Grant: Operating Grant

Skeletal metastases appear as complications in up to 70% of breast cancer patients. Once bone tumors are established, they are usually incurable. In advanced cases, the skeleton often bears the major tumor burden, causing considerable suffering and morbidity due to hypercalcemia, pathological fractures, cord compression and intractable pain. The current therapies against skeletal invasion use anti-resorptive agents such as bisphosphonates, but these compounds are not curative and new targets must be identified in the fight against bone metastases. Breast tumors and other types of cancer are composed of two main populations of cancer cells. The bulk of a tumor is composed of cells with limited proliferation capacity that are sensitive to conventional anti-cancer therapies. There is also a small population of long-lived cancer stem cells (CSCs) that are resistant to chemo- and radiotherapy. A notoriously difficult-to-treat cancer is the CSC-driven triple-negative breast cancer (TNBC). TNBCs have very poor prognosis because they currently lack effective therapies. Traditional cancer therapies can effectively de-bulk tumors but fail to produce long-term remissions and prevent metastases, possibly due to their inability to eliminate CSCs. Our laboratory has identified a novel target known as the parathyroid hormone-related protein (PTHrP), previously implicated in the development of bone metastases, but which has never before been associated with CSCs or TNBC. We have produced an anti-PTHrP antibody that blocks PTHrP action and is highly-efficient against breast cancer growth and metastases. Our preliminary studies suggest that PTHrP is very likely a driving force behind CSC proliferation and dissemination to distant organs. Our goal is to attack this resistant breast cancer cell population within bone with our novel blocking monoclonal antibodies against PTHrP, in combination with approved bone targeting bisphosphonates, to eradicate skeletal metastases.