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Patrick Vincent

Bio: Patrick Vincent is an academic researcher from Takeda Pharmaceutical Company. The author has contributed to research in topics: Kinase & MEK inhibitor. The author has an hindex of 4, co-authored 16 publications receiving 61 citations.

Papers
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Journal ArticleDOI
TL;DR: It is demonstrated that TAK-733 exhibits robust tumor growth inhibition and regression against human melanoma cell lines and patient-derived xenograft models, suggesting that further clinical development in melanoma is of scientific interest.
Abstract: The goal of this study was to investigate the activity of the selective MEK1/2 inhibitor TAK-733 in both melanoma cell lines and patient-derived melanoma xenograft models. In vitro cell proliferation assays using the sulforhodamine B assay were conducted to determine TAK-733 potency and melanoma responsiveness. In vivo murine modeling with eleven patient-derived melanoma explants evaluated daily dosing of TAK-733 at 25 or 10 mg/kg. Immunoblotting was performed to evaluate on-target activity and downstream inhibition by TAK-733 in both in vitro and in vivo studies. TAK-733 demonstrated broad activity in most melanoma cell lines with relative resistance observed at IC50 > 0.1 μmol/L in vitro. TAK-733 also exhibited activity in 10 out of 11 patient-derived explants with tumor growth inhibition ranging from 0% to 100% (P < 0.001-0.03). Interestingly, BRAF(V600E) and NRAS mutational status did not correlate with responsiveness to TAK-733. Pharmacodynamically, pERK was suppressed in sensitive cell lines and tumor explants, confirming TAK-733-mediated inhibition of MEK1/2, although the demonstration of similar effects in the relatively resistant cell lines and tumor explants suggests that escape pathways are contributing to melanoma survival and proliferation. These data demonstrate that TAK-733 exhibits robust tumor growth inhibition and regression against human melanoma cell lines and patient-derived xenograft models, suggesting that further clinical development in melanoma is of scientific interest. Particularly interesting is the activity in BRAF wild-type models, where current approved therapy such as vemurafenib has been reported not to be active.

23 citations

Journal ArticleDOI
TL;DR: Results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein.
Abstract: Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein. Mol Cancer Ther; 16(7); 1269-78. ©2017 AACR.

10 citations

Patent
04 Jun 2012
TL;DR: In this paper, a method for the treatment of proliferative disorders by combining a MEK inhibitor in combination with a selective inhibitor of Aurora A kinase was proposed. But this method is not suitable for the case of cancer patients.
Abstract: The present invention relates to methods for the treatment of proliferative disorders. In particular, the invention provides methods for treatment of proliferative disorders by administering a MEK inhibitor in combination with a selective inhibitor of Aurora A kinase.

8 citations

Journal ArticleDOI
TL;DR: A non-receptor cytoplasmic tyrosine kinase that is a common member of various signal transduction cascades in cells of the hematopoietic lineage is studied for its role in apoptosis and cell reprograming.
Abstract: 8580 Background: Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is a common member of various signal transduction cascades in cells of the hematopoietic lineage inc...

6 citations

Journal ArticleDOI
TL;DR: 18F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment and showed dose-dependent inhibition of tumor growth and 18F- FDG uptake in tumor tissue.
Abstract: Objective The aim of this study was to evaluate the potential of 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts.

5 citations


Cited by
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Journal ArticleDOI
TL;DR: In this paper, the molecular landscape of mucosal melanoma was studied and potential new therapeutic targets were found, which have a poor prognosis due to the lack of effective targeted therapies.
Abstract: Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome seque

102 citations

Journal ArticleDOI
19 Feb 2020-Cancers
TL;DR: Progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma is focused on.
Abstract: Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

102 citations

Journal ArticleDOI
19 May 2016-Oncogene
TL;DR: Second generation inhibitors such as Vemurafenib and Dabrafenib targeting BRAFV600E, Trametinib targeting MEK1/2 and the first generation pan-RAF inhibitor SorafenIB (Nexavar) have already been approved for treating renal, hepatocellular, thyroid cancers and BRAFv600E/K harboring metastatic melanoma and others against RAF and MEK 1/2 are presently undergoing clinical trials.
Abstract: The RAS-RAF-MEK1/2-ERK1/2 pathway is a key signal transduction pathway in the cells. Critically, it remains constitutively active in approximately 30% of human cancers, having key roles in cancer development, maintenance and progression, while being responsible for poorer prognosis and drug resistance. Consequently, the inhibition of this pathway has been the subject of intense research for >25 years. The advent of better patient screening techniques has increasingly shown that upstream regulators like RAS and RAF remain persistently mutated in many cancer types. These gain-of-function mutations, such as KRAS-4B(G12V/G13D/Q61K), NRAS(Q61L/Q61R) or BRAF(V600E), lead to tremendous increase in their activities, resulting in constitutively active extracellular signal-regulated kinase 1/2 (ERK1/2). They were not efficiently targeted by the first-generation inhibitors such as Lonafarnib or Sorafenib, which were essentially broad spectrum inhibitors targeting pan-RAS and pan-RAF, respectively. This triggered the development of the second-generation inhibitors selective against the mutated proteins. Second generation inhibitors such as Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar) targeting BRAF(V600E), Trametinib (Mekinist) targeting MEK1/2 and the first generation pan-RAF inhibitor Sorafenib (Nexavar) have already been approved for treating renal, hepatocellular, thyroid cancers and BRAF(V600E/K) harboring metastatic melanoma. Others against RAF and MEK1/2 are presently undergoing clinical trials. Their success would depend on the better understanding of the acquired resistance mechanisms to these drugs in the cancer cells and the identification of predictive biomarkers for the proper administration of suitable inhibitor(s).

79 citations

Journal ArticleDOI
TL;DR: The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake.
Abstract: Background: TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2. Methods: The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733. Results: Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAF V600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRAS Q61L mutant and GNAQ mutant cell lines than in BRAF V600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays. Conclusions: The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake.

71 citations

Journal ArticleDOI
TL;DR: An overview of the biological functions of aurora kinases in healthy cells and in cancer cells is provided, and small studies and high-throughput datasets that particularly implicate auroraKinase A in the pathogenesis of squamous-cell carcinomas of the head and neck are reviewed.
Abstract: In healthy cells, controlled activation of aurora kinases regulates mitosis. Overexpression and hyperactivation of aurora kinases A and B have major roles in tumorigenesis, and can induce aneuploidy and genomic instability. In squamous-cell carcinomas of the head and neck, overexpression of aurora kinase A is associated with decreased survival, and a reduction in aurora kinase A and aurora kinase B expression inhibits cell growth and increases apoptosis. In this Review, we provide an overview of the biological functions of aurora kinases in healthy cells and in cancer cells, and we review small studies and high-throughput datasets that particularly implicate aurora kinase A in the pathogenesis of squamous-cell carcinomas of the head and neck. Early phase trials are beginning to assess the activity of small-molecule inhibitors of aurora kinases. We summarise trials of aurora kinase inhibitors in squamous-cell carcinomas of the head and neck, and discuss directions for future drug combination trials and biomarkers to use with drugs that inhibit aurora kinases.

57 citations