Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients

Fabre, Claire; Gobbi, Marco; Ezzili, Cyrine; Zoubir, Mustapha; Sablin, Marie Paule; Small, Karen; Im, Ellie; Shinwari, Nabeegha; Zhang, Da; Zhou, Honghong; Tourneau, Christophe Le

doi:10.1007/s00280-014-2583-9

Cited by 46 publications

(29 citation statements)

References 38 publications

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“…Although clinical trials showed that dinaciclib displayed tolerable toxicity (Parry et al, 2010;Nemunaitis et al, 2013;Fabre et al, 2014;Asghar et al, 2015;Kumar et al, 2015), some reports of randomized phase 2 trials of dinaciclib have been disappointing (Mita et al, 2014) with no significant response, particularly in patients with non-small cell lung cancer (Stephenson et al, 2014) or acute lymphoblastic leukemia (Gojo et al, 2013). In this study, we showed that neither ABT-737 nor dinaciclib is a potent cytotoxic agent when used alone and that efficacy was poor at the clinically achievable range.…”

Section: Discussionmentioning

confidence: 71%

“…Several CDK inhibitors, including dinaciclib (Merck, Kenilworth, NJ), palbociclib (Pfizer, New York, NY), abemaciclib (Lilly, Southlake, TX), BAY1000394 (Bayer Healthcare, Leverkusen, Germany), and ribociclib (Novartis Pharmaceuticals Corp., Basel, Switzerland) are currently in clinical trials for various advanced cancers (Asghar et al, 2015, Gallorini et al, 2012. Dinaciclib inhibits CDKs 1, 2, 5, and 9 and entered phase 2 and 3 clinical trials in a range of malignancies and displayed tolerable toxicity (Parry et al, 2010;Nemunaitis et al, 2013;Fabre et al, 2014;Asghar et al, 2015, Kumar et al, 2015. Parry et al (2010) also showed that dinaciclib inhibited cell proliferation and cell-cycle progression in multiple tumor cell lines across a broad range of tumor types with different genetic backgrounds and induced regression of established solid tumors in mouse models.…”

Section: Introductionmentioning

confidence: 99%

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Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

Jane

Premkumar

Cavaleri

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The prognosis for malignant glioma, the most common brain tumor, is still poor, underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell-cycle control, there is a strong rationale for examining the potential efficacy of strategies to counteract this process. In this study, we examined the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact, deleted, or mutated p53 or phosphatase and tensin homolog on chromosome 10; intact or deleted or p14ARF or wild-type or amplified epidermal growth factor receptor. Dinaciclib inhibited cell proliferation and induced cell-cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a standard 72-hour 3-[4,5-dimethylthiazol-2yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium (MTS) assay, at clinically relevant concentrations, dose-dependent antiproliferative effects were observed, but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth-signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitors ABT-263-nitrophenyl]sulfonylbenzamide) with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential; the release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor; phosphatidylserine exposure on the plasma membrane surface and activation of caspases and poly ADP-ribose polymerase. Mechanistic studies revealed that dinaciclib promoted proteasomal degradation of Mcl-1. These observations may have important clinical implications for the design of experimental treatment protocols for malignant human glioma.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

Jane

Premkumar

Cavaleri

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Pan-CDK inhibitors have been studied intensively over the past decade, and although there is a strong mechanistic rationale and promising preclinical data, compounds in development have not yet met expectations in clinical trials. Dinaciclib, an inhibitor of CDKs 1, 2, 5, and 9, has shown encouraging clinical activity as monotherapy and in combinations in phase I trials in advanced malignancies and leukaemia (Nemunaitis et al , 2013; Fabre et al , 2014); however, phase II studies in non-SCLC and advanced breast cancer were disappointing (Mita et al , 2014; Stephenson et al , 2014). …”

Section: Discussionmentioning

confidence: 99%

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies

et al. 2017

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Background:To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D).Methods:Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway.Results:Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6).Conclusions:Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

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“…Dinaciclib has already been evaluated in clinical trials and results show that has encouraging activity in relapsed/refractory CLL (Fabre, et al 2014, Flynn, et al 2015.…”

Section: Discussionmentioning

confidence: 99%

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

et al. 2016

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Short title: Effects of Dinaciclib on pro-survival signals in CLL. 2 SUMMARYDinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including Chronic Lymphocytic Leukemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB and p38. Also, PI3K/AKT and RAF/MEK/ERK pathways showed a transient and early activation, followed by a later, permanent inhibition. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL-2 family such as MCL-1 and BCL-xL. Finally, we show that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and BCL-2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of CDK inhibitors in CLL in combination with other relevant targeted therapies.

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Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients

Abstract: Limited data from this study shows dinaciclib in combination with rituximab was well tolerated and revealed encouraging clinical activity in relapsed/refractory CLL patients.

Cited by 46 publications

References 38 publications

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

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