Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden

// Fernando Revert 1, 2 , Francisco Revert-Ros 1, 2 , Raul Blasco 1, 3 , Aida Artigot 1 , Ernesto Lopez-Pascual 1, 2 , Roberto Gozalbo-Rovira 1, 8 , Ignacio Ventura 1, 2, 9 , Elain Gutierrez-Carbonell 1, 10 , Nuria Roda 4 , Daniel Ruiz-Sanchis 1 , Jeronimo Forteza 5 , Javier Alcacer 6 , Alejandra Perez-Sastre 1, 2, 11 , Ana Diaz 7 , Enrique Perez-Paya 4 , Juan F. Sanz-Cervera 3 and Juan Saus 1, 2, 4 1 FibroStatin, Parc Cientific Universitat de Valencia, Paterna 46980, Spain 2 Centro de Investigacion Principe Felipe, Valencia 46012, Spain 3 Departament de Quimica Organica, Universitat de Valencia, Burjassot 46100, Spain 4 Departament de Bioquimica i Biologia Molecular, Universitat de Valencia, Burjassot 46100, Spain 5 Instituto Valenciano de Patologia of Universidad Catolica de Valencia, Centro de Investigacion Principe Felipe, Valencia 46012, Spain 6 Anatomia Patologica, Hospital Quironsalud de Valencia, Valencia 46010, Spain 7 Unitat Central d'investigacio en Medicina, Facultat de Medicina i Odontologia, Universitat de Valencia, Valencia 46010, Spain 8 Present address: Departament de Microbiologia i Ecologia, Facultat de Medicina i Odontologia, Universitat de Valencia, Valencia 46010, Spain 9 Present address: Universidad Catolica de Valencia, Valencia 46001, Spain 10 Present address: Sciex Spain, Alcobendas, Madrid 28108, Spain 11 Present address: Sistemas Genomicos, Paterna 46980, Spain Correspondence to: Juan Saus, email: juan.saus@uv.es Keywords: GPBP; collagen IV; EMT; drug-resistant cancer; tumor microenvironment Received: July 13, 2017      Accepted: January 03, 2018      Published: January 19, 2018 ABSTRACT Goodpasture antigen-binding protein (GPBP) is an exportable 1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260 SHCIE 264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl]propionic acid, or T12, specifically targets mesenchymal GPBP and disturbs its multimerization without affecting kinase catalytic site. Importantly, T12 reduces growth and metastases of tumors populated by EMT phenotypes. Moreover, low-dose doxorubicin sensitizes epithelial cancer precursor cells to T12, thereby further reducing tumor load. Given that T12 targets the pathogenic mesenchymal GPBP, it does not bind significantly to normal tissues and therapeutic dosing was not associated with toxicity. T12 is a first-in-class drug candidate to treat cancer by selectively targeting the collagen IV of the tumor cell microenvironment.