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Steven Grant - One of the best experts on this subject based on the ideXlab platform.
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new insights into Checkpoint Kinase 1 in the dna damage response signaling network
Clinical Cancer Research, 2010Co-Authors: Yun Dai, Steven GrantAbstract:The DNA damage response (DDR) represents a complex network of multiple signaling pathways involving cell cycle Checkpoints, DNA repair, transcriptional programs, and apoptosis, through which cells maintain genomic integrity following various endogenous (metabolic) or environmental stresses. In cancer treatment, the DDR occurs in response to various genotoxic insults by diverse cytotoxic agents and radiation, representing an important mechanism limiting chemotherapeutic and radiotherapeutic efficacy. This has prompted the development of agents targeting DDR signaling pathways, particularly Checkpoint Kinase 1 (Chk1), which contributes to all currently defined cell cycle Checkpoints, including G1/S, intra-S-phase, G2/M, and the mitotic spindle Checkpoint. Although numerous agents have been developed with the primary goal of enhancing the activity of DNA-damaging agents or radiation, the therapeutic outcome of this strategy remains to be determined. Recently, new insights into DDR signaling pathways support the notion that Chk1 represents a core component central to the entire DDR, including direct involvement in DNA repair and apoptotic events in addition to Checkpoint regulation. Together, these new insights into the role of Chk1 in the DDR machinery could provide an opportunity for novel approaches to the development of Chk1 inhibitor strategies. Clin Cancer Res; 16(2); 376–83
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new insights into Checkpoint Kinase 1 in the dna damage response signaling network
Clinical Cancer Research, 2010Co-Authors: Yun Dai, Steven GrantAbstract:The DNA damage response (DDR) represents a complex network of multiple signaling pathways involving cell cycle Checkpoints, DNA repair, transcriptional programs, and apoptosis, through which cells maintain genomic integrity following various endogenous (metabolic) or environmental stresses. In cancer treatment, the DDR occurs in response to various genotoxic insults by diverse cytotoxic agents and radiation, representing an important mechanism limiting chemotherapeutic and radiotherapeutic efficacy. This has prompted the development of agents targeting DDR signaling pathways, particularly Checkpoint Kinase 1 (Chk1), which contributes to all currently defined cell cycle Checkpoints, including G1/S, intra-S-phase, G2/M, and the mitotic spindle Checkpoint. Although numerous agents have been developed with the primary goal of enhancing the activity of DNA-damaging agents or radiation, the therapeutic outcome of this strategy remains to be determined. Recently, new insights into DDR signaling pathways support the notion that Chk1 represents a core component central to the entire DDR, including direct involvement in DNA repair and apoptotic events in addition to Checkpoint regulation. Together, these new insights into the role of Chk1 in the DDR machinery could provide an opportunity for novel approaches to the development of Chk1 inhibitor strategies.
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Dissecting the Roles of Checkpoint Kinase 1/CDC2 and Mitogen-Activated Protein Kinase Kinase 1/2/Extracellular Signal-Regulated Kinase 1/2 in Relation to 7-Hydroxystaurosporine-Induced Apoptosis in Human Multiple Myeloma Cells
Molecular pharmacology, 2006Co-Authors: Xin-yan Pei, Paul Dent, Yun Dai, Steven GrantAbstract:The functional roles of Cdc2 and Checkpoint Kinase 1 (Chk1) in synergistic interactions between 7-hydroxystaurosporine (UCN-01) and mitogen-activated protein Kinase Kinase 1/2 (MEK1/2) inhibitors [e.g., 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD184352)] were examined in human multiple myeloma cells in relation to MEK1/2/ERK1/2 activation and lethality. Time course studies revealed that MEK1/2/extracellular signal-regulated Kinase 1/2 (ERK1/2) phosphorylation preceded Cdc2 dephosphorylation (Tyr15) after UCN-01 exposure. Furthermore, enforced expression of Cdc2 or small inducible RNA (siRNA)-mediated Cdc2 knockdown failed to modify ERK1/2 activation status in either the presence or absence of UCN-01, arguing against a causal relationship between these events. However, ectopic expression of Cdc2 sensitized cells to the lethality of UCN-01/MEK inhibitor regimen, whereas Cdc2 knockdown by siRNA significantly diminished the lethal effects of this combination. Conversely, Chk1 knockdown by siRNA enhanced lethality mediated by UCN-01/PD184352. It is interesting that Chk1 knockdown reduced basal ERK1/2 activation and antagonized the ability of UCN-01 to activate ERK1/2. Finally, ectopic expression of constitutively active MEK1 significantly protected cells from the UCN-01/MEK1/2 inhibitor regimen without modifying Cdc2 activation status. Together, these findings indicate that although UCN-01-mediated Chk1 inhibition and Cdc2 activation are unlikely to be responsible for MEK1/2/ERK1/2 activation, both of these events contribute functionally to enhanced lethality in cells coexposed to MEK inhibitors. They also suggest a role for Chk1 in UCN-01-induced ERK1/2 activation, implying the existence of a heretofore unrecognized link between Chk1 and ERK1/2 signaling.
