David J. Tweardy, M.D., Michael T. Lewis, Ph.D., Mothaffar F. Rimawi, M.D.
We are proposing in this V Foundation Translational Grant application to continue to transition C188-9, a small-molecule inhibitor of the cancer-causing protein, Stat3, into an oral drug for use in treating patients with breast cancer and cancer cachexia. The target cancer is a subtype of breast cancer for which there currently are no available targeted therapies in the clinic i.e. breast cancers that do not express the estrogen receptor (ER-), the progesterone receptor (PR-) or the human epidermal growth factor receptor (HER) 2 receptor (HER2-). This subtype of breast cancer, often referred to as triple-negative breast cancer (TNBC), accounts for 20% of breast cancer, is characterized by an aggressive phenotype, is preferentially found in younger women and in African-American women, and has been associated with poor prognosis. Recent studies by us and others has demonstrated that Stat3 is activated in 70% of TNBC tested and that Stat3 activity makes a critical contribution to the growth of these tumors. Thus, Stat3 may be a key target in this subtype of breast cancer. We have developed the capability of testing C188-9 for its ability to inhibit the growth in mice of TNBC tumors that have been transplanted directly from patients. This capability allows us to determine accurately whether or not a patient with TNBC will respond to C188-9. Thus far, we have tested C188-9 in two TNBC patient-derived xenograft (TN-PDX) models in which activation of Stat3 was demonstrated. One TN-PDX model was resistant to standard chemotherapy (docetaxel), while the second TN-PDX model was sensitive to docetaxel. We observed a striking benefit in both models when C188-9 treatment was added to docetaxel. The docetaxel-resistant TN-PDX was converted to docetaxelsensitive by the addition of C188-9, while the docetaxel responsive TN-PDX demonstrated an improved tumor response by shrinking 4-fold further with the addition of C188-9. We have determined that C188-9 given by mouth at high doses is quite safe in mice, rats and dogs. C188-9 also reached high levels in the bloodstream and tumors borne by these animals with 2-fold higher levels being achieved in the tumors than in the bloodstream. As outlined in this proposal (Aim 1), we plan to perform an animal clinical trial using 23 TN-PDX models, and thereby learn the breadth of responses to C188-9 we can expect in patients with TNBC. This information will be very useful for designing clinical trials to test the effect of C188-9 in combination with docetaxel in TNBC patients. The animal clinical trial will also allow us to determine if reduction in the level of activated Stat3 in blood cells and in tumors can serve as a marker that we can follow in patients as evidence of successful targeting of Stat3 by C188-9.
Cachexia is the second clinical application for C188-9 that we are exploring in this proposal. Cachexia is the muscle wasting process causing progressive muscle weakness in nearly all patients with cancer. Cancer cachexia is a major cause of morbidity and reduced quality of life in patients with cancer, including breast cancer, and it directly causes up to 25% of all cancer deaths. We recently demonstrated that cachexia in cancer involves a signaling pathway within skeletal muscles that links Stat3 activation with upregulation of myostatin, a hormone that serves as the major negative regulator of muscle mass. Targeting myostatin in mouse models of cancer cachexia not only reversed cachexia but also improved survival despite continued growth of tumor. However, patients with cachexia who have been treated with direct myostatin inhibitors developed unexplained bleeding, which has halted further testing of this approach. We demonstrated that C188-9 treatment of mice with tumors that cause cachexia prevents activation of Stat3 within their skeletal muscles. Consequently, levels of myostatin were not increased and muscle wasting was prevented. Importantly, treatment with C188-9 did not cause any ill effects in mice. In fact, tumor-bearing mice treated with C188-9 gained weight and maintained muscle strength. One of the goals of the clinical trials outlined in Aim 2 of this proposal is to begin to determine if C188-9 treatment of patients with TNBC prevents them from developing muscle loss, weakness, and/or fatigue.
The successful completion of the studies outlined in this proposal will provide additional strong support for the overarching concept that C188-9 can be used safely and effectively as an oral agent to treat patients with breast cancer, particularly TNBC, in combination with standard chemotherapy to improve therapeutic responses, as well as to prevent cancer cachexia.