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

Published on May 7, 2020in Blood Reviews6.125
· DOI :10.1016/J.BLRE.2020.100696
Claire Fritz1
Estimated H-index: 1
(Case Western Reserve University),
Scott Portwood6
Estimated H-index: 6
+ 1 AuthorsEunice S. Wang30
Estimated H-index: 30
Abstract
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.
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References74
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#1Paulina Podszywalow-Bartnicka (Nencki Institute of Experimental Biology)H-Index: 9
#2Silvia Maifrede (TU: Temple University)H-Index: 5
Last. Tomasz Skorski (TU: Temple University)H-Index: 33
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#1Elodie ChartronH-Index: 2
#2Charles Theillet (University of Montpellier)H-Index: 58
Last. William Jacot (University of Montpellier)H-Index: 25
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Abstract Mutation or epigenetic silencing of homologous recombination (HR) repair genes is characteristic of a growing proportion of triple-negative breast cancers (TNBCs) and high-grade serous ovarian carcinomas. Defects in HR lead to genome instability, allowing cells to acquire the multiple genetic alterations essential for cancer development. However, this deficiency can also be exploited by using DNA damaging agents or by targeting compensatory repair pathways. A noteworthy example is treat...
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#1Kathleen N. Moore (OU: University of Oklahoma)H-Index: 33
#2Nicoletta ColomboH-Index: 53
Last. Paul A. DiSilvestroH-Index: 27
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Abstract Background Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the o...
128 CitationsSource
#1Claire Fritz (Case Western Reserve University)H-Index: 1
#2Scott PortwoodH-Index: 6
Last. Eunice S. Wang (Roswell Park Cancer Institute)H-Index: 30
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Background CD123 (IL-3 receptor alpha-chain) is a therapeutic target for hematological malignancies based on high expression levels in acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and other cancers. The anti-CD123 antibody-drug conjugate (ADC), IMGN632, comprises a humanized monoclonal antibody covalently linked to a DNA - alkylating cytotoxic payload which is currently in phase 1 evaluation for relapsed/refractory CD123-positive hematological malignancies ...
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Abstract Background The poly(adenosine diphosphate–ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 (BRCA1/2). Methods We conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician’s choice (capecitabine, eribulin, ge...
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: Background: PARP inhibition is a promising therapeutic strategy for the treatment of men with metastatic castration-resistant prostate cancer whose tumors harbor homologous recombination DNA repair gene alterations. However, questions remain for many practicing clinicians about which patients are ideally suited for PARP inhibitor treatment. This report details our institutional experience using PARP inhibitor therapy in patients whose tumors harbored specific DNA repair gene alterations. Patie...
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#2Margaret Nieborowska-Skorska (TU: Temple University)H-Index: 32
Last. Tomasz Skorski (TU: Temple University)H-Index: 33
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Mutations in FMS-like tyrosine kinase 3 (FLT3), such as internal tandem duplications (ITDs), can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i’s), which are rarely curative. PARP1 inhibitors (PARP1i’s) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (...
7 CitationsSource
#1Yashodhara Dasgupta (TU: Temple University)H-Index: 7
#2Konstantin Golovine (TU: Temple University)H-Index: 1
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Abstract Inhibition of Poly (ADP-ribose) polymerase (PARP) has shown marked benefit for breast cancer with homologous recombination deficiency, whether driven by defects in BRCA1, BRCA2, or other pathway components. Since the initial approval of olaparib, a mostly investigated PARP inhibitor (PARPi), the clinical development of PARPi in breast cancer treatment has been a major emphasis. Researches in investigating platinum-PARPi combination use compared with platinum monotherapy demonstrated pro...
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#1Katherine Sullivan-Reed (TU: Temple University)H-Index: 4
#2Elisabeth Bolton-Gillespie (TU: Temple University)H-Index: 4
Last. Tomasz Skorski (TU: Temple University)H-Index: 33
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Summary PARP inhibitors (PARPis) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success. We hypothesized that RAD52-mediated DNA repair remains active in PARPi-treated BRCA-deficient tumor cells and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting ...
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