Jung-min Lee - One of the best experts on this subject based on the ideXlab platform.
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prexasertib a cell cycle Checkpoint Kinase 1 inhibitor in brca mutant recurrent high grade serous ovarian cancer hgsoc a proof of concept single arm phase ii study
Journal of Clinical Oncology, 2020Co-Authors: Erika J Lampert, Stanley Lipkowitz, Christina M Annunziata, Elise C. Kohn, Ann Mccoy, Kathryn Trewhitt, Alexandra S Zimmer, Jung-min LeeAbstract:6038Background: Preclinical data suggest cell cycle Checkpoint inhibition induces greater cell death in BRCA mutant HGSOC by causing replication stress and dysregulation of DNA damage responses. We...
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Abstract 264: The cell cycle Checkpoint Kinase 1/2 inhibitor, LY2606368 with PARP inhibition results in synergistic cytotoxicity in high-grade serous ovarian cancer (HGSOC) at lower than physiologically administered concentrations
Experimental and Molecular Therapeutics, 2016Co-Authors: Yeong-ran Ahn, Takuhei Yokoyama, Nicolas Gordon, Elise C. Kohn, Jung-min LeeAbstract:Background: Chk1/2 are major cell cycle regulators in p53-deficient tumors, such as HGSOC. Chk1 plays a critical role in DNA repair, facilitating the BRCA2-RAD51 interaction by phosphorylating the BRCA2 C-terminal domain and Thr309-RAD51. Clinical activity with the Chk1/2 inhibitor, LY2606368 mesylate monohydrate (LY), has been observed in solid tumors. We hypothesize that Chk1 inhibition would sensitize HGSOC to PARP inhibition (PARPi) by preventing nuclear RAD51 foci formation, thus impairing DNA repair. We investigated potential synergy of the combination of LY and the PARPi, olaparib (O), in HGSOC cell lines, testing lower concentrations than clinically attained. Materials and Methods: We examined cytotoxicity, DNA damage, and nuclear RAD51 foci formation by LY and/or O using XTT assay, comet assay and immunofluorescence (IF), in 3 HGSOC cell lines: two BRCA1/2 wild type (CAOV3, OV90), and one with BRCA2 mutation (PEO1). We examined a dose range based on clinically achievable concentrations of LY (0.53μM–1.34μM) and O (7.8μM–11.0μM) and calculated IC 50 concentrations for cytotoxicity. The combination index (CI) was calculated to evaluate synergism. DNA damage and nuclear RAD51 foci formation were examined. DMSO was used as vehicle control. All experiments were performed in at least three replicates in all cell lines. Results are presented as mean ± SEM. Results: LY alone yielded cytotoxicity in CAOV3, OV90, and PEO1 with IC 50 6.34nM, 35.2nM, 12.6nM, respectively. O 5μM monotherapy resulted in 47%, 13%, and 69% cytotoxicity in CAOV3, OV90, and PEO1. LY/O combination showed 51%, 58% and 82% cell injury in CAOV3, OV90 and PEO1. CI values indicated cytotoxicity synergism with the combination. LY/O (5nM/5μM) treatment showed greater DNA damage than O alone in OV90 and PEO1 (p Conclusions: Our preliminary results suggest synergistic activity of the combination of LY and PARPi in HGSOC cell lines using concentrations that are lower than clinically attainable in patients. Citation Format: Yeong-ran Ahn, Takuhei Yokoyama, Minshu Yu, Nicolas Gordon, Elise C. Kohn, Jung-min Lee. The cell cycle Checkpoint Kinase 1/2 inhibitor, LY2606368 with PARP inhibition results in synergistic cytotoxicity in high-grade serous ovarian cancer (HGSOC) at lower than physiologically administered concentrations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 264.
