Phase II trial of single agent Val-boroPro (talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer

Abstract

Purpose: Fibroblast Activation Protein (FAP) is a tumor fibroblast protease that has been shown to potentiate colorectal cancer growth. The clinical impact of FAP inhibition was tested using Val-boroPro (Talabostat), the first clinical inhibitor of FAP enzymatic activity, in a phase II study of patients with metastatic colorectal cancer.Methods: Patients with metastatic colorectal cancer who had previously received systemic chemotherapies were treated with single agent Val-boroPro 200 μg p.o. BID continuously. Eligibility included measurable disease, performance status of 0 to 2, and adequate organ function. Laboratory correlates evaluated the pharmacodynamic effects of Val-boroPro on FAP enzymatic function in the peripheral blood.Results: Twenty-eight patients (median age 62; 12 males, 16 females) were enrolled in this study. There were no objective responses. Six of 28 (21%) patients had stable disease for a median of 25 weeks (range 11-38 weeks). Laboratory analysis demonstrated significant, although incomplete inhibition of FAP enzymatic activity in the peripheral blood.Conclusion: This phase II trial of Val-boroPro demonstrated minimal clinical activity in patients with previously treated metastatic colorectal cancer. However it provides the initial proof-of-concept that physiologic inhibition of FAP activity can be accomplished in patients with colorectal cancer, and lays the groundwork for future studies targeting the tumor stroma.

Dipeptidyl Peptidases as Survival Factors in Ewing Sarcoma Family of Tumors

“…Recent years have brought a strong interest in DPPIV and its homologs, which led to the development of numerous highly selective and potent DPP inhibitors. For example, DPPIV-selective inhibitors, Sitagliptin and Vildagliptin, are already used for the treatment of diabetes (48), whereas the broad range DPP inhibitor, PT-100, has been tested in clinical trials for various types of cancer (20,21,49). Using such potent inhibitors in an appropriate treatment regime may allow overcoming or avoiding induction of DPPs observed in P32/98-treated tumors.…”

“…The increasing interest in these potential therapeutic targets led to the development of numerous DPP inhibitors. For example, a broad range DPP inhibitor, PT-100, has already been tested in clinical trials for the treatment of various cancers (20,21). Surprisingly, however, this compound was introduced to clinics without knowledge of the exact mechanisms of its actions, which ultimately led to the failure of these trials.…”

Fibroblast activation protein

“…In clinical trials, Phase II trial of Val-boro-Pro demonstrates minimal clinical activity in patients with previously treated metastatic colorectal cancer. 56 In addition, Phase II trial of talabostat and docetaxel in advanced non-small cell lung cancer shows no evidence that talabostat enhanced the clinical activity of docetaxel in patients with NSCLC. 57 PT630 is more specific than talabostat, effectively inhibiting FAP and DPPIV but not the intracellular family members.…”

Colorectal Cancer Cells Activate Adjacent Fibroblasts Resulting in FGF1/FGFR3 Signaling and Increased Invasion

“…However, a clinical trial on CRC patients using talabostat, an inhibitor of FAP-enzymatic activity, showed a minimal clinical effect, and the authors suggest that the partial inhibition may be due to another contributing factor or factors. 14 In the present study, we used FAP as a marker of activated fibroblasts to investigate their occurrence in various lesions of the adenoma-carcinoma sequence in human CRC. Further in vitro studies analyzed fibroblast activation in co-culture experiments.…”