There is an unmet need to develop novel chemotherapeutics that enhance selectivity and specificity for targeting chemo-resistant tumors. In particular, new strategies that attack chemotherapy-insensitive cancer stem cells/tumor initiating cells (TICs) are lacking. The goal of this proposal is to understand the interplay between TICs and their microenvironment during the transition to invasion and metastasis, as well as to develop a novel treatment reagent to specifically induce invasive TIC death in a preclinical setting. Our central hypothesis is that a cell surface-anchored protease, matrix metalloproteinase-14 (MMP-14), is a key molecule capable of executing the switch in epithelial TICs from quiescent to invasive cells, thereby controlling metastasis. Development of reagents to selectively and specifically target invasive TICs utilizing an MMP-14 binding peptide will facilitate prevention of cancer dissemination. The rationale for this project is that the development of a specific tumor-homing vehicle that carries inhibitory peptide and cytotoxic drug will allow us to not only block cancer invasion but to also induce cancer cell death. Furthermore, this study will advance our understanding of how the microenvironment influences quiescent TICs to give rise to metastases. We plan to test our hypothesis by pursuing the following three specific aims:1) Elucidate the role and mechanism of MMP-14 in conversion of quiescent TICs to invasive cells under hypoxic conditions;2) Define the mechanism of action of an MMP-14 homing peptide;and 3) Develop a bi-functional reagent that specifically targets cancer invasiveness and induces cancer cell death. With respect to the expected outcomes, the work proposed in this application will potentially result in development of a bi-functional reagent capable of delivering a potent chemotherapeutic drug to invasive TICs. This project is innovative because it utilizes novel peptides specific for MMP-14 to selectively target invasive TICs. The proposed research will have significant future implications because it is expected to vertically advance our understanding of how quiescent TICs become reprogrammed into invasive TICs in a hypoxic environment. The developed bi-functional reagent will have a positive impact on future cancer prevention/treatment and could eventually improve the outcome of patients with cancer.

Public Health Relevance

The proposed research will increase our understanding of the reprogramming of cancer from non-metastatic to metastatic. In addition, it will facilitate the development of tools for treatment and prevention of cancer dissemination. Thus, the proposed research is relevant to the NIH's mission that pertains to developing fundamental knowledge that will help to reduce risk of death from various cancers and will improve public health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA166936-01
Application #
8275173
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
2012-04-02
Project End
2017-03-31
Budget Start
2012-04-02
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$325,775
Indirect Cost
$118,275
Name
State University New York Stony Brook
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Evensen, Nikki A; Kuscu, Cem; Nguyen, Hoang-Lan et al. (2013) Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst 105:1402-16