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PARP goes the weasel! Emerging role of PARP inhibitors in acute leukemias.

ABSTRACT: Poly (ADP-ribose) polymerase (PARP) inhibitors, which induce synthetic lethality of BRCA mutant breast and ovarian cancers, are now under active exploration for treatment of acute leukemias, specifically acute myeloid leukemia (AML). Experimental data has revealed that DNA repair deficiencies similar to those found in BRCA mutant solid tumors function in malignant hematopoietic cells to enhance cell survival and promote therapy resistance. Preclinical studies have demonstrated that inhibition of PARP with a variety of agents can dramatically enhance the efficacy of other therapeutic approaches including cytotoxic and epigenetic chemotherapy, small molecule inhibitors (IDH and FLT3 inhibitors) and antibody drug conjugates. This has led to early stage clinical trials of multiple PARP inhibitors (PARPi) for AML patients. Despite small patient numbers, evidence of modest clinical efficacy and tolerability in combinatorial regimens support the further development of PARP inhibition as a novel therapeutic strategy for AML, particularly in select molecular subsets (MLL rearranged, FLT3 and IDH1 mutant disease.

SUBMITTER: Fritz C

PROVIDER: S-EPMC9295907 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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PARP goes the weasel! Emerging role of PARP inhibitors in acute leukemias.

Fritz Claire C Portwood Scott M SM Przespolewski Amanda A Wang Eunice S ES

Blood reviews 20200507

Poly (ADP-ribose) polymerase (PARP) inhibitors, which induce synthetic lethality of BRCA mutant breast and ovarian cancers, are now under active exploration for treatment of acute leukemias, specifically acute myeloid leukemia (AML). Experimental data has revealed that DNA repair deficiencies similar to those found in BRCA mutant solid tumors function in malignant hematopoietic cells to enhance cell survival and promote therapy resistance. Preclinical studies have demonstrated that inhibition of ...[more]

PMID: 32482307

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Project description:Triple negative tumors represent 15% of breast cancer and are characterized by the lack of estrogen receptors, progesterone receptor, and HER2 amplification or overexpression. Approximately 25% of patients diagnosed with triple negative breast cancer carry a germline BRCA1 or BRCA2 mutation. They have an aggressive biology, and chemotherapy has been the mainstay of treatment for a long time. Despite intensive therapies, prognosis is still poor, and many patients will eventually relapse or die due to cancer. Therefore, novel targeted agents that can increase the treatment options for this disease are urgently needed. Recently, a new class of molecules has emerged as a standard of care for patients with triple negative breast cancer and germline BRCA1 or BRCA2 mutation: poly (ADP-ribose) (PARP) inhibitors. In the first part of the review, we summarize and discuss evidence supporting the use of PARP inhibitors. Currently, two PARP inhibitors have been approved for triple negative metastatic breast cancer-olaparib and talazoparib-based on two phase III trials, which showed a progression-free survival benefit when compared to chemotherapy. Safety profile was manageable with supportive therapies and dose reductions/interruptions. In addition, other PARP inhibitors are currently under investigation, such as talazoparib, rucaparib, and veliparib. Subsequently, we will discuss the potential role of PARP inhibitors in the future. Clinical research areas are investigating PARP inhibitors in combination with other agents and are including patients without germline BRCA mutations: ongoing phase II/III studies are combining PARP inhibitors with immunotherapy, while phases I and II trials are combining PARP inhibitors with other targeted agents such as ATM and PIK3CA inhibitors. Moreover, several clinical trials are enrolling patients with somatic BRCA mutation or patients carrying mutations in genes, other than BRCA1/2, involved in the homologous recombination repair pathway (e.g., CHECK2, PALB2, RAD51, etc.).

Dataset Information

PARP goes the weasel! Emerging role of PARP inhibitors in acute leukemias.

Publications

PARP goes the weasel! Emerging role of PARP inhibitors in acute leukemias.

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