Outsmarting cancer by understanding it will bring us closer to the end in the fight against cancer. In the Ruiz-Saenz lab, we strive to understand the molecular mechanisms underlying response and resistance to targeting therapies, with an especial focus on the role of tumor-associated aberrant glycosylation in breast cancer.
Breast cancer ranks as the most prevalent cancer in women, with one in five patients diagnosed as HER2-positive. The main driver of this disease is HER2, a glycoprotein massively overexpressed on the surface of the cancer cells. This dependency exposes a cancer vulnerability that has been exploited therapeutically with the development of HER2-targeting therapies that have significantly improved patient clinical outcomes. Yet, a significant number of patients do not respond or develop resistance to the current treatments. The molecular mechanisms driving resistance and cancer progression are complex and encompass not only the cancer cells but their interactions with the surrounding microenvironment, leading to cancer cell survival, immune evasion, and metastasis.
Our ultimate goal is to provide deeper insights into the field of personalized medicine in breast cancer, maximizing the translational impact of our research and thereby hopefully contribute to the improvement of targeted therapies for the treatment of cancer.
Research line 1: Deciphering the impact of aberrant glycosylation on the efficacy of HER2-targeting therapies
Despite the advances in cancer research, resistance to therapies and cancer progression remain a burden in the successful treatment of cancer. In HER2-positive breast cancers, multiple mechanisms of resistance have been described. However, an important aspect of cancer cells has been largely overlooked: their sugar coating. Altered glycosylation is a hallmark of cancer and is involved in processes such as invasion, angiogenesis, and immune response modulation. In this context, using clinical data and co-culture in vitro models, we aim to provide a new focus to the challenge of resistance by uncovering the impact of aberrant glycosylation of the efficacy of antibody-based HER2-targeting therapies, including a promising antibody-drug conjugate developed by AstraZeneca.
Research line 2: Identifying markers of response and resistance to the antibody-drug conjugate trastuzumab-deruxtecan (T-DXd)
The majority of breast cancers do not show amplification of HER2 and these cancer patients have not benefited from HER2-targeting treatments. Fortunately, this treatment paradigm has been recently challenged in light of the exceptional efficacy seen with a new HER2-targeting agent, trastuzumab-deruxtecan (T-DXd). T-DXd has shown impressive results in HER2-low cancer patients; an unprecedented finding for HER2-targeting therapies. Yet, a significant number of patients do not respond or will eventually develop resistance to T-DXd. Therefore, we aim to identify the molecular players that orchestrate T-DXd efficacy in breast cancer, integrating 3D cancer cell models, high-throughput approaches, CRISPR-Cas9 technology and co-culture systems.
Research line 3: Developing new tools for assessing the efficacy of antibody-based targeting therapies
Our lab has led the design and establishment of an immune-cancer co-culture in vitro assay to measure antibody-dependent cell cytotoxicity. This relevant co-culture system allows to study the interplay between cancer and immune cells. It consists of natural killer cells engineered to stably express CD16, for optimal cytotoxicity, and a fluorescence marker for imaging assays. We have successfully validated this co-culture system with the HER2-targeting agent trastuzumab, used as first line treatment for HER2-positive patients.
Collaborators
Mark Moasser (University of California San Francisco, USA), Laura van’t Veer (University of California San Francisco, USA), Jean-Philipe Coppe (University of California San Francisco, USA), John Martens (Erasmus University Medical Center, The Netherlands), Reno Debets (Erasmus University Medical Center, The Netherlands), Erik Danen (Leiden University, The Netherlands), Gema Moreno-Bueno (MD Anderson Cancer Center España; Autonomous University of Madrid, Spain), Verónica Torrano (University of the Basque Country, Spain). Pharma: Daiichi Sankyo (AstraZeneca).
