A Phase I Study of Dinaciclib in Combination With MK‐2206 in Patients With Advanced Pancreatic Cancer

Murphy, Adrian; Zahurak, Marianna; Shah, Mirat; Weekes, Colin D.; Hansen, Aaron Richard; Siu, Lillian L.; Spreafico, Anna; LoConte, Noelle K.; Anders, Nicole M.; Miles, T.; Rudek, Michelle A.; Doyle, L. Austin; Nelkin, Barry D.; Maitra, Anirban; Azad, Nilofer S.; Team, Etctn Study

doi:10.1111/cts.12802

Cited by 31 publications

(25 citation statements)

References 54 publications

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“…The critical role of suppressive phosphorylation of Akt in hepatocarcinogenesis suggests that pharmacological targeting of PTEN/Akt pathway probably offers potential therapeutic benefits for HCC patients. There were several identified compounds targeting PTEN/Akt signalling, such as perifosine and MK-2206, could suppress tumour growth in animal models or clinical trials [90,91,[93][94][95][96][97]., suggesting that the pharmacological inhibition of PTEN/Akt signalling might be a potential target for the treatment of tumour patients. Taken together, our findings might provide a cost-effective and high-throughput platform for identifying and evaluating candidate anticancer drugs, which is not feasible in mouse models.…”

Section: Discussionmentioning

confidence: 99%

Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish

Luo

Feng

et al. 2021

J Exp Clin Cancer Res

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Background Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish. Methods We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish. Results We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish. Conclusion Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.

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Section: Discussionmentioning

confidence: 99%

Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish

Luo

Feng

et al. 2021

J Exp Clin Cancer Res

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“…This drug showed promising efficacy and good tolerability in phase II clinical trials for myeloma and phase III clinical trials for chronic lymphocytic leukaemia [65,66]. However, even though generally well-tolerated, dinaciclib was less effective in solid tumours, including pancreatic cancers [67][68][69]. In a combination treatment of dinaciclib with the Akt-inhibitor MK-2206, the best clinical result was stable disease in only four pancreatic cancer patients (10 percent) with a median survival rate of 2,2 months [68].…”

Section: Clinical Trials Of Cdk1 Inhibitorsmentioning

confidence: 99%

“…However, even though generally well-tolerated, dinaciclib was less effective in solid tumours, including pancreatic cancers [67][68][69]. In a combination treatment of dinaciclib with the Akt-inhibitor MK-2206, the best clinical result was stable disease in only four pancreatic cancer patients (10 percent) with a median survival rate of 2,2 months [68]. Similar poor results have been found for flavopiridol, an inhibitor of CDKs 1/2/4/6, in a phase II clinical trial on pancreatic cancer [70], since the combination treatment of flavopiridol and docetaxel generated no objective responses, and only three patients (33 percent) achieved stable disease, with a median survival rate of 4,2 months.…”

Section: Clinical Trials Of Cdk1 Inhibitorsmentioning

confidence: 99%

“…For any therapy, but especially for a therapy targeted against CDKs, it seems essential to screen patients in order to ensure that PDAC tumour cells are indeed overexpressing CDK1. This can be done in solid tumour tissue with immunohistochemistry staining for CDK1 [24,68]. Thus, CDK1 overexpression can be used as a biomarker to distinguish between different types of PDAC.…”

Section: Importance Of Screening Patientsmentioning

confidence: 99%

“…Furthermore, siRNA-based screening might help to identify CDK1 as a target in tumour tissue [34,76], but this technique needs to be optimised further before being used to select PDAC patients likely to respond to CDK inhibition. In many clinical trials, patients are not screened for CDK1 overexpression [68,69,73]. Although Mita et al [67] demonstrated that it is feasible to include skin and tumour biopsy immunohistochemistry staining in a clinical trial, they did not apply analysis of CDK1 expression in their study.…”

Section: Importance Of Screening Patientsmentioning

confidence: 99%

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Cyclin Dependent Kinase-1 (CDK-1) Inhibition as a Novel Therapeutic Strategy against Pancreatic Ductal Adenocarcinoma (PDAC)

Wijnen

Pecoraro

Carbone

et al. 2021

Cancers

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The role of CDK1 in PDAC onset and development is two-fold. Firstly, since CDK1 activity regulates the G2/M cell cycle checkpoint, overexpression of CDK1 can lead to progression into mitosis even in cells with DNA damage, a potentially tumorigenic process. Secondly, CDK1 overexpression leads to the stimulation of a range of proteins that induce stem cell properties, which can contribute to the development of cancer stem cells (CSCs). CSCs promote tumor-initiation and metastasis and play a crucial role in the development of PDAC. Targeting CDK1 showed promising results for PDAC treatment in different preclinical models, where CDK1 inhibition induced cell cycle arrest in the G2/M phase and led to induction of apoptosis. Next to this, PDAC CSCs are uniquely sensitive to CDK1 inhibition. In addition, targeting of CDK1 has shown potential for combination therapy with both ionizing radiation treatment and conventional chemotherapy, through sensitizing tumor cells and reducing resistance to these treatments. To conclude, CDK1 inhibition induces G2/M cell cycle arrest, stimulates apoptosis, and specifically targets CSCs, which makes it a promising treatment for PDAC. Screening of patients for CDK1 overexpression and further research into combination treatments is essential for optimizing this novel targeted therapy.

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SIRT2 inhibitor SirReal2 enhances anti‐tumor effects of PI3K/mTOR inhibitor VS‐5584 on acute myeloid leukemia cells

Luo,

Zhao,

Zhu

et al. 2023

Cancer Medicine

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BackgroundAcute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML.MethodsThe up‐regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used.ResultsThrough bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small‐molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS‐5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS‐5584 induced apoptosis and cycle arrest of AML cells in a dose‐ and time‐dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS‐5584 treatment, with 287 proteins being down‐regulated and 71 proteins being up‐regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS‐5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS‐5584 caused a significant reduction in the half‐maximal inhibitory concentration (IC50) of VS‐5584 on AML cells. In vivo, experiments suggested that VS‐5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein.ConclusionsTaken together, the PI3K/mTOR inhibitor VS‐5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

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A Phase I Study of Dinaciclib in Combination With MK‐2206 in Patients With Advanced Pancreatic Cancer

Cited by 31 publications

References 54 publications

Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish

Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish

Cyclin Dependent Kinase-1 (CDK-1) Inhibition as a Novel Therapeutic Strategy against Pancreatic Ductal Adenocarcinoma (PDAC)

SIRT2 inhibitor SirReal2 enhances anti‐tumor effects of PI3K/mTOR inhibitor VS‐5584 on acute myeloid leukemia cells

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