High-grade serous carcinoma (HGSC) is the most common type of ovarian cancer. Majority of the HGSC patients experience cancer recurrence and resistance to treatments, resulting in a poor five-year survival rate of less than 40%. Research shows that genetic changes alone do not fully explain how chemotherapy resistance develops, suggesting that other factors, such as epigenetic changes that affect gene regulation, play an important role.

DYNAMITE aims to uncover the molecular mechanisms explaining why ovarian cancer cells become resistant to chemotherapy. The hypothesis is that specific cellular states, controlled by certain transcription factors (proteins that influence gene activity), can drive this resistance. By understanding these factors, DYNAMITE seeks to find new, personalized treatment targets.

DYNAMITE is a pre-clinical project with a systematic three-step approach. First, we will analyze cells from patients with recurring HGSC using single-cell epigenomics to identify pathways that define their cellular states. Next, we will study how the identified factors contribute to chemotherapy resistance by modulating their expression in patient-derived organoid cultures. These organoids will be exposed to standard-of-care chemotherapy and analyzed using genomics methods. Finally, we will test whether these organoids respond better to a panel of FDA-approved drugs or other promising compounds.

In conclusion, DYNAMITE presents an innovative strategy to identify effective therapies for ovarian cancer patients, paving the way for systematic prediction and evaluation of the most effective drug target combinations for each patient.