Targeting CEP55 in Triple-Negative Breast Cancer
Abstract
This application addresses the overarching challenge of therapeutic targeting of triple-negative breast cancer (TNBC), the most lethal type of breast cancer. Rationale: In 2020 cancer killed almost 10 million people worldwide, and there have been an estimated 19.3 million new cancer cases. Breast cancer in females has now passed lung cancer as the most common diagnosed cancer and affects over 10% of women before age 85, placing an enormous burden on our healthcare system. Despite some spectacular recent successes in fighting breast cancer with new treatments (e.g., immune checkpoint inhibitors, antibody-drug conjugates, PARP inhibitors) and surgical procedures, many patients do not respond long term or at all. Consequently, there is an urgent need for new drugs that can target newly discovered pathways that initiate, progress, or spread cancer. New therapies are especially needed for difficult-to-treat cancers, such as TNBC and certain drug-resistant metastatic breast cancers, with about one-third of breast cancers spreading to other tissues such as lungs and brain even after surgery. There is a pressing need to develop a new approach to treating TNBC. Objectives: This project aims to devise a new type of therapy to seek out and destroy a key protein called CEP55 that is highly expressed in a wide range of solid human cancers. This protein plays a crucial role in regulating cancer cell division but is silent in normal cells of adult tissues. Studies have shown that both cancer cells and tumors require CEP55 to survive and grow, and that mice overexpressing it spontaneously induce blood and solid tumors. We aim to chemically silence CEP55 by developing a novel therapy that binds to it and signals other proteins to come and destroy it in the body. We will develop this new type of drug for metastatic breast cancer, but it may also aid in fighting other types of difficult-to-treat aggressive cancers. Aim 1: To investigate the role of CEP55 and associated signaling pathways in regulating breast cancer metastasis. Aim 2: To develop a new class of drug that can silence CEP55 by breaking it down in TNBC breast cancer cells. Aim 3: To optimize delivery, efficacy, and safety of new experimental drugs in preclinical breast cancer models. Outcomes: This research will develop an innovative new drug to destroy a key cancer-causing protein CEP55, enabling therapy for difficult-to-treat aggressive breast cancers refractory to other drugs. The work plan will demonstrate a novel chemotherapeutic approach developed to silence and breakdown CEP55 in breast cancer cells and provide preclinical information on the effectiveness of chemically silencing CEP55 in mouse models of metastatic breast cancer. The study has the potential to rapidly facilitate translation of a new discovery to the clinic. This highly innovative approach may represent a new breakthrough treatment for cancers and cause a paradigm shift in how aggressive cancers might be treated in future. Furthermore, safety and efficacy will be established at an early phase of the drug development process, reducing later clinical failure and thereby lower the prohibitively high cost of drug development. Given poor outcomes for patients with aggressive cancers, and metastatic breast cancers in particular, this is an exciting new opportunity to impact a vital public health goal to reduce mortality and improve quality of life for patients with difficult-to-treat cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210428
Entities
People
- David P. Fairlie
Organizations
- United States Army
- University of Queensland