Precision medicine in ovarian cancer – Predicting platinum responsiveness via an ADAM17 substrate panel

• Applicant: Dr. Nina Hedemann
• Subject Area: Gynaecology and Obstetrics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558466534

Eventually affecting at least 2/3 of patients, resistance to platinum-based chemotherapy is a critical clinical challenge in the treatment of ovarian cancer (OC) and a major factor contributing to poor outcomes, i.e., ~60% 5-year mortality, in the population with this neoplasm. Early identification of mechanisms predicting resistance, and discovery of potential novel druggable targets, ultimately could improve survival in patients with OC. A Disintegrin And Metalloprotease 17 (ADAM17) is the major sheddase of cell membrane-hosted ligands, proteolytically cleaving >80 substrates, of which at least six bind growth factor receptors. ADAM17 over-activation leads to increased substrate shedding and growth factor receptor activation. We and others have found ADAM17 and ADAM17 substrates to be highly expressed in OC cells. Recent observations suggest that by activating downstream signaling i.e. epidermal growth factor receptor (EGFR), and hence increasing cell proliferation or inducing anti-apoptotic signaling, ADAM17 and its substrates may play important roles in OC progression and metastasis. However, the role of ADAM17 and its substrates in the development of chemo-resistance needs to be more fully elucidated. Based on our previous work showing that ADAM17 and ADAM17 substrates are relatively abundantly expressed in chemo-resistant OC cells and are increasingly activated by chemotherapeutic agents in platinum-sensitive cells, we aim in the proposed project to generate an ADAM17 substrate panel to identify intracellular pathways promoting chemotherapy resistance. To do so, we will perform an unbiased masspectrometry-based substrate screen by further deploying methods that we already have developed and applied, namely generation of ADAM17-deficient cells using CRISPR/Cas9 technology, and comparison of these cells’ substrate turnover to that of their ADAM17-proficient parental cells. Moreover, in the proposed project, we seek to identify the most differentially-activated ADAM17 substrate-targeted receptors and identify efficient combinatorial treatments using a large-scale drug screening approach. Thus, we will establish a receptor tyrosine kinase (RTK)-based biomarker panel predicting response to platinum-based chemotherapy. Lastly, we intend to clinically validate this panel in biobanked serum, ascites and corresponding malignant tissues from our clinic’s patients with OC. Our overall aim is to advance precision medicine in OC by more promptly identifying chemo-resistant patients, and helping to personalize their treatment schema. Moreover, by identifying novel druggable targets, we seek to help increase treatment options for patients with OC.

• DFG Programme: Research Grants