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Translational Development of a Targeted and Stroma-breaking Nanoparticle Drug for Pancreatic Cancer Therapy

Award Number: R43CA246827
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2022

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Translational Development of a Targeted and Stroma-breaking Nanoparticle Drug for Pancreatic Cancer Therapy - Project Summary Resistance to therapy is the major clinical challenge in pancreatic cancer therapy. Low efficiency in drug delivery and aggressive tumor biology are the major causes of a poor therapeutic response. It is well known that the presence of a dense fibrous tumor stroma creates a drug delivery barrier and promotes aggressive biology and drug resistance in pancreatic cancer cells. The objective of our translational research project is to develop a new generation of receptor-targeted and protease active targeting ligand and stroma-breaking nanoparticle drug delivery platform for effective treatment of advanced pancreatic cancer. Our extensive research led to the development of a new tumor targeting approach using a recombinant uPAR targeting ligand containing the amino terminal fragment (ATF) of uPA fused with the catalytic domain of matrix metalloproteinase- 14 (ATFmmp14). Novel designs of ATFmmp14 ligand not only ensure enhanced intratumoral delivery of therapeutic agents, but also enable breaking tumor stroma cellular and extracellular matrix barriers. We also developed a biodegradable hyaluronic acid nanoparticle carrying an active metabolite of irinotecan, SN38 (HANP/SN38). Our results demonstrated that ATFmmp14 conjugated HANP/SN38 significantly enhanced drug delivery to tumors in KRAS-driven transgenic mouse and human pancreatic PDX tumor models. Importantly, the nanoparticle-drug migrated out of tumor stroma and penetrated through the basement membrane lining ductal cancer cells to enter tumor cells. As a result, systemic delivery of ATFmmp14-HANP/SN38 significantly inhibited tumor growth. In comparison with current combination therapies (FOLFRINOX or gemcitabine-Nab-Paclitaxel), ATFmmp14-HANP/SN38 treatment significantly prolonged survival in the PDX tumor models derived from drug resistant pancreatic cancer patients. To translate this novel approach for target therapy in cancer patients, in this phase 1 study, we will develop a new generation of tagless human ATFmmp14 ligands that are optimized for the GMP production and have high binding affinity, target specificity and MMP14 enzymatic activity. The proposed studies in Aim 1 will engineer a stable ATFmmp14(R2) expressing CHO cell line and a B. subtilis secretable protein expression system for large scale production of tagless ATFmmp14(R2). We will then evaluate and compare their production procedure, protein yield, target specificity, and MMP14 activity in vitro and in vivo to select the most suitable targeting ligand for drug development (Aim 2). Finally, therapeutic effect of ATFmmp14(R2) will be determined in a pancreatic PDX tumor model (Aim 3). The milestones of this phase I research project are: 1) to develop ATFmmp14-HANP(R2) as a stroma-breaking and targeted nanoparticle drug delivery platform for future commercialization; and 2) to develop a targeted nanoparticle drug, ATFmmp14(R2)- HANP/SN38, for the Phase II study aimed at the Investigational New Drug (IND)-enabling preclinical studies for the translational development of ATFmmp14-HANP/SN38 for targeted therapy of advanced pancreatic cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $238 )
2023	2019	MIGRA-THERAPEUTICS, LLC	1750 HAYGOOD DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	1	5/12/2023	NEW	$238
														Subtotal = $238

Issue Date FY: 2022 ( Subtotal = -$238 )
2022	2019	MIGRA-THERAPEUTICS LLC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cancer Treatment Research	000	1	6/30/2022	NEW	-$238
														Subtotal = -$238

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	MIGRA-THERAPEUTICS, LLC	3175 PRESIDENTIAL DR SUITE B	ATLANTA	GA	30340	DEKALB	USA	Cancer Treatment Research	000	1	2/18/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $224,425 )
2019	2019	MIGRA-THERAPEUTICS, LLC	3175 PRESIDENTIAL DR SUITE B	ATLANTA	GA	30340	DEKALB	USA	Cancer Treatment Research	000	1	9/19/2019	NEW	$224,425
														Subtotal = $224,425

Grand Total All Awards = $224,425

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Translational Development of a Targeted and Stroma-breaking Nanoparticle Drug for Pancreatic Cancer Therapy

Award Number: R43CA246827

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/19/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2022

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