PARP Inhibitors and Haematological Malignancies—Friend or Foe?

Skelding, Kathryn A.; Lincz, Lisa F.

doi:10.3390/cancers13215328

Cited by 9 publications

(9 citation statements)

References 169 publications

(265 reference statements)

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“…The development of secondary myeloid neoplasm (t-MNs) following the use of PARPi in breast, ovarian and pancreatic cancers highlighted the potential toxicity of PARP1 inhibition in healthy hematopoietic precursors [ 163 , 164 ]. Indeed, the overall incidence of t-MNs shifts from 0.3 to 1% of patients depending on primary tumor subtypes and PARPi used in the study [ 165 ]. Nevertheless, the incidence of t-MNs after PARPi is significantly lower than the number cases of t-MNs following the use of conventional chemotherapy (overall incidence 0.8% to 6.3%) [ 166 , 167 ].…”

Section: Clinical Activity Of Parp Inhibitors In Acute Leukemiamentioning

confidence: 99%

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

et al. 2022

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The members of the Poly(ADP‐ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a “BRCAness phenotype.” AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes (FLT3-ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members (STAG2), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.

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Section: Clinical Activity Of Parp Inhibitors In Acute Leukemiamentioning

confidence: 99%

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

et al. 2022

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“…The advantages and drawbacks about a possible use of PARPi for the treatment of hematological malignancies have been recently extensively reported by Skelding and Lincz [ 312 ]. The use of PARPi was not originally assessed for the treatment of hematological malignancies due to the very low frequency of BRCA1/2 mutations in these tumors [ 313 ].…”

Section: Considerations About the Use Of Parpi For Hematological Mali...mentioning

confidence: 99%

“…Moreover, the occurrence of secondary myeloid malignancies has been described in solid cancer patients treated with PARPi, fostering doubts about their possible use for the treatment of hematological malignancies. However, since besides BRACA1/2 defects, additional deficiencies involving the DNA repair machinery might also provide a ‘BRCAness’ phenotype and be predictive of PARPi sensitivity, PARPi might play a role in the management of distinctive blood cancers, defective in HR and DSBs repair [ 312 , 314 ].…”

Section: Considerations About the Use Of Parpi For Hematological Mali...mentioning

confidence: 99%

“…Several preclinical investigations, although providing conflicting observations, have shown how olaparib, veliparib, rucaparib, and talazoparib may induce synthetic lethality in acute leukemia cells when combined with different chemotherapeutic agents or irradiation, as described by Skelding and Lincz [ 312 ]. Accordingly, veliparib, alone or in combination with chemotherapy, has provided encouraging clinical results in the context of early clinical trials performed mainly on AML, myeloproliferative neoplasms (MPN) and lymphoma patients, showing good tolerability and, when assessed, 16–25% response in AML patients [ 312 ]. Of note, experimental observations have suggested that high levels of H2AX histone phosphorylation induced by the treatment might represent the best predictor of favorable clinical outcome [ 315 , 316 ].…”

Section: Considerations About the Use Of Parpi For Hematological Mali...mentioning

confidence: 99%

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Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints

Franzese

Graziani

2022

Cancers

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Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage may affect the tumor immune microenvironment and immune-mediated anti-tumor response through several mechanisms. In particular, increased DNA damage has been shown to induce the activation of type I interferon pathway and up-regulation of PD-L1 expression in cancer cells, which can both enhance sensitivity to Immune Checkpoint Inhibitors (ICIs). Despite the recent approval of ICIs for a number of advanced cancer types based on their ability to reinvigorate T-cell-mediated antitumor immune responses, a consistent percentage of treated patients fail to respond, strongly encouraging the identification of combination therapies to overcome resistance. In the present review, we analyzed both established and unexplored mechanisms that may be elicited by PARPi, supporting immune reactivation and their potential synergism with currently used ICIs. This analysis may indicate novel and possibly patient-specific immune features that might represent new pharmacological targets of PARPi, potentially leading to the identification of predictive biomarkers of response to their combination with ICIs.

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“…Despite the clinical effectiveness of PARPi in oncology, the risk-benefit ratio of DDR inhibition pathways in cancer patients is under constant review. PARPi serves as a potential therapeutic agent for the bone marrow, but it is also emerging as a cause of these disorders [24]. When comparing de novo myeloid malignancies, myeloid malignancies associated with PARPi therapy are more likely to contain mutations in components of the DDR pathway, such as TP53 and PPM1D.…”

Section: Description Of the State Of Knowledgementioning

confidence: 99%

Poly ADP-ribose polymerase (PARP) inhibitors - new therapeutic strategies in Acute Myeloid Leukemia: a literature review

Nowicka

Obel

Panuciak

et al. 2022

J Educ Health Sport

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The use of poly (ADP-ribose) polymerase (PARP) inhibitors has recently increased as a result of demonstrating their superior efficacy compared to traditional chemotherapy in various cancer subtypes in many preclinical studies and clinical trials. A better understanding of the molecular mechanisms of PARP and their underlying foci that can be used as screening markers for potential new therapeutic options would aid rational treatment strategies and improve long-term patient outcomes. The available data on acute leukemia suggest potential windows for effective treatment of PARPi in disease subgroups. In this review, we summarize the current advances in the most common PARP-based adjuvant therapies and combination strategies for the treatment of acute leukemia and discuss the future prospects and challenges of therapy with PARP inhibitors. We also discuss reports describing an increased risk of cancer treatment in patients receiving PARP inhibitors for solid tumors. The research material were publications, the search was carried out using a combination of keywords such as: "PARP inhibitor", "acute leukemia", "therapy", "PARP clinical trials". The first step was to find relevant publications from the last 15 years. The second step was to review the publications found. Studies have shown that PARP inhibitors play an increasing role in the treatment of leukemia. In addition, focusing research efforts on identifying the most effective drug combinations and sequences could help to further shape the role of PARPi in the treatment of acute myeloid leukemia (AML).

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PARP Inhibitors and Haematological Malignancies—Friend or Foe?

Cited by 9 publications

References 169 publications

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints

Poly ADP-ribose polymerase (PARP) inhibitors - new therapeutic strategies in Acute Myeloid Leukemia: a literature review

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