Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action

Pommier, ﻿Yves; O’Connor, Mark J.; Bono, Johann S. de

doi:10.1126/scitranslmed.aaf9246

Cited by 603 publications

(568 citation statements)

References 75 publications

Supporting

Mentioning

560

Contrasting

Unclassified

Order By: Relevance

“…Maximum SUVs of tumors ranged from as low as 2 (background) to as high as 12 and a similar range of PARP-1 expression was also observed by immunofluorescence and autoradiography ( Figure 7, A and B, and Supplemental Table 5). Since [ (3,14,15,(17)(18)(19)23).…”

Section: I N I C a L M E D I C I N Ementioning

confidence: 99%

“…22-24). Furthermore, PARP-1 has been development and application of PARPis, the primary drug target poly(ADP-ribose) polymerase 1 (PARP-1) has never been evaluated in vivo, even though loss of expression in vitro is a wellcharacterized resistance mechanism (3,(14)(15)(16)(17)(18)(19). It was first hypothesized that PARPis work primarily through a synthetic lethality pathway where loss of BRCA1 or BRCA2 combined with chemical inhibition of PARP-1 results in cell death (20, 21).…”

mentioning

confidence: 99%

See 1 more Smart Citation

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

Makvandi

Pantel

Schwartz

et al. 2018

Journal of Clinical Investigation

111

107

View full text Add to dashboard Cite

50% of patients with HRD respond to PARPi therapy (3). Moreover, patients without known HRD have also shown a clinical benefit from PARPis, as seen in recent trials assessing niraparib, olaparib, or rucaparib, as maintenance therapy in platinum-sensitive recurrent ovarian cancer (5-8). Given that not all patients will respond to PARPi therapy, improved clinical tools for predicting which patients will respond are urgently needed.Numerous clinical trials have led to FDA approval of 3 PARPis since 2014 and there is continued development of 2 additional drugs within this class (9-13). Despite growth in the BACKGROUND. Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of patients with ovarian cancer; however, resistance caused by low enzyme expression of the drug target PARP-1 remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel PET imaging agent. METHODS.We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer. First, we produced PARP1-KO ovarian cancer cell lines using CRISPR/Cas9 gene editing to test the loss of PARP-1 as a resistance mechanism to all clinically used PARP inhibitors. Next, we performed preclinical microPET imaging studies using ovarian cancer patient-derived xenografts in mouse models. Finally, in a phase I PET imaging clinical trial we explored PET imaging as a regional marker of PARP-1 expression in primary and metastatic disease through correlative tissue histology. RESULTS.We found that deletion of PARP1 causes resistance to all PARP inhibitors in vitro, and microPET imaging provides proof of concept as an approach to quantify PARP-1 in vivo. Clinically, we observed a spectrum of standard uptake values (SUVs) ranging from 2-12 for PARP-1 in tumors. In addition, we found a positive correlation between PET SUVs and fluorescent immunohistochemistry for PARP-1 (r 2 = 0.60).CONCLUSION. This work confirms the translational potential of a PARP-1 PET imaging agent and supports future clinical trials to test PARP-1 expression as a method to stratify patients for PARP inhibitor therapy.TRIAL REGISTRATION. Clinicaltrials.gov NCT02637934. 22-24). Furthermore, PARP-1 has been development and application of PARPis, the primary drug target poly(ADP-ribose) polymerase 1 (PARP-1) has never been evaluated in vivo, even though loss of expression in vitro is a wellcharacterized resistance mechanism (3,(14)(15)(16)(17)(18)(19). It was first hypothesized that PARPis work primarily through a synthetic lethality pathway where loss of BRCA1 or BRCA2 combined with chemical inhibition of PARP-1 results in cell death (20, 21). However, it was later shown that deletion of PARP1 did not result in BRCA1-restored cells showed no increase in γH2AX compared with DMSO controls. Olaparib-treated OVCAR8 PARP1-KO G1 and G3 cells showed a 1.3 times increase (ANOVA, **P < 0.01 and ***P < 0.001, respectively) in γH2AX...

show abstract

Section: I N I C a L M E D I C I N Ementioning

confidence: 99%

mentioning

confidence: 99%

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

Makvandi

Pantel

Schwartz

et al. 2018

Journal of Clinical Investigation

111

107

View full text Add to dashboard Cite

show abstract

“…The inhibition of PARP1 induces the formation of SSBs, which then evolve into DSBs that in normal cells are repaired by the HR [45]. However, in cells where the HR is defective, such as those with mutated BRCA1 or BRCA2, PARP1 inhibition induces an excessive accumulation of genotoxic damage which triggers cell death, and this synthetic lethality effect has been effectively exploited in the treatment of Brca1-defective solid tumors [46].…”

Section: The Essential Function Of Ddr In the Maintenance Of Hscsmentioning

confidence: 99%

The DNA damage response pathway in normal hematopoiesis and malignancies

Delia

Mizutani

2017

Int J Hematol

View full text Add to dashboard Cite

“…It is upregulated in many malignancies and has been identified as a critical component for cellular survival. PARP inhibitors have shown therapeutic potential, either in conjunction with DNAdamaging agents or as monotherapies in tumors with defects in other DNA repair pathways (1)(2)(3). The success of PARP inhibitor therapy led to Food and Drug Administration approval of olaparib in 2014, rucaparib in 2016, and niraparib in 2017.…”

mentioning

confidence: 99%

“…More details about PARP radiotracers from the larger perspective of imaging the DNA damage response can be found in an excellent review by Knight et al (4). More details about the underlying biology can be found in reviews by Scott et al (1), Michels et al (2), and Pommier et al (3). Here, we seek to present the current state of the art of optical and radioactive PARP imaging agents and their ultimate clinical goals.…”

mentioning

confidence: 99%

Molecular Imaging of PARP

2017

View full text Add to dashboard Cite

The poly(adenosine diphosphate-ribose)polymerase (PARP) family of enzymes is an important factor in the cellular DNA damage response and has gained much attention for its role in many diseases, particularly cancer. Targeted molecular imaging of PARP using fluorescent or radiolabeled tags has followed on the success of therapeutic inhibitors and gained momentum over the past few years. This review covers PARP imaging from the very first imaging agents up to the current state of the technology, with a focus on the clinical applications made possible by these agents.

show abstract

Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action

Cited by 603 publications

References 75 publications

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

The DNA damage response pathway in normal hematopoiesis and malignancies

Molecular Imaging of PARP

Contact Info

Product

Resources

About