Description:
Leukemia stem cells (LSCs), and especially quiescent LSCs, have a dual role as tumor initiating and therapy-refractory cells. Therefore, even if anti-tumor treatment clears a disease burden consisting mostly of leukemia progenitor cells (LPCs), it usually fails to eradicate LSCs and therapy-resistant LPCs. One of the major obstacle is the bone marrow niche condition (hypoxia, cytokines, cell-cell interaction), which protects leukemia cells from cytotoxic activity of currently used drugs. LSCs, including quiescent LSCs, and also LPCs accumulate spontaneous and drug-induced highly lethal DNA double-strand breaks (DSBs). Thus, survival of LSCs/LPCs may depend on DSB repair and targeting these pathways could sensitize LSCs/LPCs to the lethal effect of unrepaired DSBs. DSBs, the most lethal DNA lesions, are repaired by two major mechanisms, homologous recombination (HR) and non-homologous end-joining (NHEJ). BRCA -mediated HR and DNA-PK –mediated D-NHEJ repair DSBs in proliferating cells and D-NHEJ plays a major role in quiescent cells. PARP1 -dependent back-up NHEJ (B-NHEJ) serves as back-up in both proliferating and quiescent cells. Co-existence of these pathways creates the opportunity to apply “synthetic lethality” triggered by PARP1 inhibitors (PARP1i) in DNA-PK –deficient therapy-refractory quiescent LSCs and BRCA/DNA-PK-deficient therapy-resistant proliferating LSCs/LPCs.
Cel:
The first hypothesis is that Gene Expression and Mutation Analysis (GEMA) can select individual patients with AML/ALL which will be sensitive to “synthetic lethality” triggered by PARP1i combined with standard drugs. In Aim #1 leukemia samples from individual patients expressing low levels of at least one gene in each BRCA and DNA-PK pathway (BRCA/DNA-PK deficient), and also these which are BRCA/DNA-PK proficient will be identified by GEMA. BRCA/DNA-PK deficient and proficient AMLs/ALL will be treated in vitro (in conditions mimicking peripheral blood and bone marrow niche) and in vivo (NSG mice bearing primary leukemia xenografts) with PARP1i (olaparib, talazoparib) +/- standard drugs. This precision medicine-guided synthetic lethality should eliminate BRCA/DNA-PK deficient quiescent LSCs and proliferating LSCs/LPCs (dual cellular synthetic lethality). The second hypothesis is that alternative RAD52-RAD51 HR pathway diminishes therapeutic effect of PARP1i in BRCA/DNA-PK deficient leukemia cells. Therefore PARP1i should be combined with RAD52 inhibitor (RAD52i) to achieve the best therapeutic effect. In Aim #2 we will determine if targeting of RAD52 enhance anti-leukemia effect of PARP1i (dual molecular synthetic lethality) in BRCA/DNA-PK deficient leukemias in vitro (in conditions mimicking peripheral blood and bone marrow niche) and in vivo (NSG mice bearing primary leukemia xenografts).
Requirements:
Accomplished Master degree in biotechnology, biology or related studies, experience in cellular biology is required. Candidate should have high motivation and dedication to work in science as well as determination to solve scientific problems; should be able to work independently and as a part of the team. Good command of English (both, oral and written) is necessary. Previous experience in the laboratory work is necessary. Candidates must not have resided or carried out their main activity (work, studies, etc.) in Poland for more than 12 months in the past 3 years.
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