Bone metastases treatment
Breast cancers are prone to metastasize to bone and around 70-80% of patients with advanced disease exhibit bone metastases. These skeletal lesions can be fatal or may rapidly impede the quality of life of patients by causing pathological fractures, hypercalcemia, nerve compression and loss of mobility. Most of these patients will also experience substantial, life-altering cancer-induced bone pain. Therefore bone metastases from breast cancer represent a major problem of public health. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and have demonstrated clinical utility in the palliative treatment of patients with bone metastases. There is now extensive in vivo preclinical evidence that bisphosphonates can reduce skeletal tumor burden and inhibit the formation of bone metastases in animal models. In addition, bisphosphonates appear to have direct antitumor effects but with doses that are not compatible with clinical use. It may be relevant to combine the action of bisphosphonates with a physical agent. Indeed, ultrasound treatment has been proposed by several authors to enhance the repair of long bone injury. In addition, other studies indicate that combined treatment using chemotherapy and HIFU has a synergistic effect on solid tumors progression through a prolonged slowing of tumour growth, suggesting that such combined therapy could be useful. The use these osteogenic effects with or without the action of drug for tumor growth inhibition or anti-tumor effects in bones has never been suggested.
In a preliminary unpublished study we have observed that the treatment of metastatic animals with a bisphosphonate in combination with ultrasound not only inhibits bone destruction but also exhibits antitumor effects, suggesting that such a therapeutic strategy might be a promising approach for treating bone metastasis from breast cancer. However, the reasons why such a treatment strategy combining a bisphosphonate with ultrasound reduces skeletal tumor growth are unknown. Further investigations are therefore needed to understand the physical and/or biological phenomena responsible for this antitumor effect, and then optimize this novel treatment strategy. A clinical use of this method is not conceivable without this understanding. Thus, it is important to determine if a clinically relevant combination of ultrasound producing mechanical and/or thermal effects in combination with a relevant dosing regimen of bisphosphonate can achieve meaningful antitumor effects in animal models of bone metastasis. We will use a mouse model of human breast cancer bone metastasis to examine the effects of different treatment strategies combining ultrasound and different dosing regimens of a bisphosphonate (zoledronic acid) on osteolysis and skeletal tumor growth.