Despite improvements in surgery, chemotherapy, and the advent of targeted therapies, mortality rates in women with advanced breast cancer have remained largely unchanged. Particularly, triple-negative breast cancers are highly aggressive and are associated with poor prognosis. Due to a lack of receptor expression, triple negative breast cancers are currently managed with standard chemotherapy, further highlighting the urgent need for biological targeted therapy for the control of cancer progression and metastatic spread for women with triple negative breast cancer. Tissue migration of disseminated cancer cells is an essential process in metastasis and governed by a sequential adhesion cascade from initial contact with the vascular endothelium and subsequent transmigration across the endothelial lining. E-selectin is exclusively expressed on the inflamed tumor vasculature and plays a pivotal role in the adhesion of metastatic cancer cells and monocytes that differentiate into tumor associated macrophages (TAM) that mediate invasion and subsequent metastasis. Therefore, the blockade of the adhesion cascade is an attractive strategy control metastasis;however, such strategies are largely missing and currently present unmet clinical needs. Herein, we propose a novel intervention/prevention strategy to block the adhesion cascade using an aptamer against E-selectin (ESTA). We have demonstrated that that ESTA a) binds to E-selectin and blocks the adhesion of monocytes and metastatic breast cancer cells to E-selectin-expressing endothelial cells at a nanomolar range, b) impairs monocyte infiltration and reduces TAM density in the tumor, d) reduces the production of TAM associated pro- tumor factors, and e) consequently inhibits growth and development of metastatic tumors (80 % reduction in foci number) in a mouse model of breast cancer. In addition, we demonstrated that both E-selectin and TAM density are particularly high in the triple negative breast cancers with close special association. The hypothesis that we will test in this proposal is that ESTA blocks the adhesion cascade and inhibits metastasis through two distinct mechanisms simultaneously: 1) targeting the vasculature of the primary tumor will reduce invasiveness of cancer cells by inhibiting TAM development and 2) targeting the vasculature of the intended metastatic site will directly impair the formation of new metastases. In the proposed study, we will elucidate the mechanisms and biological consequences of ESTA therapy on metastatic tumor development and growth in Aim 1. We will further expand our scope and develop a combination therapy that targets both the epithelial cancer and TAM to achieve better outcomes.
In Aim 2, we will perform two retrospective analyses to determine whether vascular E-selectin expression correlates with TAM density and poor prognosis with an ultimate goal to establish a prediction biomarker to pre-select a subpopulation of patients who will likely benefit from ESTA. Lastly, we will develop a second-generation ESTA compound with a cost-effective minimal structure and improved pharmacokinetics, which is the major limitation for an aptamer therapeutic to be clinically applicable.

Public Health Relevance

Despite improvements in surgery, chemotherapy, and the advent of targeted therapies, mortality rates in women with advanced carcinoma have remained largely unchanged. Therefore, a development of a novel therapeutic intervention/prevention is urgently needed. The overall goal of our proposal is to develop a novel tumor vasculature targeted preventive/therapeutic strategy through an intervention of an adhesion cascade that is essential for tissue migration of both monocytes and metastatic cancer cells via functional blockade of E-selectin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160271-02
Application #
8451326
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2012-04-01
Project End
2013-08-06
Budget Start
2013-04-01
Budget End
2013-08-06
Support Year
2
Fiscal Year
2013
Total Cost
$48,490
Indirect Cost
$23,324
Name
Thomas Jefferson University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107