Many malignant sarcomas such as angiosarcomas are refractory to currently available treatments. However, sarcomas possess unique vascular properties, which indicate they may be more responsive to therapeutic agents that target endothelial function. MEKs have been demonstrated to play an essential role in growth and vascularization of carcinomas. We hypothesize that signaling through multiple MEK pathways is also essential for growth and vascularization of sarcomas. LeTx is a toxin, which targets receptors that are highly expressed in tumor endothelial cells. However, unlike small molecule inhibitors, which target a single biochemical pathway, LeTx inactivates multiple MEK pathways, which are essential for tumor cell proliferation and vascularization. These properties of LeTx indicate that it is uniquely suited to block sarcoma growth and vascularization. The objective of this proposal is to define the role of MEK signaling in growth and vascularization of human sarcoma and determine whether inhibition of multiple MEKs by agents such as LeTx may form the basis of a novel and innovative therapeutic approach in the treatment of human sarcoma. To do this we will define the basic relationship between signal transduction through MEK pathways and growth and vascularization of human sarcoma-derived cell lines using in vitro and in vivo models. Then, we will apply the concepts we will have derived from these models and extend them to the study of a large number and variety of archived clinical sarcoma samples to establish unifying features of prognostic value.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109308-03
Application #
7099619
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Jhappan, Chamelli
Project Start
2004-07-07
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$327,898
Indirect Cost
Name
Van Andel Research Institute
Department
Type
DUNS #
129273160
City
Grand Rapids
State
MI
Country
United States
Zip Code
49503
Bromberg-White, Jennifer L; Boguslawski, Elissa; Duesbery, Nicholas S (2009) Perturbation of mouse retinal vascular morphogenesis by anthrax lethal toxin. PLoS One 4:e6956
Ding, Yan; Boguslawski, Elissa A; Berghuis, Bree D et al. (2008) Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma. Mol Cancer Ther 7:648-58
Bromberg-White, Jennifer L; Duesbery, Nicholas S (2008) Biological and biochemical characterization of anthrax lethal factor, a proteolytic inhibitor of MEK signaling pathways. Methods Enzymol 438:355-65
Depeille, P E; Ding, Y; Bromberg-White, J L et al. (2007) MKK signaling and vascularization. Oncogene 26:1290-6