The Role of αvβ6 Integrin Binding Molecules in the Diagnosis and Treatment of Cancer

Abstract

: Peptidic and non-peptidic αvβ6 integrin-binding molecules have been used in clinic for detection and treatment of tumors expressing αvβ6 integrin, because this protein is expressed in malignant epithelial cells of the oral cavity, pancreas, breast, ovary, colon and stomach carcinomas but it is not expressed in healthy adult tissue except during wound healing and inflammation. This review focuses on the landscape of αvβ6 integrin-binding molecules and their use in cancer treatment and detection, and discusses recent designs for tumor detection, treatment, and immunotherapy. In the last ten years several reviews about the αvβ6 integrin have been published but no one assesses the landscape of the αvβ6 integrin-binding molecules and their role in cancer detection and treatment. Firstly, this review describes the role of the αvβ6 integrin in normal tissues, how the expression of this protein is correlated with cancer severity and its role in cancer development. Having into account the potential of αvβ6 integrin-binding molecules in detection and treatment of specific tumors, special attention is given to several high-affinity αvβ6 integrin-binding peptides used for tumor imaging; particularly, the αvβ6-binding peptide NAVPNLRGDLQVLAQKVART [A20FMDV2], derived from the foot and mouth disease virus. This peptide labeled with either 18F, 111In or with 68Ga has been used for PET imaging of αvβ6 integrin-positive tumors. Moreover, αvβ6 integrin-binding peptides have been used for photoacoustic and fluorescence imaging and could potentially be used in clinical application in cancer diagnosis and intraoperative imaging of αvβ6-integrin positive tumors. Additionally, non-peptidic αvβ6-binding molecules have been designed and used in clinic for the detection and treatment of αvβ6-expressing tumors. Anti-αvβ6 integrin antibodies are another useful tool for selective identification and treatment of αvβ6 (+) tumors. The utility of these αvβ6 integrin-binding molecules as a tool for tumor detection and treatment is discussed, considering specificity, sensitivity and serum stability. Another use of the αvβ6 integrin-binding peptides is to modify the Ad5 cell tropism for inducing oncolytic activity of αvβ6- integrin positive tumor cells by expressing A20FMDV2 peptide within the fiber knob protein (Ad5NULL-A20). The newly designed oncolytic Ad5NULL-A20 virotherapy is promising for local and systemic targeting of αvβ6-overexpressing cancers. Finally, new evidence has emerged, indicating that chimeric antigen receptor (CAR) containing the αvβ6 integrin binding peptide on top of CD28+CD3 endodomain displays a potent therapeutic activity in a diverse repertoire of solid tumor models.

Structural analysis of peptide binding to integrins for cancer detection and treatment

“…It is typically expressed at low levels or absent in healthy adult tissue epithelia but specifically upregulated during tissue repair, embryogenesis, and carcinogenesis. It also binds to latency-associated peptides (LAPs), resulting in the release of active TGF-β from the latent complex (Breuss et al 1995 ; Busk et al 1992 ; Dong et al 2017 ; Larjava et al 2011 ; Brzozowska and Deshmukh 2022 ; Urquiza et al 2020 ).…”

“…This review will focus on integrins involved in cancer development, having the three-dimensional structure determined in complexes with a peptidic ligand (see also Table 1 ). Understanding the molecular basis of ligand affinity and specificity for these integrins is helpful in designing molecules for tumor detection and treatment with high affinity and specificity (Urquiza et al 2020 ; Takada et al 2007 ; Desgrosellier and Cheresh 2010 ; Barczyk et al 2010 ; Slack et al 2022 ).…”