Design and Evaluation of PEGylated Liposomal Formulation of a Novel Multikinase Inhibitor for Enhanced Chemosensitivity and Inhibition of Metastatic Pancreatic Ductal Adenocarcinoma

Vijay Sagar Madamsetty, Krishnendu Pal, Shamit Kumar Dutta, Enfeng Wang, James R Thompson, Raj Kumar Banerjee, Thomas R Caulfield, Kabir Mody, Yun Yen, Debabrata Mukhopadhyay, Hsu-Shan Huang

研究成果: 雜誌貢獻文章

摘要

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among cancers. Chemotherapy is the standard first-line treatment, but only modest survival benefits are observed. With the advent of targeted therapies, epidermal growth factor receptor (EGFR) has been acknowledged as a prospective target in PDAC since it is overexpressed in up to 60% of cases. Similarly, the tyrosine-protein kinase Met (cMET) is also overexpressed in PDAC (27-60%) and is a prognostic marker for poor survival. Interestingly, EGFR and cMET share some common signaling pathways including PI3K/Akt and MAPK pathways. Small molecule inhibitors or bispecific antibodies that can target both EGFR and cMET are therefore emerging as novel options for cancer therapy. We previously developed a dual EGFR and cMET inhibitor (N19) that was able to inhibit tumor growth in nonsmall cell lung cancer models resistant to EGFR tyrosine kinase inhibitors (TKI). Here, we report the development of a novel liposomal formulation of N19 (LN19) and showed significant growth inhibition and increased sensitivity toward gemcitabine in the pancreatic adenocarcinoma orthotopic xenograft model. Taken together, our results suggest that LN19 can be valued as an effective combination therapy with conventional chemotherapy such as gemcitabine for PDAC patients.

原文英語
期刊Bioconjugate Chemistry
DOIs
出版狀態打印前電子出版 - 十月 4 2019

指紋

Epidermal Growth Factor Receptor
gemcitabine
Adenocarcinoma
Chemotherapy
Protein-Tyrosine Kinases
Bispecific Antibodies
Drug Therapy
Neoplasms
Survival
Therapeutics
Growth
Phosphatidylinositol 3-Kinases
Heterografts
Antibodies
Non-Small Cell Lung Carcinoma
Tumors
Cells
Epidermal Growth Factor
Proteins
Molecules

引用此文

Design and Evaluation of PEGylated Liposomal Formulation of a Novel Multikinase Inhibitor for Enhanced Chemosensitivity and Inhibition of Metastatic Pancreatic Ductal Adenocarcinoma. / Madamsetty, Vijay Sagar; Pal, Krishnendu; Dutta, Shamit Kumar; Wang, Enfeng; Thompson, James R; Banerjee, Raj Kumar; Caulfield, Thomas R; Mody, Kabir; Yen, Yun; Mukhopadhyay, Debabrata; Huang, Hsu-Shan.

於: Bioconjugate Chemistry, 04.10.2019.

研究成果: 雜誌貢獻文章

Madamsetty, Vijay Sagar ; Pal, Krishnendu ; Dutta, Shamit Kumar ; Wang, Enfeng ; Thompson, James R ; Banerjee, Raj Kumar ; Caulfield, Thomas R ; Mody, Kabir ; Yen, Yun ; Mukhopadhyay, Debabrata ; Huang, Hsu-Shan. / Design and Evaluation of PEGylated Liposomal Formulation of a Novel Multikinase Inhibitor for Enhanced Chemosensitivity and Inhibition of Metastatic Pancreatic Ductal Adenocarcinoma. 於: Bioconjugate Chemistry. 2019.
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title = "Design and Evaluation of PEGylated Liposomal Formulation of a Novel Multikinase Inhibitor for Enhanced Chemosensitivity and Inhibition of Metastatic Pancreatic Ductal Adenocarcinoma",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among cancers. Chemotherapy is the standard first-line treatment, but only modest survival benefits are observed. With the advent of targeted therapies, epidermal growth factor receptor (EGFR) has been acknowledged as a prospective target in PDAC since it is overexpressed in up to 60{\%} of cases. Similarly, the tyrosine-protein kinase Met (cMET) is also overexpressed in PDAC (27-60{\%}) and is a prognostic marker for poor survival. Interestingly, EGFR and cMET share some common signaling pathways including PI3K/Akt and MAPK pathways. Small molecule inhibitors or bispecific antibodies that can target both EGFR and cMET are therefore emerging as novel options for cancer therapy. We previously developed a dual EGFR and cMET inhibitor (N19) that was able to inhibit tumor growth in nonsmall cell lung cancer models resistant to EGFR tyrosine kinase inhibitors (TKI). Here, we report the development of a novel liposomal formulation of N19 (LN19) and showed significant growth inhibition and increased sensitivity toward gemcitabine in the pancreatic adenocarcinoma orthotopic xenograft model. Taken together, our results suggest that LN19 can be valued as an effective combination therapy with conventional chemotherapy such as gemcitabine for PDAC patients.",
author = "Madamsetty, {Vijay Sagar} and Krishnendu Pal and Dutta, {Shamit Kumar} and Enfeng Wang and Thompson, {James R} and Banerjee, {Raj Kumar} and Caulfield, {Thomas R} and Kabir Mody and Yun Yen and Debabrata Mukhopadhyay and Hsu-Shan Huang",
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AU - Pal, Krishnendu

AU - Dutta, Shamit Kumar

AU - Wang, Enfeng

AU - Thompson, James R

AU - Banerjee, Raj Kumar

AU - Caulfield, Thomas R

AU - Mody, Kabir

AU - Yen, Yun

AU - Mukhopadhyay, Debabrata

AU - Huang, Hsu-Shan

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AB - Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among cancers. Chemotherapy is the standard first-line treatment, but only modest survival benefits are observed. With the advent of targeted therapies, epidermal growth factor receptor (EGFR) has been acknowledged as a prospective target in PDAC since it is overexpressed in up to 60% of cases. Similarly, the tyrosine-protein kinase Met (cMET) is also overexpressed in PDAC (27-60%) and is a prognostic marker for poor survival. Interestingly, EGFR and cMET share some common signaling pathways including PI3K/Akt and MAPK pathways. Small molecule inhibitors or bispecific antibodies that can target both EGFR and cMET are therefore emerging as novel options for cancer therapy. We previously developed a dual EGFR and cMET inhibitor (N19) that was able to inhibit tumor growth in nonsmall cell lung cancer models resistant to EGFR tyrosine kinase inhibitors (TKI). Here, we report the development of a novel liposomal formulation of N19 (LN19) and showed significant growth inhibition and increased sensitivity toward gemcitabine in the pancreatic adenocarcinoma orthotopic xenograft model. Taken together, our results suggest that LN19 can be valued as an effective combination therapy with conventional chemotherapy such as gemcitabine for PDAC patients.

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