TY - JOUR
T1 - Design and Evaluation of PEGylated Liposomal Formulation of a Novel Multikinase Inhibitor for Enhanced Chemosensitivity and Inhibition of Metastatic Pancreatic Ductal Adenocarcinoma
AU - Madamsetty, Vijay Sagar
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
N1 - Funding Information:
D.M. and H.S.H.: Equal contributing senior authors. This work was supported by NIH grants CA150190, CA78383, Florida Department of Health Cancer Research Chair Fund Florida #3J (D.M.), and Ministry of Science and Technology, Taiwan (MOST 106-2113-M-038-003 and 107-2113-M-038-002) (H.S.H.). The authors declare the following competing financial interest(s): D.M. and H.S.H. have applied for protection of intellectual property related to the results in the manuscript. There are no other conflicts of interest to declare.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/10/16
Y1 - 2019/10/16
N2 - 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.
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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U2 - 10.1021/acs.bioconjchem.9b00632
DO - 10.1021/acs.bioconjchem.9b00632
M3 - Article
C2 - 31584260
SN - 1043-1802
VL - 30
SP - 2703
EP - 2713
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 10
ER -