Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours

Seto, Takashi; Esaki, Taito; Hirai, Fumihiko; Arita, Shuji; Nosaki, Kaname; Makiyama, Akitaka; Kometani, Takuro; Fujimoto, Chinatsu; Hamatake, Motoharu; Takeoka, Hiroaki; Agbo, Felix; Shi, Xiaojin

doi:10.1007/s00280-013-2234-6

Cited by 90 publications

(63 citation statements)

References 16 publications

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“…As a result of these data, clinical trials with early CHK1 inhibitors focused on the chemopotentiation of cytotoxic drugs. Although phase I trials demonstrated proof of concept that CHK1 inhibitors could be safely combined with chemotherapy (17)(18)(19)(20)(21)(22)(23)(24)(25), phase II studies failed to meet their primary endpoints (26,27). Early CHK1 inhibitors were not successful for a variety of reasons, including pharmacokinetic properties, unacceptable toxicities, and business considerations.…”

Section: Strategies For Clinical Development: Past and Presentmentioning

confidence: 99%

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Lin

McNeely

Beckmann

2017

Clinical Cancer Research

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All cancers are characterized by defects in the systems that ensure strict control of the cell cycle in normal tissues. The consequent excess tissue growth can be countered by drugs that halt cell division, and, indeed, the majority of chemotherapeutics developed during the last century work by disrupting processes essential for the cell cycle, particularly DNA synthesis, DNA replication, and chromatid segregation. In certain contexts, the efficacy of these classes of drugs can be impressive, but because they indiscriminately block the cell cycle of all actively dividing cells, their side effects severely constrain the dose and duration with which they can be administered, allowing both normal and malignant cells to escape complete growth arrest. Recent progress in understanding how cancers lose control of the cell cycle, coupled with comprehensive genomic profiling of human tumor biopsies, has shown that many cancers have mutations affecting various regulators and checkpoints that impinge on the core cell-cycle machinery. These defects introduce unique vulnerabilities that can be exploited by a next generation of drugs that promise improved therapeutic windows in patients whose tumors bear particular genomic aberrations, permitting increased dose intensity and efficacy. These developments, coupled with the success of new drugs targeting cell-cycle regulators, have led to a resurgence of interest in cellcycle inhibitors. This review in particular focuses on the newer strategies that may facilitate better therapeutic targeting of drugs that inhibit the various components that safeguard the fidelity of the fundamental processes of DNA replication and repair. Clin Cancer Res; 23(13); 3232-40. Ó2017 AACR.

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Section: Strategies For Clinical Development: Past and Presentmentioning

confidence: 99%

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Lin

McNeely

Beckmann

2017

Clinical Cancer Research

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“…So far, there are still several CHK1 inhibitors which are undergoing clinical trials. The potent Chk1/Chk2 inhibitor AZD7762 is under phase I, dose-escalation study to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy alone or in combination with gemcitabine in Japanese patients with advanced solid malignancies (Seto et al, 2013). Similarly, other CHK1 inhibitors including PF-477736 (Pfizer) and SCH900776 (Schering Plough) are also under Phase I or II clinical evaluation in patients (Ashwell et al, 2008;Karp et al, 2012 (Mizuno et al, 1995) Chk1 (Busby et al, 2000) Mytomycin C (Akinaga et al, 1993) Cisplatin (Bunch and Eastman, 1996) Topoisomerase I poisons (Tse et al, 2007a) Gemcitabine (Shi et al, 2001) Phase I/ II Gö6976 PKC(Martiny-Baron et al, 1993…”

Section: Figure16 Schematic Representation Of the Effect Of Chk1 Onmentioning

confidence: 99%

“…Gemcitabine (Ashwell et al, 2008;Seto et al, 2013) Phase I PF-477736 Chk1 (Dent et al, 2011) Gemcitabine (ClinicalTrials.gov) Phase I SCH900776 Chk1 (Dent et al, 2011) Gemcitabine (Daud et al, 2010 cytosine arabinoside (Karp et al, 2012) Phase I/II with about 14, 32 and 70kDa respectively (Wold and Kelly, 1988). It has been…”

Section: )mentioning

confidence: 99%

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

2014

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“…As expected, this combined treatment inhibits colony formation (4), increases clonogenic cell death (6) and inhibits tumor growth compared with GEM treatment alone (7)(8)(9)(10). Phase I clinical trials have been initiated, and the recommended phase II dose has been shown (11)(12)(13)(14)(15). However, concerns about unpredicted effects of Chk1 inhibitors on normal cells have been raised (12,16).…”

Section: Introductionmentioning

confidence: 89%

Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells

et al. 2017

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Abstract. Although gemcitabine (GEM) is frequently used in the treatment of pancreatic cancer, the effects are limited. To increase the inhibitory effect of GEM, the identification of a molecular target is needed. Recent studies have revealed that doublecortin-like kinase 1 (Dclk1) positively regulates tumor growth, invasion, metastasis, factors related to epithelialmesenchymal transition (EMT), pluripotency, angiogenesis, and anti-apoptosis in pancreatic cancer cells. Therefore, Dclk1 is a potential therapeutic target for pancreatic cancer. However, the Dclk1-signaling pathway including its substrate proteins remains to be elucidated. To identify the candidate substrate proteins phosphorylated by Dclk1, we performed a cancer-related phosphorylated protein microarray using Dclk1-inhibited MIA Paca2 cells. Expression levels of phosphorylated cdc25A (p-cdc25A) and phosphorylated Chk1 (p-Chk1), belonging to the ATR pathway, were decreased by treatment with Dclk1 inhibitor LRRK2-IN-1 (LRRK), indicating Dclk1 involvement in the ATR pathway. Consistent with this finding, the GEM-induced p-Chk1 expression was significantly decreased by treatment with LRRK. Notably, combined treatment with GEM and LRRK allowed cell cycle progression without arresting at S phase, while individual treatment with GEM induced cell cycle arrest at S phase. In addition, combined treatment with GEM and LRRK increased the number of γ-H2AX-positive cells compared with that upon individual treatments. Moreover, LRRK alone, and combined treatment with GEM and LRRK, induced caspase-3 activation and PARP1 cleavage, in contrast to treatment with GEM alone. Finally, combined treatment with GEM and LRRK significantly reduced cell survival compared to individual treatment with GEM. These results indicate that Dclk1 inhibition in combination with GEM treatment offers a novel approach to treat pancreatic cancer cells.

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Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours

Abstract: The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m(2) was determined as 21 mg in Japanese patients.

Cited by 90 publications

References 16 publications

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells

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