Ruxolitinib in Preventing Human ADH Progression to Cancer
Abstract
The overarching challenge addressed in this proposal is “prevent breast cancer.” So far, only antiestrogens are U.S. Food and Drug Administration (FDA)-approved for preventing breast cancer. They are effective, but they require 5 years of continuous treatment, have concerns of significant side effects including increased uterine cancer and blood clots, and do not prevent ER-negative cancers, which are more difficult to treat than the ER+ subtype. Consequently, even high-risk women who are still cancer-free often decline antiestrogen prevention or discontinue the treatment prematurely. Thus, new chemoprevention modalities that do not need years of treatment and can prevent both ER+ and ER-negative breast cancers are needed. Only a small fraction of premalignant lesions of the breast, atypical ductal hyperplasia (ADH), progress to cancer. Studies in several tissue types suggest that these precancerous lesions are prevented from progression due to an anticancer barrier that is normally “erected” to cause cell death in these early lesions. This is a programmed cell death, i.e., apoptosis, that is tightly controlled by a complex network of proteins. Thus, overcoming this apoptosis anticancer barrier is crucial for precancerous lesions to progress to cancer, so that protecting or restoring this apoptosis anticancer barrier pharmacologically could be an effective chemoprevention strategy. Since such an approach kills precancerous cells, a short-course treatment should be adequate, in contrast to antiestrogens, which generally only prevent cell growth and expansion, so that stopping the treatments allows the precancerous cells to resume progression towards cancer, necessitating multiple years of treatment for effective prevention. In our previous published studies using mouse models of breast cancer, we have found that the STAT5 protein activity helps overcome the apoptosis anticancer barrier and allows early lesion progression to cancer and that a short course of prophylactic treatment with ruxolitinib, which inhibits the protein (JAK1/2) responsible for activation of STAT5, slowed progression of these early lesions. These mouse data and some correlative human data have led us to start a window-of-opportunity clinical trial (TBCRC042) to examine whether in women with a premalignant lesion on core needle biopsy requiring subsequent surgical resection, short-term ruxolitinib blocks STAT5 protein activity and induces apoptosis. However, we have not yet performed laboratory experiments to test whether STAT5 also plays a crucial role in human precancerous lesions and whether pharmacologic blockade of STAT5 activity can prevent human precancerous lesions from progressing to cancer. Therefore, the hypothesis to be tested in this proposal is that in human precancerous lesions, STAT5 breaks the apoptosis anticancer barrier and instigates the progression to cancer; therefore, inhibition of anti-apoptosis protein could reduce the load of precancerous lesions in the breast and thus lower breast cancer risk. We predict that even transient or intermittent inhibition of STAT5 activity in early lesions could devitalize them and lower the risk of invasive breast cancer, while the possible adverse effects, cost, and inconvenience to women would be small. To test our hypothesis, we will pursue three specific aims. In Aim 1, we will grow human ADH in mice and test whether short-term or intermittent ruxolitinib restores the apoptosis anticancer barrier and prevents human ADH from progressing to cancer. We will also test whether ruxolitinib is superior to tamoxifen for cancer prevention and whether combining ruxolitinib with tamoxifen can better prevent cancer than either alone. In Aim 2, we will determine the impact of ruxolitinib on ADH in our ongoing window-of-opportunity clinical trial, which tests whether in women with a premalignant lesion on core biopsy requiring subsequent surgical resection, short-term ruxolitinib blocks S
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010415
Entities
People
- Yi Li
Organizations
- Baylor College of Medicine
- United States Army