DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Amplification of JAK2 in Breast Cancer: A Molecular Lesion that Can Be Exploited Now

Posted October 07, 2016
Rebecca Cook, Ph.D., Justin Balko, Pharm.D., Ph.D., and Melinda Sanders, M.D., Vanderbilt University

Rebecca Cook, Ph.D., Justin Balko, Pharm.D., Ph.D., Melinda Sanders, M.D. (left to right) Vanderbilt University

(Left to right): Rebecca Cook, Ph.D., Justin Balko, Pharm.D., Ph.D., Melinda Sanders, M.D.
Vanderbilt University

The recipients of a fiscal year 2013 (FY13) Breakthrough Award Level 2, Drs. Rebecca Cook, Justin Balko, and Melinda Sanders are advancing molecular medicine for women with triple-negative breast cancer (TNBC), one of the deadliest forms of breast cancer.

Molecular targeted therapies have led to some success stories in breast cancer research. Drugs targeting the estrogen receptor and HER2 receptor have received clinical approval, and they are routinely used to treat women whose breast cancers express the corresponding target. Unfortunately, TNBCs lack these targets (including the progesterone receptor), which means these patients cannot benefit from precision medicine as it now stands. TNBCs are instead primarily treated with traditional chemotherapy and surgery. Unfortunately, many patients either do not respond to treatment or respond only partially before developing distant metastases.

The key to unlocking precision medicine for TNBC is to discover and attack new molecular targets. The team has been studying one potential target, a protein called Janus Kinase 2 (JAK2). In an earlier study, they examined the tumors of patients with TNBC who did not respond to chemotherapy and found that many patients' tumors had extra copies of the JAK2 gene. They further demonstrated that TNBC patients with amplified JAK2 have markedly lower recurrence-free and overall survival compared to patients whose TNBCs lack extra copies of JAK2. Interestingly, their team showed that receiving chemotherapy increases the number of copies of JAK2 in these patients, and the number continues to rise as they develop metastases. This suggests a critical role for JAK2 in tumor progression and resistance to chemotherapy.

The team is investigating exactly how JAK2 contributes to cancer spread in TNBC and are testing whether treatments that block JAK2 function will improve the efficacy of chemotherapy for TNBC patients with amplified JAK2. They discovered that combining paclitaxel with the JAK2 inhibitor NVP-BSK805 significantly reduced both tumor growth and metastatic potential in mouse xenograft models. Moreover, combining NVP-BSK805 with docetaxel was found to be effective in tumors that were already resistant to docetaxel alone, suggesting that the combination may be therapeutically beneficial. Furthermore, they also discovered that ruxolitinib, another approved drug that targets both JAK2 and its cousin JAK1, was not effective, suggesting that specific JAK2 inhibitors may be the better approach.

Most importantly, drugs that block the function of JAK2 are already used in the treatment of other cancers, and patients report side effects that are easily manageable. Therefore this research is positioned to make an immediate impact in the lives of breast cancer patients. Early clinical trials in TNBC are already underway, and Drs. Cook, Balko, and Sanders are working in collaboration with the leaders of these trials to test whether their findings in the laboratory are also seen in patients. This research points the way forward for precision medicine in TNBC, as the team plans to investigate whether screening for JAK2 amplifications is a good way to determine which patients should receive JAK2 inhibitors.

These exciting results are pushing the boundaries of precision medicine for one of the deadliest forms of breast cancer, bringing hope for a breakthrough to TNBC patients.

Publications:

Balko JM, Schwarz LJ, Luo N, et al. 2016. Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence. Sci. Transl. Med. 8(334):334ra53.
http://stm.sciencemag.org/content/8/334/334ra53

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Last updated Friday, October 7, 2016