bc9b00632_si_001.pdf (986.85 kB)
Design and Evaluation of PEGylated Liposomal Formulation of a Novel Multikinase Inhibitor for Enhanced Chemosensitivity and Inhibition of Metastatic Pancreatic Ductal Adenocarcinoma
journal contribution
posted on 2019-10-03, 21:13 authored by 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 HuangPancreatic 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.
History
Usage metrics
Categories
Keywords
first-line treatmentoverexpressedNovel Multikinase Inhibitorgemcitabinecombination therapyMAPK pathwaysgrowth inhibitionbispecific antibodiesTKIepidermal growth factor receptorSmall molecule inhibitorscMET inhibitornonsmall cell lung cancer modelstumor growthEnhanced ChemosensitivitycMET sharePEGylated Liposomal Formulationprognostic markerpancreatic adenocarcinoma orthotopic xenograft modelmortality ratesN 19Metastatic Pancreatic Ductal Adenocarcinoma Pancreatic ductal adenocarcinomatyrosine-protein kinase MetEGFR tyrosine kinase inhibitorsnovel liposomal formulationPDAC patientsPI 3Ksurvival benefitsnovel optionsLN 19cancer therapy
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC