Suppression of Tumor Growth in Mice by Rationally Designed Pseudopeptide Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

Abstract

Tumor microenvironments (TMEs) are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP) and prolyl oligopeptidase (POP), are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth > 90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs.

How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive

“…MSC can become a target for anti-tumor vaccines as well ( 141 – 162 ). For instance, the strong production of collagen type I by MSC can interfere with the uptake of anti-tumor drugs ( 149 , 150 ); thus the targeting of MSC and the inhibition of extracellular matrix components can render more sensitive tumor cells to chemotherapy. Furthermore, antigens shared by tumor cells and TAF can be good targets for a vaccine.…”

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

“…In this context, it is conceivable that surface markers expressed mainly, if not exclusively, by MSC should be considered to regulate the TME. Indeed, FAP, CD73, and CD105 can be considered as suitable markers to target MSC [11,13,14,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150]. In hematological malignancies, but also in solid tumors, the administration of immunomodulatory drugs (IMiDs) derived from their prototype Thalidomide to CC-122 has given very attractive results because these compounds can hit MSC besides tumor cells [151,152,153].…”

“…Several kinds, compositions, and modes of administration of anti-tumor vaccines have been used with different results [160,161,162,163,164,165,166,167]. More recently, the focus of anti-tumor vaccines has been moved from tumor cells to TME too [7,9,10,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175]. Indeed, the possibility of targeting tumor endothelial cells or the VEGF signaling axis with specific vaccines has been assessed in preclinical studies, and clinical trials are ongoing [168].…”

Inhibitor-conjugated harmonic nanoparticles targeting fibroblast activation protein

“…28 The development of NP-based diagnostic and delivery systems targeting the proteolytic activity of FAP could contribute both to a better understanding of the role of FAP activity in modulating tumor behavior and to develop new anticancer treatments acting against the cancer-stroma symbiotic interactions. 29,30 Recently, harmonic nanoparticles (HNPs), which are based on non-centrosymmetric metal oxide nanocrystals, have emerged as promising nanomaterials for bioimaging applications 31 due to several favorable properties, [32][33][34] including their efficient nonlinear response to excitation from the UV to mid-IR, 35 their long-term photostability under pulsed laser irradiation and their spectrally narrow emission signal. 36 Upon screening of different types of HNPs, bismuth ferrite (BiFeO 3 , BFO) HNPs demonstrated very high second harmonic efficiency 37,38 as well as excellent in vitro cell compatibility aer surface modication with poly(ethylene glycol) (PEG) derived coatings.…”