Zebrafish Avatar for CLL Therapy Screening

Chronic lymphocytic leukemia (CLL) is the most common leukemia in western countries, typically occurs in elderly patients and has a variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis. New drugs were approved for the treatment of CLL, such as specific inhibitors targeting pathways involved in cell survival (ibrutinib, idelalisib, and venetoclax). The international recommendations on CLL treatment in case of loss of the gene TP53, which gives the patient a very dismal prognosis, include these last options as match possibilities. No biomarkers were identified to guide the choice of treatment for each individual patient and treatments are selected based on the drugs’ toxicity profile and patients’ comorbidities rather than tumor sensitivity. Often the patient is treated with some of these expensive drugs in sequence, being exposed to unnecessary toxicity. By pre-testing tumor cells’ sensitivity to the available drugs, we believe that tailored therapy would avoid unnecessary toxicities and costs and would have a significant impact on the patients’ quality of life and healthcare systems. In this project, we will explore the zebrafish Avatar model to determine in vivo differential sensitivity of patient-derived CLL cells to novel drugs available. We will compare patient response to treatment to their matching zPDX. If this project proves successful we will have developed a new in vivo screening platform for CLL, possibly extensive to other lymphoproliferative diseases.