PM.20.049 – Tackling the genomic complexity of endocrine resistance in breast cancer
The central aim of this project is to improve clinical management of patients with metastatic luminal breast cancer (BC). Luminal BC is the most common cancer in women and the cause of the majority of breast cancer related deaths. Both in early- and late-stage luminal BC, the estrogen receptor (ER) is considered a key driver, and multiple treatments are centered around the blockade of hormone-dependent ER activation by anti-hormonal treatment alone or in combination with inhibitors of cyclin-dependent kinases (CDK) 4/6. Unfortunately, resistance to these treatments is common in luminal BC patients, and the mechanisms of resistance are poorly understood. In addition, since clear guidelines for selecting the most promising treatments are currently lacking, it is of the utmost importance to generate tools to identify those patients benefiting from a specific therapeutic strategy, in order to maximize efficacy whilst minimizing adverse side effects. Genome sequencing of metastatic breast cancer patients, including concerted efforts in the Netherlands through the Hartwig Medical Foundation, has shown that the genetic causes of resistance are multifactorial. In this project we will generate isogenic breast cancer models which represent all known genetic heterogeneity of the disease. This resource allows us to study therapy resistance mechanistically in vitro and in vivo as well as to exploit this to screen for effective targeted drugs. We aim to engage SMEs and big Pharma, diagnostic companies, regulatory bodies and patient organizations to develop personized treatment from the bench to the bed-side. The results from this project are expected to deliver novel targeted combination treatments accompanied by companion diagnostic biomarkers. These results will impact the quality of life for mBC patients directly and, in the long run, improve cure rates for patients with primary disease.
Breast cancer, drug screening, therapy resistance
Leiden University (LEI), The Netherlands Cancer Institute (NKI)
|Organisation||Erasmus MC (EMC) Cancer Institute, Rotterdam, the Netherlands|
|Name||Prof. dr. J.W.M. (John) Martens|