Determinants of the Response to BTK Degraders (BTKd) in Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (CLL) is a malignant hematological disease of B cells, primarily observed in older adults. Although it is classified among indolent hematological malignancies, CLL exhibits significant heterogeneity, both in terms of its biological characteristics and its disease progression and the therapeutic strategies employed. In patients requiring treatment, the disease can relapse. Until recently, immunochemotherapy remained the standard treatment for this disease, but the last decade has seen the emergence of oral targeted therapies, such as Bruton's tyrosine kinase inhibitors (BKT1s) and BCL-2 inhibitors (BCL-2 inhibitors), which have profoundly altered patient prognosis. While the introduction of these two classes of drugs has led to improved prognosis, a rare but significant subgroup of patients, known as "double refractory," has emerged. These patients, exposed to both BKT and BCL-2 inhibitors and who have become refractory to both treatments, have a poor prognosis. To overcome this problem of resistance, molecules targeting the degradation of the BTK protein (BTKd) are currently under development. The main investigator propose the creation of a cohort and a biobank of samples from CLL patients who are candidates for or have been exposed to BTKd, in order to study the mechanisms of response and resistance to these molecules.

• Development of preclinical ex vivo culture models [Срок оценки: Up to 5 years after inclusion]
• Genetic modification of primary CLL cells [Срок оценки: Up to 5 years after inclusion]
• Genomic data analysis to identify resistance-related genes [Срок оценки: Up to 5 years after inclusion]
• Pharmacological targeting of novel candidate molecules [Срок оценки: Up to 5 years after inclusion]
• Generation of knockout cell lines for genes of interest [Срок оценки: Up to 5 years after inclusion]
• Generation of drug-resistant cell lines and comparative RNA sequencing [Срок оценки: Up to 5 years after inclusion]
• Reconstruction of the tumor microenvironment using co-culture systems [Срок оценки: Up to 5 years after inclusion]