Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors

Neeb, Antje; Herranz, Nicolás; Arce-Gallego, Sara; Miranda, Susana; Buroni, Lorenzo; Yuan, Wei; Athie, Alejandro; Casals, Teresa; Carmichael, Juliet; Rodrigues, Daniel Nava; Gürel, Bora; Rescigno, Pasquale; Rekowski, Jan; Welti, Jon; Riisnaes, Ruth; Gil, Veronica; Ning, Jian; Wagner, Verena; Casanova-Salas, Irene; Cordoba, Shaun-Paul; Castro, Natália; Maza, Maria D. Fenor de la; Seed, George; Chandran, Khobe; Ferreira, Ana; Figueiredo, Ines; Bertan, Claudia; Bianchini, Diletta; Aversa, Caterina; Paschalis, Alec; González, M.; Morales-Bárrera, Rafael; Suárez, Cristina; Carles, Joan; Swain, Amanda; Sharp, Adam; Gil, Jesús; Serra, Violeta; Lord, Christopher J.; Carreira, Suzanne; Mateo, Joaquín; Bono, Johann S. de

doi:10.1016/j.eururo.2020.10.029

Cited by 87 publications

(76 citation statements)

References 24 publications

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“…However, the responses seen in ATM and CDK12 aberrant advanced prostate cancer with treatment with olaparib administered for >6 months were observed in tumors with high RAD51 scores, indicating that the PARP inhibitor antitumor activity in this subgroup may not be related to complete loss of homologous recombination repair function but perhaps due to the genomic instability in these tumors associated with ATM loss (28). Interestingly, unlike BRCA2 mutation associated cancers, a significant number of the ATM aberrant prostate cancers in the TOPARP-B trial did not have detectable biallelic loss (29) the response rate in this subgroup is low and exploratory analyses of the PROfound trial failed to demonstrate a significant benefit in the ATM mutated disease subset, we have observed durable tumor responses in some prostate cancers with ATM aberrations in keeping with preclinical genomic screen data (30).…”

Section: Discussionmentioning

confidence: 98%

“…ATM protein expression in the ATM group was determined by immunohistochemistry (IHC) staining on 3 to 4μM-thick FFPE sections using the rabbit monoclonal anti-ATM antibody Y170 at 1:400 (catalog no. ab32420; Abcam plc, Cambridge, UK) as previously described (28). IHC slides were assessed by a pathologist, blinded to the patients' clinical characteristics, sequencing findings, and outcome data.…”

Section: Atm Immunohistochemistrymentioning

confidence: 99%

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Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial

et al. 2021

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Serra received grants from Fundacion Cientifica AECC (LABAE16020PORTT) and an ERAPERMED2019-215. J. Mateo gratefully acknowledges funding from the European Union's Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant 837900), Instituto de Salud Carlos III (Grant PI18/01384), Fundación AECC, CRIS Cancer Foundation and the US Department of Defense CDMRP (Impact Award PC170510P1). S. Arce-Gallego Research.

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Section: Discussionmentioning

confidence: 98%

Section: Atm Immunohistochemistrymentioning

confidence: 99%

Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial

et al. 2021

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“…Synthetic lethality is explored with PARP inhibitors in several cancers such as ATMdeficient tumors from breast and ovaries, aggressive prostate cancers in combination with ATR inhibitors [243,244], and high-risk neuroblastomas under ATR inhibition [245]. POLQ deficiency is synthetically lethal in combination with PARP inhibitors and associated with mutations of ATM, BRCA, Ku, 53BP1, and FA (Fanconi anaemia) [226,229,246].…”

Section: Targeting the Ddr Protein Network With Synthetic Lethalitymentioning

confidence: 99%

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Molinaro

Martoriati

Cailliau

2021

Cancers

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Cells respond to genotoxic stress through a series of complex protein pathways called DNA damage response (DDR). These monitoring mechanisms ensure the maintenance and the transfer of a correct genome to daughter cells through a selection of DNA repair, cell cycle regulation, and programmed cell death processes. Canonical or non-canonical DDRs are highly organized and controlled to play crucial roles in genome stability and diversity. When altered or mutated, the proteins in these complex networks lead to many diseases that share common features, and to tumor formation. In recent years, technological advances have made it possible to benefit from the principles and mechanisms of DDR to target and eliminate cancer cells. These new types of treatments are adapted to the different types of tumor sensitivity and could benefit from a combination of therapies to ensure maximal efficiency.

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“…4 Loss of the ataxia telangiectasia mutated protein is a common DNA repair defect, being present in up to 10% of advanced prostate cancers. 76 Interestingly, ataxia telangiectasia mutated loss can confer sensitivity to ataxia telangiectasia and Rad3-related protein inhibition in preclinical models; preclinical studies have shown that olaparib-resistant cancer cells with or without ataxia telangiectasia mutated loss may be resensitized to olaparib when combined with ataxia telangiectasia and Rad3-related protein inhibitors. [76][77][78] This has provided rationale for using ataxia telangiectasia and Rad3related protein inhibitors, either alone or in combination with PARP inhibitors, in phase I and II clinical trials, which are currently ongoing.…”

Section: The New Avengers In the Treatment Of Prostate Cancermentioning

confidence: 99%

Beyond the Androgen Receptor: The Sequence, the Mutants, and New Avengers in the Treatment of Castrate-Resistant Metastatic Prostate Cancer

Westaby

Viscuse

Ravilla

et al. 2021

American Society of Clinical Oncology Educational Book

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Targeting the androgen receptor by depriving testosterone with gonadotropin-releasing hormone agonists or antagonists, or surgical castration, has been the backbone of metastatic prostate cancer treatment. Although most prostate cancers initially respond to androgen deprivation, metastatic castration-resistant prostate cancer evolves into a heterogeneous disease with diverse drivers of progression and mechanisms of therapeutic resistance. Development of castrate resistance phenotype is associated with lethality despite the recent noteworthy strides gained via increase in therapeutic options. Identification of novel therapeutics to further improve survival and achieve durable responses in metastatic castration-resistant prostate cancer is a clinical necessity. In this review, we outline the existing avengers for treatment of metastatic castration-resistant prostate cancer by clinical presentation, placing into context the clinical state of the patient, such as burden of disease and symptoms. Doing so might aid in the ability to optimize the sequence of agents and allow for maximal exposure to life-prolonging therapeutics. Realizing the limitations of the androgen signaling inhibition, we explore the androgen-indifferent prostate cancer: the mutants. Classically, these subtypes have been associated with variant histology, but androgen-indifferent prostate cancer features are now frequently observed in association with heterogeneous morphologies, including double-negative prostate cancers, lacking both androgen receptor and neuroendocrine features, or clinicopathologic criteria, such as the aggressive variant prostate cancer criteria. The framework of new avengers against metastatic castration-resistant prostate cancer based on mechanism, including DNA repair, immune checkpoint inhibition, PTEN/PI3K/AKT pathway, prostate-specific membrane antigen targets, bispecific T-cell engagers, and radionuclide therapies, is summarized in this review.

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Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors

Cited by 87 publications

References 24 publications

Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial

Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Beyond the Androgen Receptor: The Sequence, the Mutants, and New Avengers in the Treatment of Castrate-Resistant Metastatic Prostate Cancer

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