BRCAness as a Biomarker of Susceptibility to PARP Inhibitors in Glioblastoma Multiforme

Xavier, Mary-Ann E.; Rezende, Fernando; Titze‐de‐Almeida, Ricardo; Cornelissen, Bart

doi:10.3390/biom11081188

Cited by 13 publications

(14 citation statements)

References 103 publications

(152 reference statements)

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“…PARP expression has been reported to be associated with tumor grade as well as poorer survival ( 162 ). An increase in tumor radiotherapy sensitivity was observed in in vitro experiments applying PARPi against GBM models ( 163 ). With a better understanding of the molecular relationship between PARP and GBM ( 164 ), PARP may be used as a biomarker to assess prognosis and drug resistance mechanisms.…”

Section: Combined Dna Damage Repair-based Therapy With Immunotherapymentioning

confidence: 99%

DNA Damage Repair in Brain Tumor Immunotherapy

Zhao

et al. 2022

Front. Immunol.

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With the gradual understanding of tumor development, many tumor therapies have been invented and applied in clinical work, and immunotherapy has been widely concerned as an emerging hot topic in the last decade. It is worth noting that immunotherapy is nowadays applied under too harsh conditions, and many tumors are defined as “cold tumors” that are not sensitive to immunotherapy, and brain tumors are typical of them. However, there is much evidence that suggests a link between DNA damage repair mechanisms and immunotherapy. This may be a breakthrough for the application of immunotherapy in brain tumors. Therefore, in this review, first, we will describe the common pathways of DNA damage repair. Second, we will focus on immunotherapy and analyze the mechanisms of DNA damage repair involved in the immune process. Third, we will review biomarkers that have been or may be used to evaluate immunotherapy for brain tumors, such as TAMs, RPA, and other molecules that may provide a precursor assessment for the rational implementation of immunotherapy for brain tumors. Finally, we will discuss the rational combination of immunotherapy with other therapeutic approaches that have an impact on the DNA damage repair process in order to open new pathways for the application of immunotherapy in brain tumors, to maximize the effect of immunotherapy on DNA damage repair mechanisms, and to provide ideas and guidance for immunotherapy in brain tumors.

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Section: Combined Dna Damage Repair-based Therapy With Immunotherapymentioning

confidence: 99%

DNA Damage Repair in Brain Tumor Immunotherapy

Zhao

et al. 2022

Front. Immunol.

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“…A more complex “BRCAness” signature has been defined to denote HRD tumors that share molecular features of BRCA1/2-mutant tumors, which are likely to benefit from DDRi [ 31 , 32 , 33 ]. The most promising biomarkers of BRCAness in GB relate to IDH1/2, epidermal growth factor receptor (EGFR), PTEN, MYC proto-oncogene, and estrogen receptors beta (ERβ) signatures [ 34 ]. For example, the anti-tumor effect of TMZ with ATMi or PARPi is enhanced in IDH1 mutant gliomas, and TMZ increases ATRi sensitivity in MGMT-deficient GB cells [ 35 , 36 , 37 ].…”

Section: Targeting Ddr Pathways In Gbmentioning

confidence: 99%

Section: Ddr (Radio)pharmaceuticalsmentioning

confidence: 99%

“…PARPi have shown significant promise in a variety of malignancies with deficiencies in HR signaling [ 34 , 188 ]. In GB, the BRCAness phenotype leads to impairment of HR and thus PARPi sensitivity [ 34 ]. Glioma biomarkers of predictive value for PARPi therapeutic efficacy include IDH1/2 mutations, a low BRCA1 expression, aberrant ATM or ATR signaling, MYC overexpression, and inactivation of mismatch repair genes, especially MSH6 [ 36 , 123 , 189 , 190 , 191 , 192 , 193 , 194 ].…”

Section: Ddr (Radio)pharmaceuticalsmentioning

confidence: 99%

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Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Everix

Nair

Driver

et al. 2022

Cancers

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Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.

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“…DNA damage and dysfunctions of repair are also features of cancer etiology [ 8 ]. BRCA1 is involved in the DNA damage repair (DDR) processes, in particular the repair of double strand breaks (DSBs), hence safeguarding genomic stability and integrity [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

PARP-1 Expression and BRCA1 Mutations in Breast Cancer Patients’ CTCs

Sklias

Vardas

Pantazaka

et al. 2022

Cancers

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BRCA1 and PARP are involved in DNA damage repair pathways. BRCA1 mutations have been linked to higher likelihood of triple negative breast cancer (TNBC). The aim of the study was to determine PARP-1 expression and BRCA1 mutations in circulating tumor cells (CTCs) of BC patients. Fifty patients were enrolled: 23 luminal and 27 TNBC. PARP expression in CTCs was identified by immunofluorescence. Genotyping was performed by PCR-Sanger sequencing in the same samples. PARP-1 expression was higher in luminal (61%) and early BC (54%), compared to TNBC (41%) and metastatic (33%) patients. In addition, PARP-1 distribution was mostly cytoplasmic in luminal patients (p = 0.024), whereas it was mostly nuclear in TNBC patients. In cytokeratin (CK)-positive patients, those with the CK+PARP+ phenotype had longer overall survival (OS, log-rank p = 0.046). Overall, nine mutations were detected; M1 and M2 were completely new and M4, M7 and M8 were characterized as pathogenic. M7 and M8 were predominantly found in metastatic TNBC patients (p = 0.014 and p = 0.002). Thus, PARP-1 expression and increased mutagenic burden in TNBC patients’ CTCs, could be used as an indicator to stratify patients regarding therapeutic approaches.

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BRCAness as a Biomarker of Susceptibility to PARP Inhibitors in Glioblastoma Multiforme

Cited by 13 publications

References 103 publications

DNA Damage Repair in Brain Tumor Immunotherapy

DNA Damage Repair in Brain Tumor Immunotherapy

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

PARP-1 Expression and BRCA1 Mutations in Breast Cancer Patients’ CTCs

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