Grant: Project Grant

Bone metastases occur in ~70% of patients with advanced breast cancer. Most patients die because of metastatic invasion to sites such as the skeleton, brain, liver etc., not from the primary breast tumour. Once breast cancer-derived metastases are established, the condition is generally considered incurable. The skeleton is the main target for breast cancer-derived metastasis, and bone is speculated to be a crucial "reservoir" for cancer expansion to further sites. Current treatments (bisphosphonates and Denosumab) have limited efficacy and aren't curative: they only target the bone. The parathyroid hormone-related protein (PTHrP) is a signalling molecule associated with many tumour types. PTHrP is also a crucial driver of skeletal metastasis. However, there are no treatments currently targeting PTHrP. We hypothesize that targeting both the bone and PTHrP may be curative. We will further investigate PTHrP's role using the latest RNA sequencing technology to determine the cellular mechanisms tied to PTHrP's actions at all stages of metastasis. We will evaluate two new therapeutic approaches (anti-PTHrP monoclonal antibodies combined with bisphosphonates) to counter PTHrP's driving action in metastatic expansion. We will use rapid, low intrusiveness diagnostics (liquid biopsies) to validate the therapeutic efficacy of anti-PTHrP monoclonal antibodies on circulating tumour cells from patients with advanced triple-negative breast cancer (a notoriously hard-to-treat condition). We aim to address the urgent need to improve cancer detection technologies and therapies that address cancer spread and bone metastasis. Earlier intervention and new treatment options can lead to better health outcomes in the fight against cancer.