PARP Inhibition, a New Therapeutic Avenue in Patients with Prostate Cancer

Flippot, Ronan; Patrikidou, Anna; Aldea, Mihaela; Colomba, Emeline; Lavaud, Pernelle; Albigès, Laurence; Naoun, Natacha; Blanchard, Pierre; Terlizzi, Mario; Garcia, Camilo; Bernard‐Tessier, Alice; Fuerea, Alina; Palma, Mario Di; Escudier, Bernard; Loriot, Yohann; Baciarello, Giulia; Fizazi, Karim

doi:10.1007/s40265-022-01703-5

Cited by 12 publications

(8 citation statements)

References 96 publications

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“…The HR repair plays an important role in the combination strategy of PARP inhibitors. Mutations in the key HR repair pathway genes BRCA1, BRCA2, and ATM are often critical for PARP inhibitor sensitization 47–50 . It has been reported that CDK4/6 inhibitors can induce DNA damage and genomic instability, which in turn can have a synthetic lethal effect with PARP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the key HR repair pathway genes BRCA1, BRCA2, and ATM are often critical for PARP inhibitor sensitization. 47 , 48 , 49 , 50 It has been reported that CDK4/6 inhibitors can induce DNA damage and genomic instability, which in turn can have a synthetic lethal effect with PARP inhibitors. Interestingly, MEnZn‐CuO NPs were found for the first time as metal nanoparticles to negatively regulate the expression of HR repair pathway genes in tumors with defective HR repair capacity.…”

Section: Discussionmentioning

confidence: 99%

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Micelle encapsulation zinc‐doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair

Luo

Xing

et al. 2023

Bioengineering & Transla Med

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Micelle Encapsulation Zinc‐doped copper oxide nanocomposites (MEnZn‐CuO NPs) is a novel doped metal nanomaterial prepared by our group based on Zinc doped copper oxide nanocomposites (Zn‐CuO NPs) using non‐micellar beam. Compared with Zn‐CuO NPs, MEnZn‐CuO NPs have uniform nanoproperties and high stability. In this study, we explored the anticancer effects of MEnZn‐CuO NPs on human ovarian cancer cells. In addition to affecting cell proliferation, migration, apoptosis and autophagy, MEnZn‐CuO NPs have a greater potential for clinical application by inducing HR repair defects in ovarian cancer cells in combination with poly (ADP‐ribose) polymerase inhibitors for lethal effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Micelle encapsulation zinc‐doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair

Luo

Xing

et al. 2023

Bioengineering & Transla Med

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“…Patients with localized stage disease do not routinely undergo molecular analysis, and current recommendations are to limit next-generation sequencing (NGS) to mCRPC patients. Germline and somatic mutation testing of the HRR gene are now used clinically to predict the efficacy of PAPR inhibitors ( 39 ). In contrast, many other mutations that have clinical value in metastatic PCa are still not recommended for testing ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer

et al. 2022

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BackgroundAlthough TP53 and SPOP are frequently mutated in metastatic prostate cancer (PCa), their prognostic value is ambiguous, and large sample studies are lacking, especially when they co-occur with other genetic alterations.MethodsGenomic data and patients’ clinical characteristics in PCa were downloaded from the cBioPortal database. We extensively analyzed other gene alterations in different mutation status of TP53 and SPOP. We further subdivided TP53 and SPOP mutation into subgroups based on different mutation status, and then evaluated the prognostic value. Two classification systems for TP53 survival analysis were used.ResultsA total of 2,172 patients with PCa were analyzed in our study, of which 1,799 were metastatic PCa patients. The mutual exclusivity analysis showed that TP53 and SPOP mutation has a strong mutual exclusion (p<0.001). In multivariable analysis, truncating TP53 mutations (HR=1.773, 95%CI:1.403-2.239, p<0.001) and other TP53 mutations(HR=1.555, 95%CI:1.267-1.908, p<0.001) were independent negative prognostic markers in metastatic PCa, whereas SPOP mutations(HR=0.592, 95%CI:0.427-0.819, p<0.001) were an independent prognostic factor for better prognosis. Mutations in TP53 were significantly associated with wild-type status for SPOP and CDK12, structural variants/fusions for TMPRSS2 and ERG, AR amplification and PTEN deletion (p<0.001). And truncating TP53 mutations have higher AR amplification rates than other TP53 mutations (p=0.022). Consistently, truncating TP53 mutations had a worse prognosis than other TP53 mutations (p<0.05). Then Kaplan-Meier survival curve showed that Co-occurring TP53 mutations in AR amplification or PTEN deletion tumors significantly reduced survival (p<0.05). Furthermore, those with SPOP-mutant tumors with co-occurring TP53 truncating mutations had shorter overall survival than those with SPOP-mutant tumors with wild-type or other TP53 mutations.ConclusionsThis study found that TP53 and SPOP mutations were mutually exclusive and both were independent prognostic markers for metastatic PCa. Genomic alteration and survival analysis revealed that TP53 and SPOP mutations represented distinct molecular subtypes. Our data suggest that molecular stratification on the basis of TP53 and SPOP mutation status should be implemented for metastatic PCa to optimize and modify clinical decision-making.

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“…However, about 10% to 20% of the patients develop castration-resistant prostate cancer (CRPC), most of whom lack appropriate clinical treatment, eventually leading to death ( 3 ). New studies have brought PARP inhibitors into the treatment of metastatic CRPC, but only for patients harboring BRCA1 , BRCA2 , or ATM mutations ( 4 ). Despite beneficial advances in the treatment of prostate cancer with newer therapies such as immunotherapy, patient options remain limited ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Nifuroxazide Activates the Parthanatos to Overcome TMPRSS2:ERG Fusion-Positive Prostate Cancer

Zhang

et al. 2023

Molecular Cancer Therapeutics

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Fusion of the ETS (E-26 transformation-specific)-related gene (ERG) with transmembrane serine protease 2 (TMPRSS2) is a crucial step in the occurrence and progression of approximately 50% of prostate cancers. Despite significant progress in drug discovery, ERG inhibitors have yet to be approved for the clinical treatment of prostate cancer. In this study, we used computer-aided drug design (CADD)-based virtual screening to screen for potential inhibitors of ERG. In vivo and in vitro methods revealed that nifuroxazide inhibited the proliferation of a TMPRSS2:ERG fusion-positive prostate cancer cell line (VCaP) with an IC50 lower than that of ERG-negative prostate cancer cell lines (LNCaP, DU145 and WPMY cells). PARP1, the critical mediator of parthanatos, is known to bind ERG and required for ERG-mediated transcription. Nifuroxazide blocked this interaction, and overly activated PARP1, leading to cell death that was reduced by olaparib, a PARP1 inhibitor. These results show that nifuroxazide inhibits ERG, leading to parthanatic cell death.

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PARP Inhibition, a New Therapeutic Avenue in Patients with Prostate Cancer

Cited by 12 publications

References 96 publications

Micelle encapsulation zinc‐doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair

Micelle encapsulation zinc‐doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair

Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer

Nifuroxazide Activates the Parthanatos to Overcome TMPRSS2:ERG Fusion-Positive Prostate Cancer

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