Fox Chase Cancer Center Study Shows That Inhibitors of Fibroblast Activation Protein (FAP) Attenuate Tumor Growth in Mice

    PHILADELPHIA, April 4 /PRNewswire/ -- A study conducted by researchers at
 Fox Chase Cancer Center supports a possible novel approach for attacking
 cancer.
     The research involves two inhibitors of fibroblast activation protein
 (FAP), which has been implicated in human tumor growth.  Talabostat (PT-100)
 and PT-630- developed by Point Therapeutics (Boston, Mass.) suppressed tumor
 growth in mouse models, according to new data presented today at the American
 Association for Cancer Research 97th Annual Meeting in Washington, D.C., by
 Jonathan Cheng, M.D., Fox Chase Cancer Center.
     FAP is a member of the DPP family, which are enzymes that appear to
 regulate several different physiological processes including tumor growth and
 immune responses.
     Cheng's study demonstrated that both PT-100 and PT-630 inhibited FAP
 enzymatic activity and attenuated tumor growth in mice.  PT-100 has been
 reported to upregulate the production of cytokines and chemokines leading to
 stimulation of the innate and adaptive immune system.  In contrast, PT-630
 inhibits FAP activity but is not known to induce cytokine and chemokine
 upregulation.  Fox Chase scientists used mice that lack an adaptive immune
 system due the absence of T and B lymphocytes to control for talabostat's
 immunostimulatory activity and isolate the role of FAP in tumor growth.
     "The anti-tumor activity of both talabostat and PT-630 is intriguing
 because it suggests a mechanism of action involving tumor-targeted FAP
 inhibition that may be distinct from immune stimulation in tumor types where
 FAP is expressed clinically," said Cheng.  "This may be a potentially novel
 way to treat cancer."
 
     About fibroblast activation protein (FAP)
     Fibroblast activation protein is a member of the dipeptidyl peptidase
 (DPP) family of serine proteases that is not present in most healthy tissues
 but is expressed on the tumor stroma of epithelial cancers, melanoma, and by
 certain sarcomas. It has been suggested that the enzymatic activity of FAP
 might play a role in promoting the growth of tumors or in tissue remodeling
 required for tumor progression. The tumor-promoting role of FAP is supported
 by previous studies by the Fox Chase group demonstrating that FAP increases
 the growth of an experimental kidney epithelial tumor (HEK293) in mice. The
 DPP enzymatic activity of FAP was shown to be important for tumor growth,
 suggesting FAP as a molecular target in cancer. By targeting FAP, agents that
 inhibit FAP would be predicted to have an antitumor effect.
 
     Study Details
     Nanomolar amounts of talabostat and PT-630 inhibit certain DPPs including
 FAP. Talabostat not only inhibits FAP but also has immunomodulatory effects
 including the upregulation of cytokines and chemokines. Talabostat was
 previously demonstrated to be a potent antitumor agent in preclinical models
 of various tumor types, including epithelial tumors. Point scientists
 established that talabostat could stimulate host antitumor responses involving
 both innate and adaptive immunity. Both compounds were administered orally to
 immunodeficient SCID mice inoculated with either HEK293 tumor cells or HT-29
 colorectal carcinoma cells. These are human cancer cells that can form tumors
 due to the absence of graft rejection in the SCID mouse. HEK293 cells were
 engineered to express the FAP protein and HT-29 tumors induce FAP expression
 by the tumor stromal cells. Both talabostat and PT-630 decreased HEK293 and
 HT-29 tumor volumes by approximately 50% and were shown to inhibit FAP
 enzymatic activity at the tumor sites.
     Fox Chase Cancer Center was founded in 1904 in Philadelphia as the
 nation's first cancer hospital.  In 1974, Fox Chase became one of the first
 institutions designated as a National Cancer Institute Comprehensive Cancer
 Center.  Fox Chase conducts basic, clinical, population and translational
 research; programs of prevention, detection and treatment of cancer; and
 community outreach.  For more information about Fox Chase activities, visit
 the Center's web site at http://www.fccc.edu or call 1-888-FOX CHASE.
 
     Contact:
      Diana Quattrone
      215-728-7784
      Diana.Quattrone@fccc.edu
 
 

SOURCE  Fox Chase Cancer Center