Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial

Konstantinopoulos, Panagiotis A.; Cheng, Su Chun; Hendrickson, Andrea E. Wahner; Penson, Richard T.; Schumer, Susan; Doyle, L. Austin; Lee, Elizabeth K.; Kohn, Elise C.; Duska, Linda R.; Crispens, Marta A.; Olawaiye, Alexander; Winer, Ira; Barroilhet, Lisa; Fu, Siqing; McHale, Michael; Schilder, Russell J.; Färkkilä, Anniina; Chowdhury, Dipanjan; Curtis, Jennifer; Quinn, Roxanne; Bowes, Brittany; D’Andrea, Alan D.; Shapiro, Geoffrey I.; Matulonis, Ursula A.

doi:10.1016/s1470-2045(20)30180-7

Cited by 153 publications

(115 citation statements)

References 28 publications

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“…Interestingly, in a randomised, phase II clinical trial, the combination of gemcitabine with the ATRi berzosertib was more efficacious than gemcitabine monotherapy treatment, in highgrade serous ovarian cancer (HGSOC) patients. 48 Similarly, the combination of gemcitabine (and radiation) with WEE1i in pancreatic cancer showed efficacy in a recent phase I clinical trial. 49 Future analysis of clinical cohorts will enable to ascertain whether the efficacy of the combinations may be attributed to low or absent SLFN11 protein in the tumour cells of these patients.…”

Section: Du145 Isogenic Cellsmentioning

confidence: 97%

SLFN11 informs on standard of care and novel treatments in a wide range of cancer models

et al. 2020

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Background Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDRi) therapies. Methods We used a multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies and mechanistic studies to assess SLFN11 as a potential biomarker for stratification of patients treated with several DDA and/or DDRi in the preclinical and clinical setting. Results SLFN11 protein associated with both preclinical and patient treatment response to DDA, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib in breast cancer. SLFN11-low/absent cancers were identified across different tumour types tested. Combinations of DDA with DDRi targeting the replication-stress response (ATR, CHK1 and WEE1) could re-sensitise SLFN11-absent/low cancer models to the DDA treatment and were effective in upper gastrointestinal and genitourinary malignancies. Conclusion SLFN11 informs on the standard of care chemotherapy based on DDA and the effect of selected combinations with ATR, WEE1 or CHK1 inhibitor in a wide range of cancer types and models.

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Section: Du145 Isogenic Cellsmentioning

confidence: 97%

SLFN11 informs on standard of care and novel treatments in a wide range of cancer models

et al. 2020

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“…In ovarian cancer, increased replication stress and DNA damage are prevalent, and inhibition of ATR may represent an effective strategy for ovarian cancer therapy. Recently, a phase 2 clinical trial has shown that administration of the ATR inhibitor berzosertib with gemcitabine increased progression-free survival in patients with high-grade ovarian cancer compared with gemcitabine alone 22 , suggesting that ATR inhibitor is bene cial for ovarian cancer therapy. Additionally, myeloid leukemia cells with R-loop accumulation induced by splicing factor disorder has been reported to be more sensitive to ATR inhibitors 27 .…”

Section: Discussionmentioning

confidence: 99%

ADAR1 Prevents R-loop Accumulation-Driven ATR Pathway Activation in Ovarian Cancer

Cui¹,

Qian²,

Tian³

et al. 2020

Preprint

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BackgroundAdenosine (A)-to-inosine (I) RNA editing is the most prevalent RNA editing mechanism, in which adenosine deaminases acting on RNA 1 (ADAR1) is a major adenosine deaminase. Increasing evidence suggests that editing dysregulation of ADAR1 plays an important role in human tumorigenesis, while the underlying mechanism remains elusive. MethodsThe clinical relevance of ADAR1 was analyzed by real-time PCR, western blotting and immunohistochemistry of ovarian cancer tissues. ADAR1 function on ovarian cancer cells in vitro were explored by colony formation assay, transwell assay and Brdu-based cell cycle assay in vitro and xenograft models in vivo. Western blotting, immunostaining and DNA/RNA immunoprecipitation-qPCR were conducted to confirm DNA damage and R-loop accumulation in ovarian cancer cells. Co-immunoprecipitation and DNA/RNA immunoprecipitation were performed to detect interaction of DHX9, ADAR1 and R-loop complex in ovarian cancer cells.ResultsWe demonstrated that ADAR1 was highly expressed in ovarian cancer tissues and negatively correlated with progression free survival of ovarian cancer patients. Importantly, silence of ADAR1 repressed ovarian cancer cell growth and colony formation in vitro and inhibited ovarian cancer cell tumorigenesis in vivo. Further cell cycle and transcriptome profile analysis revealed that silence of ADAR1 in ovarian cancer cells induced cell cycle arrest at G1/G0 stage. Mechanically, loss of ADAR1 caused R-loop abnormal accumulation, thereby contributing to single stand DNA break and ATR pathway activation. Additionally, ADAR1 interacted with DHX9 to regulate R-loop complex formation, and A-to-I editing of nascent RNA repressed R-loop formation during co-transcriptional process. ConclusionsOur results identify a novel ADAR1/R-loop/ATR axis critical for ovarian cancer progression and a potential target for ovarian cancer therapy.

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“…With published results, several of them have fostered high expectations supported by the number and diversity of trials. Berzosertib (IV administration) was shown to be well tolerated in monotherapy or in combination with carboplatin, topotecan, and gemcitabine [118][119][120]. Results from 17 patients enrolled in berzosertib monotherapy showed good tolerability and were recommended the phase II dose (RP2D = 240 mg/m 2 once or twice a week) without any dose-limiting toxicities (DLTs).…”

Section: Atr Inhibitors In Clinical Trialsmentioning

confidence: 99%

“…A higher objective response rate was achieved in the gemcitabine alone group; however, the clinical benefit rate as well as the 6 month PFS was better in the combination group. Moreover, higher PFS was especially evident in patients with shorter platinum-free periods [120]. Regarding ceralasertib, only some preliminary outputs can be drawn from clinical trials.…”

Section: Atr Inhibitors In Clinical Trialsmentioning

confidence: 99%

Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

Górecki

Andrš

Korábečný

2021

Cancers

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Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra‑S or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intra‑S and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival.

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Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial

Cited by 153 publications

References 28 publications

SLFN11 informs on standard of care and novel treatments in a wide range of cancer models

SLFN11 informs on standard of care and novel treatments in a wide range of cancer models

ADAR1 Prevents R-loop Accumulation-Driven ATR Pathway Activation in Ovarian Cancer

Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

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