER2) has changed the lives of many patients with breast cancer. In this application, we will perform experiments that will form the basis of a clinical trial of JAK2 inhibitors to see whether these inhibitors are active alone or in combination with chemotherapy for the treatment of TNBCs with JAK2 amplification. Based on what is known about the function of the JAK2 gene, we believe these amplifications may promote the metastatic spread of TNBC and may help protect the tumor cells from the toxic effects of chemotherapy. Thus, using JAK2 inhibitors could complement chemotherapy approaches.

In this project, we will (1) find out how the JAK2 gene contributes to cancer spread in TNBC, (2) test new treatments that block JAK2 function in order to improve efficacy of neoadjuvant chemotherapy treatment, and (3) identify which TNBC patients would most benefit from these new treatments. Importantly, drugs that block the function of the JAK2 gene are already used in the treatment of other cancers, and patients report side effects that are easily manageable. Early clinical trials in TNBC are already underway, and we will collaborate with the leaders of these trials to test whether our findings in the laboratory are also seen in TNBC patients treated with JAK2 inhibitors. Also, we will be able to find out if screening patients for JAK2 amplifications in their tumor is a good way to determine which patients should get JAK2 inhibitors. Because JAK2 inhibitors are already approved for use in some cancers, and because of our access to an existing clinical trial of JAK2 inhibitors in TNBC, this proposal is set to make an immediate impact on the lives of breast cancer patients. Furthermore, our translational laboratory work will help in the design of larger more focused trials to decide how to use JAK2 inhibitors and which patients are most likely to benefit.