Once colorectal cancer metastasizes, it becomes a lethal disease with a 5-year survival rate of approximately 10%. Effective therapeutics that can specifically target metastatic colorectal tumor cells are sorely needed. Delivery of nucleic-acids (e.g. genes or RNAi) to combat cancer is a highly promising therapeutic approach;unfortunately, targeted delivery of gene vectors to tumor cells has been largely difficult to achieve. Most vector targeting approaches to date have relied on cell surface receptors overexpressed on some subpopulation of target cancer cells. Unfortunately, there is no unique cell surface biomarker that specifically identifies all cells in a tumor. To overcome this limitation, we propose to develop protease- activatable viruses (PAVs) that use extracellular proteases overexpressed in metastatic colorectal tumor microenvironments as the biomarkers to achieve targeted delivery. Specifically, matrilysin (also known as matrix metalloproteinase 7, MMP7) has been shown to be overexpressed in colorectal cancer. High levels of MMP7 in the tumor microenvironment will activate the PAVs in a localized manner and enable the vectors to bind cellular receptors that are broadly expressed, including on colorectal cancer cells, and mediate efficient gene delivery. Our PAV technology is based on the clinically promising adeno-associated virus (AAV), which has recently been approved as the first human gene therapy product in Europe. We have key pilot data demonstrating we have created MMP7-sensing PAVs that dramatically increase their gene delivery efficiency once exposed to the protease. Moreover, in an orthotopic cancer model, a PAV prototype is able to significantly increase transgene delivery and expression in tumors.
In aim 1, we will synthesize and characterize a panel of MMP7-sensing PAVs. Our design process will harness both rational and combinatorial approaches in order to expedite achievement of the design solution.
In aim 2, we will test the gene delivery performance of PAVs in vitro on colorectal cancer cells, and mechanistic studies will be done to probe the interaction of PAVs with the cells. Finally, we will test the PAVs in an orthotopic model of metastatic colorectal cancer in order to determine their in vivo specificity and therapeutic efficacy. If successful, this project will generate protease-responsive AAV vectors that may become viable therapeutic options for metastatic colorectal cancer.

Public Health Relevance

This project will develop therapeutics that can find metastatic colorectal cancer cells by seeking out proteases that are present in high concentrations in the tumor environments. Such technological advances may enable more colorectal cancer patients to become cancer survivors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA187316-01
Application #
8749004
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Yovandich, Jason L
Project Start
2014-09-10
Project End
2016-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$214,335
Indirect Cost
$52,515
Name
Rice University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005