MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer

Walker, Alexandra K.; Karászi, Katalin; Valentine, Helen; Strauss, Victoria Y; Choudhury, Ananya; McGill, Shaun; Kong, Wen; Brown, Michael D.; Ramani, Vijay; Bhattarai, Selina; Teo, Mark; Yang, Lingjian; Myers, Kevin A.; Deshmukh, Nayneeta; Denley, Helen; Browning, Lisa; Love, Sharon; Iyer, Gopa; Clarke, Noel W.; Hall, Emma; Huddart, Robert; James, Nicholas D.; Hoskin, Peter; West, Catharine M L; Kiltie, Anne E.

doi:10.1016/j.ijrobp.2019.03.015

Cited by 23 publications

(16 citation statements)

References 27 publications

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“…It has been reported that high levels of MRE11 predict the outcome after radical radiotherapy [132, 133]. However, Walker et al later showed that there is no significant association between MRE11 and the rate of success of radiation-based bladder preservation therapy [134]. This inconsistency may be attributed to the lack of an automated quantitative methods or standard reassessment of MRE11.…”

Section: Introductionmentioning

confidence: 99%

MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment

et al. 2019

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Genome instability is a hallmark of cancer cells and can be accelerated by defects in cellular responses to DNA damage. This feature of malignant cells opens new avenues for tumor targeted therapy. MRE11-RAD50-NBS1 complex plays a crucial role in sensing and repair of DNA damage. Through interacting with other important players of DNA damage response, MRE11-RAD50-NBS1 complex is engaged in various DNA damage repair pathways. Mutations in any member of this complex may lead to hypersensitivity to genotoxic agents and predisposition to malignancy. It is assumed that the defects in the complex may contribute to tumorigenesis and that treatments targeting the defect may be beneficial to cancer patients. Here, we summarized the recent research findings of the role of MRE11-RAD50-NBS1 complex in tumorigenesis, cancer treatment and discussed the potential approaches of targeting this complex to treat cancer.

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Section: Introductionmentioning

confidence: 99%

MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment

et al. 2019

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“…Pre‐treatment bladder cancer expression of DSB repair gene MRE11 was found to be predictive of survival following radical radiotherapy but not cystectomy by the Kiltie group, a result that was independently verified by Laurberg et al Interestingly, the SNP rs1805363 in MRE11A was also found predictive of survival in a gene‐dosage effect in patients with bladder cancer treated by radical radiotherapy but not by cystectomy . New work by the Kiltie group aimed to standardize and develop a clinical assay for MRE11 immunohistochemistry assay across several centers in the United Kingdom using transurethral resection of bladder (TURBT) samples from prior bladder‐preservation trials . However, they were unable to replicate prior results, which was attributed to problems in automatic staining and poor scoring reproducibility among histopathologists.…”

Section: Tumor Radiosensitivitymentioning

confidence: 93%

“…74 New work by the Kiltie group aimed to standardize and develop a clinical assay for MRE11 immunohistochemistry assay across several centers in the United Kingdom using transurethral resection of bladder (TURBT) samples from prior bladder-preservation trials. 75 However, they were unable to replicate prior results, which was attributed to problems in automatic staining and poor scoring reproducibility among histopathologists.…”

Section: A Gene Expression To Predict Radiotherapy Benefitmentioning

confidence: 98%

Genomics models in radiotherapy: From mechanistic to machine learning

et al. 2020

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Machine learning (ML) provides a broad framework for addressing high‐dimensional prediction problems in classification and regression. While ML is often applied for imaging problems in medical physics, there are many efforts to apply these principles to biological data toward questions of radiation biology. Here, we provide a review of radiogenomics modeling frameworks and efforts toward genomically guided radiotherapy. We first discuss medical oncology efforts to develop precision biomarkers. We next discuss similar efforts to create clinical assays for normal tissue or tumor radiosensitivity. We then discuss modeling frameworks for radiosensitivity and the evolution of ML to create predictive models for radiogenomics.

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“…Unfortunately, even the most promising biomarkers, such as double strand break repair nuclease MRE11 (MRE11), have failed to generate reproducible data. In the latest multicentre collaborative effort to validate MRE11 as a biomarker, the immunohistochemistry scoring results varied considerably and failed to attain a reliable dataset [ 33 ]. Finally, a complete or near complete response assessed by cystoscopy after 4–5 weeks induction phase remains as the only reliable predictor of treatment outcome [ 34 , 35 ]…”

Section: Limitations Of Use Of Rt In Mibc In Clinicsmentioning

confidence: 99%

Review of Experimental Studies to Improve Radiotherapy Response in Bladder Cancer: Comments and Perspectives

Silina

Maksut

Bernard‐Pierrot

et al. 2020

Cancers

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Bladder cancer is among the top ten most common cancer types in the world. Around 25% of all cases are muscle-invasive bladder cancer, for which the gold standard treatment in the absence of metastasis is the cystectomy. In recent years, trimodality treatment associating maximal transurethral resection and radiotherapy combined with concurrent chemotherapy is increasingly used as an organ-preserving alternative. However, the use of this treatment is still limited by the lack of biomarkers predicting tumour response and by a lack of targeted radiosensitising drugs that can improve the therapeutic index, especially by limiting side effects such as bladder fibrosis. In order to improve the bladder-preserving treatment, experimental studies addressing these main issues ought to be considered (both in vitro and in vivo studies). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews, we conducted a literature search in PubMed on experimental studies investigating how to improve bladder cancer radiotherapy with different radiosensitising agents using a comprehensive search string. We made comments on experimental model selection, experimental design and results, formulating the gaps of knowledge still existing: such as the lack of reliable predictive biomarkers of tumour response to chemoradiation according to the molecular tumour subtype and lack of efficient radiosensitising agents specifically targeting bladder tumour cells. We provided guidance to improve forthcoming studies, such as taking into account molecular characteristics of the preclinical models and highlighted the value of using patient-derived xenografts as well as syngeneic models. Finally, this review could be a useful tool to set up new radiation-based combined treatments with an improved therapeutic index that is needed for bladder preservation.

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MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer

Cited by 23 publications

References 27 publications

MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment

MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment

Genomics models in radiotherapy: From mechanistic to machine learning

Review of Experimental Studies to Improve Radiotherapy Response in Bladder Cancer: Comments and Perspectives

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