Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations

Sztupinszki, Zsófia; Dióssy, Miklós; Krzystanek, Marcin; Börcsök, Judit; Pomerantz, Mark; Tisza, Viktória; Spisák, Sándor; Rusz, Orsolya; Csabai, István; Freedman, Matthew L.; Szállási, Zoltán

doi:10.1158/1078-0432.ccr-19-2135

Cited by 73 publications

(73 citation statements)

References 42 publications

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“…PARP inhibitors, such as olaparib, have been demonstrated to have monotherapy activity against tumor cells harboring BRCA1 or BRCA2 mutations, exerting effects via synthetic lethality interactions [6] , [7] , [8] . Tumor cells with a compromised HR pathway are known to be susceptible to becoming highly dependent upon PARP activity for maintaining the genomic integrity and survival, even in the cells without BRCA1/2 mutations [34] . Similar to other PARP inhibitors, pamiparib was found to show strong inhibitory activities with a selectivity to the BRCA1/2 mutation or HRD cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor

et al. 2020

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Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].

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Section: Discussionmentioning

confidence: 99%

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor

et al. 2020

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“…HR deficiency is also assessed in the clinical setting by a large scale genomic aberration based signature, namely the HRD score[28], which is also approved as companion diagnostic for PARP inhibitor therapy. Recently a composite mutational signature, HRDetect[29], combining several of the mutational features listed above was evaluated as an alternative method to detect HR deficiency in prostate adenocarcinoma[30]. In order to further strengthen the link between CHD1 loss, HR deficiency and potentially increased PARP inhibitor sensitivity we performed a detailed analysis on the mutational signature profiles of CHD1 deficient prostate cancer.…”

Section: Resultsmentioning

confidence: 99%

SubclonalCHD1deletion is more frequent in African American prostate cancers and associated with rapid disease progression and limited levels of homologous recombination deficiency

Dióssy

Tisza

et al. 2021

Preprint

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Background: African American (AA) men have significantly higher mortality rates from prostate cancer (PC) than individuals of European ancestry (EA). Therapeutically targetable molecular differences may hold the potential to reduce this disparity. Objective: To investigate chromodomain helicase DNA-binding protein 1 (CHD1) deletion both as a cause of aggressive disease and therapeutic vulnerability in the prostate cancer of AA men. Design, setting, and participants: 91 AA and 109 EA prostate cancer cases were analyzed by fluorescence in situ hybridization (FISH) for the deletion of CHD1. Whole exome and whole genome sequencing data from prostate adenocarcinoma cases were analyzed for mutational signatures from AA and EA individuals. Outcome measurements and statistical analysis: Associations with biochemical recurrence were evaluated using Cox proportional hazard regression models. Association between mutational signatures and CHD1 deletion were assessed by Wilcoxon ranked sum tests. Results and limitations: Subclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of men than in EA men. CHD1 deletion is associated with some of the homologous recombination deficiency associated mutational signatures in prostate cancer. In a cell line model CHD1 deletion induced 1-10 kb deletions resembling those induced by BRCA2 deficiency. CHD1 deficient cells showed markedly increased sensitivity to both talazoparib and the radiomimetic bleomycin. Conclusions: CHD1 is more frequently deleted in the prostate cancer of AA men. This deletion is both associated with and induces mutational signatures characteristic of BRCA2 deficiency. CHD1 deficient prostate cancer is more sensitive to talazoparib or bleomycin treatment. Patient summary: Subclonal deletion of CHD1 is more frequent in the prostate cancer of AA men and this could be one of the reasons behind more aggressive disease. CHD1 deletion, however, also constitutes a therapeutic vulnerability to the PARP inhibitor talazoparib. This treatment may significantly improve the outcome of disease in AA men.

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“…The HRD profile has also been detected in some patients without gremlin or somatic mutations in BRCA1 / 2 / other HR-related genes. This is likely to define a subset of PC patients accurately identified by the WGS data, and these patients are likely to benefit from PARP inhibitors or platinum therapy [13]. The presence of BRCA1 / 2 mutations is related to the presence of mutation characteristics associated with HR deficiency in adenocarcinoma of the prostate.…”

Section: Brca1 and Brca2 Mutationmentioning

confidence: 99%

Personalized Therapy of Prostate Cancer

Tizar¹,

Kadmiri²

2022

Health Sci

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As prostate cancer is the second leading cause of death after lung cancer, several diagnostic strategies have been introduced in recent years. Among these prostate-specific antigens, it is widely recognized that this is the simplest and most common clinical endpoint - genetic instability is part of the oncogenic process. Gene mutations involved in DNA repair mechanisms may promote this genetic instability and participate in oncogenesis and metastatic progression. In prostate cancer, abnormalities in DNA repair are primarily due to somatic or constitutional mutations in the BRCA1/2 genes. Treatment options for prostate cancer are currently widely discussed in the media and by urological associations. Focal therapy is expected to have the same oncological efficacy as whole gland therapy with fewer side effects. Accurate diagnosis with multipara metric magnetic resonance imaging (MRI). In this review we examine the various studies described present the molecular targets for personalized prostate cancer therapy.

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Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations

Cited by 73 publications

References 42 publications

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor

SubclonalCHD1deletion is more frequent in African American prostate cancers and associated with rapid disease progression and limited levels of homologous recombination deficiency

Personalized Therapy of Prostate Cancer

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