Translational development of a targeted and stroma-penetrating nanoparticle drug for pancreatic cancer therapy
Ended Project Grant Awarded Last action
- Award ID
- R44CA246827
- Recipient
-
Migra-Therapeutics, LLC UEI NCN6HK3N2SG3
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,710,795
Award facts
- Assistance listing
- 93.395 Cancer Treatment Research
- Completion date
- Originally
- Place of performance
- Georgia, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $841,919 | |
| Amendment | $934,438 | |
| Original award | $934,438 |
Quick answers
Who received award R44CA246827?
R44CA246827 was awarded to Migra-Therapeutics, LLC by National Cancer Institute (National Institutes of Health) on September 19, 2019.
How much is award R44CA246827 worth?
$2,710,795 has been obligated on R44CA246827.
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