Parathyroid Hormone-Related Peptide (PTHrP) as a New Target for Metastatic Breast Cancer: Evaluation in Preclinical Models
Abstract
Overarching Challenges: The first one addresses the question of why some breast cancers become life-threatening metastasis by examining the link between a hormone called parathyroid hormone related protein (PTHrP) and tumor progression. The second overarching challenge aims at the elimination of mortality associated with metastatic breast cancer by testing the ability of a monoclonal antibody against PTHrP to halt the progression of triple-negative breast cancer (TNBC) to the skeleton. What types of patients will it help and how will it help them? The main patient population targeted by our study is women suffering or at risk of developing metastases to the skeleton. Our targeted therapy with a blocking mAb against PTHrP may be effective in all types of breast cancer spreading to the skeleton by targeting the cancer cell at all stages of tumor progression. In this proposal, we will target preferentially TNBC, a notoriously hard to treat disease with poor prognosis. TNBC are also enriched in a subtype of tumor cells called "tumor initiating cells" or TICs, which is particularly resistant to all forms of chemotherapy. Our proposal aims to study parathyroid hormone-related protein (PTHrP), a hormone frequently deregulated in breast and other solid tumors. Our research results to date suggest that PTHrP helps drive breast cancer throughout its entire course, from early stages of the primary tumor in the breast to extensive metastatic invasion and that it controls the development of TIC. We have produced in our laboratory a monoclonal antibody against PTHrP that efficiently blocks its action and stops the spread of cancer cells to other organs in animal models very efficiently. What are the potential clinical applications, benefits, and risks? Our blocking mAb is highly effective in skeletal metastases. Current therapies for skeletal metastases are targeting the bone microenvironment to slow its activity. Such agents known as bisphosphonates are currently approved for the treatment of established bone metastases and are effective in reducing its complications such as pain, nerve compression, and fractures. However, they do not cure the disease and do not extend the life of these patients. Our mAb therapeutic approach used in combination with these potent bisphosphonates may eradicate bone metastases, providing a complementary and potent combination. We propose to confirm the usefulness of our antibody as a potential treatment in human preclinical systems both in the preventive setting prior to the development of bone lesions and when these bone lesions are established. The confirmation of PTHrP as a novel target will open the door to testing this treatment in many PTHrP-overexpressing oncological conditions that frequently spread to the skeleton such as prostate, lung, and thyroid cancers. At present, the risks of the proposed therapy are not known. Our preliminary studies in mice have shown no detectable side effects. However, toxicology studies in larger animals are needed and will be conducted prior to submission to regulatory agencies for approval in early phase clinical trials. What is the projected time it may take to achieve a patient-related outcome? We are planning to move rapidly to the next phases of clinical application within the next 2 years by producing human monoclonal antibodies and testing their efficacy and potential side effects in rats and monkeys. Successful early phase trials will clear the path for Food and Drug Administration approval shortly thereafter. What is the likely impact of this study on ending breast cancer? Because PTHrP is overexpressed in over 50% of all breast tumors and with higher frequency in TNBC, the potential benefit of this novel therapy in achieving remission or cure of the disease in chemoresistant patients is high.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510723
Entities
People
- Richard Kremer
Organizations
- McGill University Health Centre
- United States Army