2. Academic Validation
  3. Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden

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

  • Oncotarget. 2018 Jan 19;9(13):11020-11045. doi: 10.18632/oncotarget.24280.
Fernando Revert 1 2,  Francisco Revert-Ros 1 2,  Raül Blasco 1 3,  Aida Artigot 1,  Ernesto López-Pascual 1 2,  Roberto Gozalbo-Rovira 1 4,  Ignacio Ventura 1 2 5,  Elain Gutiérrez-Carbonell 1 6,  Nuria Roda 7,  Daniel Ruíz-Sanchis 1,  Jerónimo Forteza 8,  Javier Alcácer 9,  Alejandra Pérez-Sastre 1 2 10,  Ana Díaz 11,  Enrique Pérez-Payá 7,  Juan F Sanz-Cervera 3,  Juan Saus 1 2 7
Affiliations

Affiliations

  • 1 FibroStatin, Parc Científic Universitat de València, Paterna 46980, Spain.
  • 2 Centro de Investigación Príncipe Felipe, Valencia 46012, Spain.
  • 3 Departament de Química Orgànica, Universitat de València, Burjassot 46100, Spain.
  • 4 Present address: Departament de Microbiologia i Ecologia, Facultat de Medicina i Odontologia, Universitat de València, Valencia 46010, Spain.
  • 5 Present address: Universidad Católica de Valencia, Valencia 46001, Spain.
  • 6 Present address: Sciex Spain, Alcobendas, Madrid 28108, Spain.
  • 7 Departament de Bioquímica i Biologia Molecular, Universitat de València, Burjassot 46100, Spain.
  • 8 Instituto Valenciano de Patología of Universidad Católica de Valencia, Centro de Investigación Príncipe Felipe, Valencia 46012, Spain.
  • 9 Anatomía Patológica, Hospital Quirónsalud de Valencia, Valencia 46010, Spain.
  • 10 Present address: Sistemas Genómicos, Paterna 46980, Spain.
  • 11 Unitat Central d'investigació en Medicina, Facultat de Medicina i Odontologia, Universitat de València, Valencia 46010, Spain.
PMID: 29541394 DOI: 10.18632/oncotarget.24280
Abstract

Goodpasture antigen-binding protein (GPBP) is an exportable1 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 260SHCIE264 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.

Keywords

EMT; GPBP; collagen IV; drug-resistant cancer; tumor microenvironment.

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