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 www.fccc.edu or call 1-888-FOX CHASE.