Titles and Affiliations
Professor of Experimental Surgical Oncology
Group Leader, Department of Biomedicine
Research Area
Identification of mechanisms of resistance to endocrine therapy plus CDK4/6 inhibitors in estrogen receptor-positive/HER2-negative advanced breast cancer.
Impact
Breast cancer is the most common cancer among women worldwide with 2.6 million new cases diagnosed per year, over 70 percent of which are estrogen receptor (ER)-positive. Endocrine therapy, the standard of care for this subtype, improves overall survival compared to chemotherapy but 30 to 40 percent of cases, tumors will become resistant to it. Further, endocrine-resistant breast cancer cells can metastasize, initiating an inexorable downhill course; drug-resistant metastasis is the main cancer-related cause of death and currently incurable. Several studies have shown that CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy are highly effective compared to endocrine therapy alone in some patients. However, resistance can still occur and the mechanisms underlying it remain poorly understood. Dr. Bentires-Alj is focused on uncovering the molecular mechanisms involved in therapy resistance in ER-positive breast cancer.
Progress Thus Far
Dr. Bentires-Alj and his colleagues have developed patient-derived breast cancer laboratory models and treated them with endocrine therapy alone or in combination with CDK4/6 inhibitors to generate models of therapy resistance. Analyzing RNA and protein profiles from sensitive versus resistant models, the team identified specific candidate pathways that may drive resistance to these standard-of-care treatments. After validating these candidates at both the RNA and protein levels, the team employed overexpression and CRISPR-based gene knockout techniques to simulate activating or inhibitory signaling through these pathways, establishing the key tools needed to pinpoint the precise mechanisms that allow tumors to escape treatment.
What’s Next
In the coming year, they will manipulate the genes and proteins necessary for this candidate pathway to function in order to tease out the causal mechanisms involved in the development of resistance. In parallel, his team will test new inhibitors of the target proteins as they become available. In the coming year, Dr. Bentires-Alj and his team will run larger-scale drug screening tests to study resistance to hormone therapy and CDK4/6i drugs in breast cancer cells. Their ultimate goal is to develop strategies to circumvent resistance to therapy in ER-positive breast tumors as well as identify new mechanism-based personalized therapies for these patients.
Biography
Mohamed Bentires-Alj, PharmPhD is a Professor at the University of Basel, Switzerland and Chair of the Basel personalized health cancer cluster and Chair of the Swiss Personalized Oncology Scientific Board. His research focuses on the mechanisms of breast cancer plasticity, resistance to therapy, and metastasis in order to develop strategies to personalize breast cancer treatment. His team utilizes a multi-level approach–molecular, cellular, and whole organism—to assess mechanisms that influence normal and neoplastic breast stem cells, the role of tumor dormancy in metastasis, and the development of therapy resistance.
Prof. Bentires-Alj established a solid niche in cancer research with early studies published in prestigious journals such as Nature, Cancer Cell, and Nature Medicine. His achievements have garnered several international grants, and he has been recognized by several national and international awards including The Cloëtta Prize (2020) which honors those who have distinguished themselves in medical research, The American Association for Cancer Research
(AACR) Outstanding Investigator in Breast Cancer Research Award (2015), The Wenner
Award, Swiss Cancer League (2014), and Komen for the Cure EACR award (2014). In addition to mentoring students in the biology of stem cells and metastasis, and experimental cancer research, Prof. Bentires-Alj has (co)organized numerous international meetings, workshops, and courses and is frequently invited to speak at national and international conferences and Think tanks.
