Research Theme 5

Identification of critical drug combinations and biomarkers for personalized cancer treatments.

Background

New and more effective cancer therapies will require an expansion of the repertoire of selective cancer drugs. We will focus on identifying novel drug targets and drug combinations using gene inactivation and chemical compound screening technologies. These analyses will be carried out in all model systems available within Oncode. We will focus specifically on drugs that have limited or no clinical efficacy as single therapies. We will search for more effective combinations involving these existing agents. In addition, we will employ modern technologies to study the biological workings of effective existing anticancer drugs. These will reveal biomarkers for genes actively involved in the drug biology, which will be investigated as biomarkers for more personalized treatments.

Theme aims

  1. Identification of novel combination therapies for cancer – Existing targeted cancer drugs with limited activity will be used in genetic screens. We aim to identify enhancers for these drugs and thereby create effective combination therapies from drugs with limited individual efficacy.
  2. Identification of context-dependent drug targets – Specific tumours may harbour specific undruggable cancer mutations. We will search for vulnerabilities in these mutations and study the underlying biology to identify new druggable targets and biomarkers.
  3. Novel targets in signalling pathways – Up to 15 major signalling pathways are perturbed in cancer. We aim to identify currently unknown components of these pathways using our recently developed approach to measure activity of these signalling pathways. These new components could potentially be druggable targets and biomarkers of cancer.
  4. Identifying vulnerabilities in drug-resistant cancer cells – Drug resistance currently hampers the treatment of cancer. We will look for acquired vulnerabilities using genetic screening of resistant human tumour samples and models. Understanding the clonal and nonclonal development of such vulnerabilities can potentially yield new druggable targets.
  5. Studying drug responses in organoid-based models – Linking drug response to specific genetic mutations in heterogeneous tumour samples is challenging. We will therefore use organoids combined with CRISPR/Cas9 technology to create models that harbour only specific genetic mutations. This will permit evaluation of drug responses in specific genetic settings.
  6. Defining the biological effects of established anticancer drugs – Many cancer drugs we know of to date have substantial toxicity. Reanalysis to better understand how these drugs work biologically may reveal additional anticancer effects. Exploring the chemical space around the drugs may lead to new treatment options with less toxicity.

Please find a more detailed description in our Strategic Plan.

Theme leader

Wilbert Zwart
Huib Ovaa

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