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4 results on '"her receptor family"'

1. In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines

Author

Dokduang H, Jamnongkarn W, Promraksa B, Suksawat M, Padthaisong S, Thanee M, Phetcharaburanin J, Namwat N, Sangkhamanon S, Titapun A, Khuntikeo N, Klanrit P, and Loilome W

Subjects
cholangiocarcinoma, varlitinib, pan her inhibitor, her receptor family, Therapeutics. Pharmacology, RM1-950
Abstract

Hasaya Dokduang,1,2 Wassana Jamnongkarn,1,2 Bundit Promraksa,2,3 Manida Suksawat,3 Sureerat Padthaisong,2,3 Malinee Thanee,1,2 Jutarop Phetcharaburanin,1– 3 Nisana Namwat,1– 3 Sakkarn Sangkhamanon,2,4 Attapol Titapun,1,2,5 Narong Khuntikeo,1,2,5 Poramate Klanrit,1– 3 Watcharin Loilome1– 3 1Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; 2Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; 3Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; 4Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; 5Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCorrespondence: Watcharin LoilomeDepartment of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandTel/Fax +66 43 348 386Email watclo@kku.ac.thBackground: Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and biliary tract cancer, which includes CCA. This study aims to evaluate the anti-tumor effect of varlitinib on CCA using both in vitro and in vivo models.Materials and Methods: HER family expression profiles and the cytotoxic activity of varlitinib were determined in CCA cell lines (KKU-214, KKU-213, KKU-156 and KKU-100) and cholangiocyte (MMNK-1). Anti-proliferation and apoptosis induction were examined in KKU-214 and KKU-100 cell lines. A combination of varlitinib with PI3K inhibitor, BKM-120, was explored for efficacy in the KKU-100 cell line. In addition, the anti-tumor activity of varlitinib on CCA and the key metabolites were evaluated in tumor tissues from CCA xenograft model.Results: Elevated expressions of EGFR and HER2 were observed in KKU-214 and KKU-100 cells and varlitinib can suppress CCA cell growth in the micromolar range. Varlitinib inhibits cell proliferation and enhances cell death via the suppression of Akt and Erk1/2 activity in the KKU-214 cell line. While KKU-100 cells showed a poor response to varlitinib, a combination of varlitinib with BKM-120 improved anti-tumor activity. Varlitinib can significantly suppress tumor growth in the CCA xenograft model after oral administration for 15 days without noticeable toxicity, and aspartate can be the key metabolite to correlate with varlitinib response.Conclusion: Our study indicates that varlitinib is a promising therapeutic agent for CCA treatment via the inhibition of EGFR/HER2. The anti-tumor effect of varlitinib on CCA also showed synergism in combination with PI3K inhibition. Aspartate metabolite level was correlated with varlitinib response. Combination of varlitinib with targeted drug or cytotoxic drug was recommended.Keywords: cholangiocarcinoma, varlitinib, pan HER inhibitor, HER receptor family

Published
2020

2. In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines

Author

Hasaya, Dokduang, Wassana, Jamnongkarn, Bundit, Promraksa, Manida, Suksawat, Sureerat, Padthaisong, Malinee, Thanee, Jutarop, Phetcharaburanin, Nisana, Namwat, Sakkarn, Sangkhamanon, Attapol, Titapun, Narong, Khuntikeo, Poramate, Klanrit, and Watcharin, Loilome

Subjects
Mice, Inbred BALB C, Receptor, ErbB-2, fungi, Mice, Nude, Antineoplastic Agents, Apoptosis, Neoplasms, Experimental, Cholangiocarcinoma, ErbB Receptors, Mice, Bile Duct Neoplasms, HER receptor family, Tumor Cells, Cultured, Animals, Humans, Female, Drug Screening Assays, Antitumor, varlitinib, pan HER inhibitor, Protein Kinase Inhibitors, Cell Proliferation, Original Research
Abstract

Background Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and biliary tract cancer, which includes CCA. This study aims to evaluate the anti-tumor effect of varlitinib on CCA using both in vitro and in vivo models. Materials and Methods HER family expression profiles and the cytotoxic activity of varlitinib were determined in CCA cell lines (KKU-214, KKU-213, KKU-156 and KKU-100) and cholangiocyte (MMNK-1). Anti-proliferation and apoptosis induction were examined in KKU-214 and KKU-100 cell lines. A combination of varlitinib with PI3K inhibitor, BKM-120, was explored for efficacy in the KKU-100 cell line. In addition, the anti-tumor activity of varlitinib on CCA and the key metabolites were evaluated in tumor tissues from CCA xenograft model. Results Elevated expressions of EGFR and HER2 were observed in KKU-214 and KKU-100 cells and varlitinib can suppress CCA cell growth in the micromolar range. Varlitinib inhibits cell proliferation and enhances cell death via the suppression of Akt and Erk1/2 activity in the KKU-214 cell line. While KKU-100 cells showed a poor response to varlitinib, a combination of varlitinib with BKM-120 improved anti-tumor activity. Varlitinib can significantly suppress tumor growth in the CCA xenograft model after oral administration for 15 days without noticeable toxicity, and aspartate can be the key metabolite to correlate with varlitinib response. Conclusion Our study indicates that varlitinib is a promising therapeutic agent for CCA treatment via the inhibition of EGFR/HER2. The anti-tumor effect of varlitinib on CCA also showed synergism in combination with PI3K inhibition. Aspartate metabolite level was correlated with varlitinib response. Combination of varlitinib with targeted drug or cytotoxic drug was recommended.

Published
2020

3. Combinatorial Protein Engineering Of Affibody Molecules Using E. Coli Display And Rational Design Of Affibody-Based Tracers For Medical Imaging

Author

Andersson, Ken G. and Andersson, Ken G.

Abstract

Directed evolution is today an established strategy for generation of new affinity proteins. This thesis describes the development of a cell-display method using Escherichia coli for directed evolution of Affibody molecules. Further, the thesis describes rational design of Affibody-based tracers, intended for future patient stratification using medical imaging. Fusing recombinant proteins to various autotransporters is a promising approach for efficient surface display on the surface of E. coli, as well as for construction of high-complexity libraries. In paper I, we successfully engineered an expression vector for display of Affibody molecules using the autotransporter AIDA-I. In paper II, a large Affibody library of 2.3x109 variants was constructed and screening using FACS resulted in new specific binders in the nanomolar range. In paper III, we demonstrated Sortase-mediated secretion and conjugation of binders directly from the E. coli surface. The three following studies describe rational design of Affibody-based tracers against two cancer-associated targets for molecular imaging. First, anti-HER3 Affibody molecules were labelled with 111In, and SPECT imaging showed that the conjugates specifically targeted HER3-expressing xenografts. Furthermore, labeling with 68Ga for PET imaging showed that tumor uptake correlated with HER3 expression, suggesting that the tracers have potential for patient stratification. The last study describes the development and investigation of anti-EGFR Affibody-based imaging agents. Labeled with 89Zr, the Affibody tracer demonstrated higher tumor uptake at 3 h post injection than the anti-EGFR antibody cetuximab at 48 h post injection. In conclusion, this thesis describes new tools and knowledge that will hopefully contribute to the development of affinity proteins for biotechnology, therapy and medical imaging in the future., QC 20170904

Published
2017

4. Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors.

Author

Barlaam B, Anderton J, Ballard P, Bradbury RH, Hennequin LF, Hickinson DM, Kettle JG, Kirk G, Klinowska T, Lambert-van der Brempt C, Trigwell C, Vincent J, and Ogilvie D

Abstract

Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.

Published
2013
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