PT-100, a Small Molecule Dipeptidyl Peptidase Inhibitor, Has Potent Antitumor Effects and Augments Antibody-Mediated Cytotoxicity via a Novel Immune Mechanism

Abstract

The amino boronic dipeptide, PT-100 (Val-boro-Pro), a dipeptidyl peptidase (DPP) inhibitor, has been shown to up-regulate gene expression of certain cytokines in hematopoietic tissue via a high-affinity interaction, which appears to involve fibroblast activation protein. Because fibroblast activation protein is also expressed in stroma of lymphoid tissue and tumors, the effect of PT-100 on tumor growth was studied in mice in vivo. PT-100 has no direct cytotoxic effect on tumors in vitro. Oral administration of PT-100 to mice slowed growth of syngeneic tumors derived from fibrosarcoma, lymphoma, melanoma, and mastocytoma cell lines. In WEHI 164 fibrosarcoma and EL4 and A20/2J lymphoma models, PT-100 caused regression and rejection of tumors. The antitumor effect appeared to involve tumor-specific CTL and protective immunological memory. PT-100 treatment of WEHI 164-inoculated mice increased mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells. The role of innate activity was further implicated by observation of significant, although reduced, inhibition of WEHI 164 and A20/2J tumors in immunodeficient mice. PT-100 also demonstrated ability to augment antitumor activity of rituximab and trastuzumab in xenograft models of human CD20 ؉ B-cell lymphoma and HER-2 ؉ colon carcinoma where antibody-dependent cytotoxicity can be mediated by innate effector cells responsive to the cytokines and chemokines up-regulated by PT-100. Although CD26/ DPP-IV is a potential target for PT-100 in the immune system, it appeared not to be involved because antitumor activity and stimulation of cytokine and chemokine production was undiminished in CD26 Ϫ/Ϫ mice.

A Hybrid Model of Tumor–Stromal Interactions in Breast Cancer

“…25) that tumor invasion could be reduced by introducing an inhibitor that blocks secretion of proteinase by stromal cells (fibroblasts/myofibroblasts). Targeting FAP by developing more effective drugs based on proven anti-FAP compounds such as Sibrotuzumab (Kloft et al 2004) and PT-100 (Adams et al 2004) is one possible strategy. Of course, other pathways are also potential targets, such as those involved in attachment of cells to the ECM (Chen et al 2008), but it has also been shown that when integrins are reduced cells may adopt other modes of movement, such as swimming by shape changes (Renkawitz et al 2009;Renkawitz and Sixt 2010).…”

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

“…Preclinical studies revealed tumor growth inhibition in lymphoma, melanoma, mastocytoma, and fibrosarcoma xenograft models. 16 In phase I dose-escalation studies in healthy volunteers, Val-boroPro doses greater than 100-150 μg showed significant, sustained inhibition of DPP-IV, and Val-boroPro was tolerated at doses up to 1200 μg per day. 17,18 In a phase I trial of Val-boroPro in patients receiving myelosuppressive chemotherapy, the maximum tolerated dose was not reached up to 1200 μg per day, although orthostatic hypotension was observed at 800 μg per day.…”

Effect of fibroblast activation protein and α2-antiplasmin cleaving enzyme on collagen Types I, III, and IV

“…Consequently, FAP's effect on collagen remains cloudy, as evidenced by results that appear to conflict [4;14]. Since clinical trials targeting FAP are proposed or underway to determine if neoplastic invasion of ECM can be slowed or halted [31][32][33], and given that neither gelatin or denatured collagen is a component of ECM, the actual effect of this enzyme on its alleged ECM substrate, i.e., collagen, is important to clarify. The difficulty of producing FAP uncontaminated by other trace membrane proteinases could complicate efforts to obtain definitive collagen cleavage data; however, new purification methods developed in our laboratory for the production of significant amounts of pure human plasmaderived APCE as well as human rFAP prompted us to examine the potential proteolytic effects of each enzyme toward purified types I, III and IV collagens as substrates.…”