The long-term objective of this research program is to develop novel therapeutic strategies targeting the bidirectional interactions between tumor cells and the stromal cells that are found in tumors. The central hypothesis of this proposal is that inhibition of fibroblast activation protein (FAP) proteolytic activity will abrogate the invasive and metastatic capabilities of tumors, leading to attenuated tumor growth and diminished metastatic potential. This hypothesis is based on the highly selective expression of human FAP by tumor stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissue. Pathways by which tumor fibroblasts participate in tumor growth can be targeted for disruption by monoclonal antibodies, which can be developed for clinical use. This proposal aims to generate monoclonal antibodies targeting murine FAP, and characterize their binding properties. This has been initiated by immunizing mice with murine FAP, and screening of hybridoma supernatants by ELISA for FAP binding. Antibodies that target FAP have been identified, and will be further characterized by surface plasmon resonance, live cell binding assays, and immunohistochemistry studies. FAP antibodies are also being assessed for inhibition of FAP proteolytic activity by dipeptidyl peptidase assays, enzyme immunocapture assays, and quantitative zymography. FAP inhibitory antibodies will be administered in an animal model to test the hypothesis that inhibition of FAP proteolytic activity inhibits tumor growth and metastases. If FAP inhibitory monoclonal antibodies cannot be produced by conventional immunization and fusion techniques, a human single-chain Fv (scFv) phage display library will be panned for FAP binding and enzymatic function inhibition. Inhibitory scFv fragments will be converted into IgG formats. Disruption of murine FAP proteolytic pathways by inhibitory antibodies resulting in inhibition of tumor growth and metastases will be considered sufficiently significant to warrant the clinical development of a novel therapeutic strategy targeting human cancers that induce FAP proteolytic activity. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA090468-04
Application #
7122837
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$125,374
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Zhang, Jiping; Valianou, Matthildi; Simmons, Heidi et al. (2013) Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens. FASEB J 27:581-9
Lee, Hyung-Ok; Mullins, Stefanie R; Franco-Barraza, Janusz et al. (2011) FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer 11:245
Lee, Hyung-Ok; Silva, Ariosto S; Concilio, Susanna et al. (2011) Evolution of tumor invasiveness: the adaptive tumor microenvironment landscape model. Cancer Res 71:6327-37
Zhang, Jiping; Valianou, Matthildi; Cheng, Jonathan D (2010) Identification and characterization of the promoter of fibroblast activation protein. Front Biosci (Elite Ed) 2:1154-63
Lo, Pui-Chi; Chen, Juan; Stefflova, Klara et al. (2009) Photodynamic molecular beacon triggered by fibroblast activation protein on cancer-associated fibroblasts for diagnosis and treatment of epithelial cancers. J Med Chem 52:358-68
Lai, Koon Siew; Ho, Nan-Hui; Cheng, Jonathan D et al. (2007) Selective fluorescence probes for dipeptidyl peptidase activity-fibroblast activation protein and dipeptidyl peptidase IV. Bioconjug Chem 18:1246-50
Narra, Kalyani; Mullins, Stefanie R; Lee, Hyung-Ok et al. (2007) Phase II trial of single agent Val-boroPro (Talabostat) inhibiting Fibroblast Activation Protein in patients with metastatic colorectal cancer. Cancer Biol Ther 6:1691-9
Henry, Leonard R; Lee, Hyung-Ok; Lee, John S et al. (2007) Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res 13:1736-41
Cheng, Jonathan D; Valianou, Matthildi; Canutescu, Adrian A et al. (2005) Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth. Mol Cancer Ther 4:351-60