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Principal Investigator: Panupong Mahalapbutr
Organization: KHON KAEN UNIVERSITY
Fiscal Year: 2024
Award: $112,974
Funding agency: John E. Fogarty International Center for Advanced Study in the Health Sciences
Title: Development of a smart transformable nanotherapeutic against cancers with acquired resistance to
EGFR-targeted therapies caused by MET amplification
Study Section & Awarding Component Assignment Request: Fogarty International Center
Project summary/Abstract:
Cancer, a significant public health challenge, is the leading cause of mortality in Thailand and
worldwide. The ongoing rise in cancer cases among Thais, resulting in over a hundred thousand annual
fatalities, has created a compelling necessity and demand for the development of potent pharmaceuticals to
address diverse types of cancer. Unlike conventional chemotherapy, targeted therapy minimizes the risk of
side effects by specifically targeting proteins overexpressed or activated in tumors. Among various identified
oncotargets, the epidermal growth factor receptor (EGFR) represents a particularly appealing one, due to its
overexpression, amplification, and gain of function in several types of cancer. Two classes of EGFR inhibitors
have been clinically approved, including monoclonal antibodies and small-molecule tyrosine kinase inhibitors.
Despite a good initial response rate to these drugs, most patients eventually develop drug resistance, mainly
caused by a mesenchymal-epithelial transition (MET) amplification. One promising approach that can
overcome drug resistance to EGFR-targeted therapies caused by MET amplification is co-targeting both
EGFR and MET receptors using a peptide-based nanotherapeutic platform. The specific aims of the proposed
research are (1) To design and synthesize smart transformable EGFR/MET-targeting peptide
nanoparticles (PNPs) and (2) To elucidate the anticancer effects and the underlying mechanisms of the
PNPs on cancers resistant to EGFR-targeted therapies due to MET amplification in vitro and in vivo.
The potential EGFR/MET-targeting peptides will be achieved by the combination between a computer-aided
peptide design strategy and an ultra-high-throughput one-bead one-compound (OBOC) combinatorial library
technology in Dr. Kit S Lam’s laboratory at the University of California, Davis, USA. Dr. Lam is the inventor
of the OBOC technology. Subsequently, the lead EGFR/MET-targeting peptides will be used for the design
and synthesis of smart supramolecular peptides capable of (i) assembling into nanoparticles, (ii) in situ
transformation into nanofibrils upon binding to EGFR/MET at tumor sites, (iii) capturing T effector cells and
facilitating their prolonged retention within the tumor microenvironment, and (iv) releasing the cytotoxic drug
from the nanofibrillar network into cancer cells, maximizing the therapeutic efficacy. At the end of this five-
year project, at least one efficient PNP for treatment of cancer with acquired resistance to EGFR-targeted
therapies due to MET amplification can be obtained, which will be chosen for further clinical studies. The
proposed career development plan will advance not only my research capacity but also essential skills for
manuscript writing, NIH grant writing, and leadership, culminating in publication of high-quality research
articles, submission of R01 grant proposal, professional networking, academic promotion, and development
into a successful, independent researcher.
Terms: <1-Phosphatidylinositol 3-Kinase><Address><Affinity><Applications Grants><Award><Beta Sheet><Binding><Blood Plasma><Breast Cancer><Bypass><California><Cancer Patient><Cancer Treatment><Cancer cell line><Cancers><Cell surface><Cervical Cancer><Cervix Cancer><Characteristics><Chemicals><Clinical><Clinical Research><Clinical Study><Clinical Treatment Moab><Colorectal Cancer><Computer Assisted><Cytotoxic agent><Cytotoxic drug><Development><Development Plans><Drug resistance><Drugs><EGF Receptor><EGFR><EGFR Blocker><EGFR Inhibitor><EGFR Tyrosine Kinase Inhibitor><EGFR-TK Inhibitor><ERBB Protein><Engineering><Enzyme Gene><Enzymes><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Inhibitor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor><Epidermal Growth Factor-Urogastrone Receptors><Epithelium><Exhibits><Fogarty International Center><Gel><Grant><Grant Proposals><HER1><Hepatic Cancer><High Throughput Assay><Human><In Situ><In Vitro><Incidence><Individual><Investigators><Laboratories><Lead><Leadership><Libraries><Malignant Breast Neoplasm><Malignant Cell><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Tumor of the Lung><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of cervix uteri><Malignant neoplasm of liver><Malignant neoplasm of lung><Manuscripts><Mechanics><Medication><Mesenchymal><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><NIH><Nanostructures><National Institutes of Health><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PTK Inhibitors><Pathway interactions><Patients><Pb element><Peptide Library><Peptide Synthesis><Peptides><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Phase Transition><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Phosphorylation><Plasma><Plasma Serum><Preparation><Process><Property><Protein Phosphorylation><Protein Tyrosine Kinase Inhibitors><Proteins><PtdIns 3-Kinase><Public Health><Publications><Pulmonary Cancer><Pulmonary malignant Neoplasm><R-Series Research Projects><R01 Mechanism><R01 Program><Receptor Protein><Reporting><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resistance><Reticuloendothelial System, Serum, Plasma><Scientific Publication><Site><Solid><Study Section><TGF-alpha Receptor><TK Inhibitors><Techniques><Technology><Teff cell><Thailand><Therapeutic><Toxin><Transforming Growth Factor alpha Receptor><Treatment Efficacy><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Tyrosine Kinase Inhibitor><United States National Institutes of Health><Universities><Urogastrone Receptor><Uterine Cervix Cancer><World Health Organization><Writing><acquired drug resistance><alpha helix><anti-cancer><anti-cancer therapy><aqueous><aspirate><beta pleated sheet><biocompatibility><biomaterial compatibility><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer microenvironment><cancer therapy><cancer type><cancer-directed therapy><career development><career fair><career networking><chemical stability><chemotherapy><combinatorial><computer aided><design><designing><develop drug resistance><developmental><drug resistance development><drug resistant><drug/agent><effector T cell><epithelial to mesenchymal transition><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><gain of function><heavy metal Pb><heavy metal lead><high throughput screening><immunogenicity><in vivo><innovate><innovation><innovative><intervention efficacy><liver cancer><liver malignancy><lung cancer><mAbs><malignancy><malignant breast tumor><malignant liver tumor><mechanic><mechanical><monoclonal Abs><mortality><nano fibrillar><nano fibrils><nano meter scale><nano meter sized><nano particle><nano-sized particle><nano-sized structures><nano-structures><nanofibrillar><nanofibrils><nanomaterials><nanometer scale><nanometer sized><nanoparticle><nanoscale><nanosized particle><nanotherapeutic><neoplasm/cancer><overexpress><overexpression><pathway><peptide structure><pharmaceutical><preparations><professional networking><proto-oncogene protein c-erbB-1><receptor><refractory cancer><resistance mechanism><resistance to Drug><resistant><resistant cancer><resistant mechanism><resistant to Drug><response><risk minimization><scaffold><scaffolding><screening><screenings><self assembly><side effect><skills><small molecule><speed networking><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapy efficacy><tumor><tumor microenvironment><α-helix><β-Sheet><β-pleated sheet>