Projects & Grants
|Detection of new biomarkers in resistance to Venetoclax
|doc. RNDr. Michal Šimíček, PhD.
|1/2018 - 12/2019
|Specifický VŠ výzkum
|For the successful treatment of cancer and the elimination of side effects, it is necessary to develop effective therapy that targets specificaly the aberrant cells. A wide variety of drugs with a known mechanism of action are currently available. Parameters for patient stratification are, however, very limited. A typical feature of haematological tumors is increased expression of BCL family anti-apoptotic proteins (BCL2, BCL-XL, MCL-1). In recent years, a highly specific BCL2 inhibitor - venetoclax (ABT199), which mimics the binding of BH3 protein to BCL2 and inhibits the anti-apoptotic function of BCL2, results in induction of apoptosis specifically in tumor cells with high BCL2 expression. Pilot studies with venetoclax give promising results esp. in chronic lymphocytic leukemia. Cell line models and initial studies in patients with haematological malignancies suggest that increased expression of other BCL family proteins (BCL-XL and MCL1) leads to saturation of BH3 proteins and resistance to BCL2-specific venetoclax. The mutation ratio of BCL2 and BCL-XL/MCL1 can thus be potentially used to stratify patients eligible for venetoclax treatment. In some cases, however, this ratio does not correlate with a positive therapeutic response. The primary objective of the present project is therefore a determination of the BCL2 vs BCL-XL / MCL1 expression ratio and a its correlation with the treatment response in patients with multiple myeloma and other haematological malignancies who have been determined for venetoclax treatment. Samples obtained from patients with a preferred expression ratio (BCL2>>BCLXL/MCL1) who resemble a resistance to venetoclax will be an important resource in follow-up projects for the identification of new molecular genetic markers. Application of acquired knowledge in the diagnosis and selection of patients for targeted therapy will thus significantly increase treatment efficiency and, in particular, prevent the development of resistant cells.