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The Use of Zoledronate to Impact Organ Metastasis in Breast Cancer Patients
Tumor Cell Biology IV
Bisphosphonates are the current standard care for breast cancer patients with evidence of skeletal metastasis. There are various types of bisphosphonate drugs with the newer nitrogen-containing versions (e.g. zoledronate and pamidronate) having additional properties as well as higher potency than the previous drugs (e.g. clodronate). Recent evidence suggests that zoledronate not only targets osteoclast activity in the bone, but can also inhibit activity of the matrix metalloproteinase MMP-9 in macrophages. Since we have data indicating that inflammatory cell-expressed MMP-9 is critical for the development of lung metastases in the MMTV-PyMT model of breast cancer, we propose to test if zoledronate could limit lung metastasis in this model. Liver is another common site of metastatic disease in breast cancer, hence we will also explore the potential for zoledronate to reduce liver metastasis. The cellular target of interest in these studies is the macrophage, thus there is the potential for the use of blood samples to screen for drug efficacy. We will test the feasibility of this idea using the mouse models and then screen human blood samples from patients currently receiving zoledronate to test if macrophage MMP-9 is indeed down-regulated in these patients. Our goal is to accumulate sufficient evidence to warrant a clinical trial of zoledronate as a therapeutic approach in the setting of soft tissue metastasis. While an older bisphosphonate, clodronate, failed in such a trial, we believe that positive results of the studies described here would indicate that the mechanism of action of zoledronate is sufficiently different to justify clinical testing. As a direct outcome of our proposed studies, a simple blood test would be available for use in any future clinical trial to monitor drug efficacy. Since zoledronate is already an approved drug, we envisage rapid translation of proof-of-concept studies to clinical use in a new setting.
Limiting metastatic disease is a major goal of breast cancer therapeutic approaches. One of the currently approved therapies for breast cancer patients with evidence of bone metastasis is zoledronate (Zometa ™), a bisphosphonate. The prime targets of bisphosphonates are the bone-metabolizing cells known as osteoclasts. By inhibiting osteoclast activity, bisphosphonates halt further breakdown of bone and so are valuable drugs both for patients with skeletal metastasis as well as osteoporosis from other causes. Recent studies suggest that zoledronate in particular can also affect one of the enzymes, called MMP-9, found in macrophages. Macrophages are white blood cells that are important in inflammation. In breast tumors, the presence of macrophages is known to be associated with a poor prognosis. Since we have evidence that inflammatory cell –produced MMP-9 is critical for lung metastasis in a mouse model of breast cancer, we now ask the question “can the clinically approved drug zoledronate block macrophage MMP-9 and thus limit soft tissue metastasis from breast cancer?” We will explore the answer to this question using a transgenic mouse model of breast cancer that shows metastasis to the lungs as well as a liver metastasis model. These models will also be used to test if the effectiveness of the drug can be monitored in blood samples. Finally we will turn to human patients already receiving bisphosphonates to see if evidence for the drug working on MMP-9 can be seen in their blood samples. At the end of our studies we should have accumulated sufficient evidence to warrant a clinical trial in breast cancer patients to test if treatment with zoledronate for limiting metastasis can be expanded outside of the bone setting. Importantly, we will have developed a simple test to be used in any clinical trial so that drug effectiveness can be readily monitored. Since zoledronate is an already approved drug, rapid translation of laboratory studies to the clinic could proceed following our validation of the concept of using it to target breast cancer metastasis to soft tissues.