Danaadriana Botesteanu - One of the best experts on this subject based on the ideXlab platform.
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prexasertib a cell cycle Checkpoint Kinase 1 and 2 inhibitor in brca wild type recurrent high grade serous ovarian cancer a first in class proof of concept phase 2 study
Lancet Oncology, 2018Co-Authors: Jayakumar R Nair, Alexandra Zimmer, Stanley Lipkowitz, Christina M Annunziata, Maria Merino, Elizabeth M Swisher, Maria I Harrell, Jane B Trepel, Mohammad H. Bagheri, Danaadriana BotesteanuAbstract:Summary Background High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle Checkpoint Kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. Methods In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m 2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA -mutated ovarian cancer cohort. Findings Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4–8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression. Interpretation Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease. Funding Intramural Research Program of the National Institutes of Health and National Cancer Institute.
Stanley Lipkowitz - One of the best experts on this subject based on the ideXlab platform.
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prexasertib a cell cycle Checkpoint Kinase 1 inhibitor in brca mutant recurrent high grade serous ovarian cancer hgsoc a proof of concept single arm phase ii study
Journal of Clinical Oncology, 2020Co-Authors: Erika J Lampert, Stanley Lipkowitz, Christina M Annunziata, Elise C. Kohn, Ann Mccoy, Kathryn Trewhitt, Alexandra S Zimmer, Jung-min LeeAbstract:6038Background: Preclinical data suggest cell cycle Checkpoint inhibition induces greater cell death in BRCA mutant HGSOC by causing replication stress and dysregulation of DNA damage responses. We...
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prexasertib a cell cycle Checkpoint Kinase 1 and 2 inhibitor in brca wild type recurrent high grade serous ovarian cancer a first in class proof of concept phase 2 study
Lancet Oncology, 2018Co-Authors: Jayakumar R Nair, Alexandra Zimmer, Stanley Lipkowitz, Christina M Annunziata, Maria Merino, Elizabeth M Swisher, Maria I Harrell, Jane B Trepel, Mohammad H. Bagheri, Danaadriana BotesteanuAbstract:Summary Background High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle Checkpoint Kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. Methods In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m 2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA -mutated ovarian cancer cohort. Findings Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4–8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression. Interpretation Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease. Funding Intramural Research Program of the National Institutes of Health and National Cancer Institute.
Christina M Annunziata - One of the best experts on this subject based on the ideXlab platform.
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prexasertib a cell cycle Checkpoint Kinase 1 inhibitor in brca mutant recurrent high grade serous ovarian cancer hgsoc a proof of concept single arm phase ii study
Journal of Clinical Oncology, 2020Co-Authors: Erika J Lampert, Stanley Lipkowitz, Christina M Annunziata, Elise C. Kohn, Ann Mccoy, Kathryn Trewhitt, Alexandra S Zimmer, Jung-min LeeAbstract:6038Background: Preclinical data suggest cell cycle Checkpoint inhibition induces greater cell death in BRCA mutant HGSOC by causing replication stress and dysregulation of DNA damage responses. We...
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prexasertib a cell cycle Checkpoint Kinase 1 and 2 inhibitor in brca wild type recurrent high grade serous ovarian cancer a first in class proof of concept phase 2 study
Lancet Oncology, 2018Co-Authors: Jayakumar R Nair, Alexandra Zimmer, Stanley Lipkowitz, Christina M Annunziata, Maria Merino, Elizabeth M Swisher, Maria I Harrell, Jane B Trepel, Mohammad H. Bagheri, Danaadriana BotesteanuAbstract:Summary Background High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle Checkpoint Kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. Methods In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m 2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA -mutated ovarian cancer cohort. Findings Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4–8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression. Interpretation Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease. Funding Intramural Research Program of the National Institutes of Health and National Cancer Institute.