Targeting PARP and RAD52 to induce "dual synthetic lethality" in leukemia patients identified by gene expression and mutation profiling

Temple Univ Of The Commonwealth, Philadelphia PA

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Abstract

? DESCRIPTION (provided by applicant): Acute Myeloid Leukemia (AML) stem and progenitor cells (LSCs and LPCs) accumulate a large number of lethal double strand breaks (DSBs) due to exposure to reactive oxygen species and cytotoxic therapies, yet they survive due to their addiction to altered DNA DSB repair mechanisms. Thus, targeting these repair pathways could sensitize LSCs/LPCs to the lethal effect of DSBs. Due to the enhanced self-renewal capacity of LSCs and the high proliferation rate of LPCs, DSBs in these cells are mainly repaired by Homologous Recombination Repair (HRR). HRR is normally mediated by the BRCA1/2-RAD51 pathway, but BRCA1/2-deficient cancer cells rely on the redundant RAD52-RAD51 for DNA repair. We recently reported a peptide aptamer that exerted synthetic lethality in BRCA-deficient AML patients by targeting the RAD52 DNA-binding domain. Additionally, we demonstrated the ability to predict AML patients that would be sensitive or resistant to RAD52-dependent synthetic lethality based on BRCA1/2 mutation analyses and expression profiles. PARP inhibitors have also shown promise at inducing synthetic lethality in tumor cell lines carrying BRCA1 and BRCA2 inactivating mutations. However, PARP inhibitors were not very successful in clinical trials, and this failure may be due, in part, to the persistent activity of he RAD52-RAD51 pathway. Our preliminary data demonstrates an enhanced synthetically lethal effect in BRCA-deficient cancer cells following combination treatment with the RAD52 aptamer and PARP inhibitor. Therefore, we propose to simultaneously target RAD52 and PARP to enhance the effectiveness of PARP inhibitors in BRCA-deficient patients by inducing dual synthetic lethality. We hypothesize that patients displaying defects in BRCA pathway can be identified by gene expression profiling and that they will be sensitive to dual synthetic lethality triggered by simultaneous RAD52 and PARP inhibition.