Development of a smart transformable nanotherapeutic against cancers with acquired resistance to EGFR-targeted therapies caused by MET amplification - 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.
