Translational Development of a Targeted and Stroma-penetrating Nanoparticle Drug for Pancreatic Cancer Therapy - Project Summary
Low efficiency in drug delivery and aggressive tumor biology are the major causes of resistance to therapy in
pancreatic cancer. The presence of a dense fibrous tumor stroma creates a drug delivery barrier and promotes
aggressive biology and drug resistance in pancreatic cancer cells. We have developed a targeted stroma
penetrating hyaluronic acid nanoparticle carrying SN38, an active metabolite of irinotecan. Results of preclinical
studies demonstrated significantly enhanced nanoparticle/drug delivery into ductal carcinoma cells to produce
strong therapeutic effects in drug resistant pancreatic cancer patient derived xenograft (PDX) models.
Importantly, the stroma-penetrating nanodrug has unique properties to modulate tumor stroma that allows the
nanodrug to pass through the stromal barrier but retain a protective stromal structure. For clinical translation of
this novel nanodrug, our SBIR phase I study focused on the re-engineering a tagless stroma penetrating ligand,
ATFmmp14 (R2), that consists of a urokinase plasminogen activator receptor (uPAR) binding domain and a
catalytic domain of MMP14, following the recommendation of the FDA Pre-IND team. We have developed the
tagless ATFmmp14(R2) with the capacity of large scale production in an endotoxin-free bacterial expressing
system. We also demonstrated that ATFmmp14 (R2) conjugated HANP/SN38 has comparable tumor targeting
ability and therapeutic efficacy to the first generation of His-tagged ATFmmp14(R1)-HANP/SN38 in pancreatic
cancer PDX models. The proposed phase II project aims to accelerate the translational process by conducting
important Investigational New Drug (IND)-enabling preclinical studies. In Aim 1, we will optimize and finalize
nanoformulation of MIGRA-NP01 for large-scale production under GLP/GMP conditions. We will then
characterize in vitro and in vivo properties of MIGRA-NP01, including biophysical and biochemical parameters
in vitro, and systemic toxicity, pharmacokinetics/pharmacodynamics, biodistribution, and clearance in normal
and tumor bearing mice (Aim 2). During those studies, we will establish the Stand Operating Protocols (SOPs)
and metrics for quality control (QC) of MIGRA-NP01 for drug development (Aim 2). Next, we will determine an
optimized dose and schedule for MIGRA-NP01 in pancreatic PDX models with different pathological and genetic
features, and sensitivity to chemotherapy (Aim 3). Finally, therapeutic responses of pancreatic PDX tumors will
be correlated with the gene expression signatures to identify the potential predicative biomarkers for MIGRA-
NP01 treatment (Aim 3). The outcomes of this translational research project include: 1) obtaining the final
optimized nanoformulation of MIGRA-NP01 with established SOPs for the GLP/GMP production of MIGRA-NP01
and producing two lots of the GLP grades of MIGRA-NP01; and 2) determining systemic toxicity, biodistribution,
therapeutic dose/schedule of the MIGRA-NP01 in normal mice and pancreatic PDX tumor bearing mice. Results
of the SBIR phase II project should have a great impact on the future submission of an IND application for the
FDA approval of a phase 1 clinical trial in advanced pancreatic cancer patients.
