Targeting Integrins for Cancer Therapy - Disappointments and Opportunities

Abstract

Integrins mediate adhesive interactions between cells and their environment, including neighboring cells and extracellular matrix (ECM). These heterodimeric transmembrane receptors bind extracellular ligands with their globular head domains and connect to the cytoskeleton through multi-protein interactions at their cytoplasmic tails. Integrin containing cell-matrix adhesions are dynamic force-responsive protein complexes that allow bidirectional mechanical coupling of cells with their environment. This allows cells to sense and modulate tissue mechanics and regulates intracellular signaling impacting on cell faith, survival, proliferation, and differentiation programs. Dysregulation of these functions has been extensively reported in cancer and associated with tumor growth, invasion, angiogenesis, metastasis, and therapy resistance. This central role in multiple hallmarks of cancer and their localization on the cell surface makes integrins attractive targets for cancer therapy. However, despite a wealth of highly encouraging preclinical data, targeting integrin adhesion complexes in clinical trials has thus far failed to meet expectations. Contributing factors to therapeutic failure are 1) variable integrin expression, 2) redundancy in integrin function, 3) distinct roles of integrins at various disease stages, and 4) sequestering of therapeutics by integrin-containing tumor-derived extracellular vesicles. Despite disappointing clinical results, new promising approaches are being investigated that highlight the potential of integrins as targets or prognostic biomarkers. Improvement of therapeutic delivery at the tumor site via integrin binding ligands is emerging as another successful approach that may enhance both efficacy and safety of conventional therapeutics. In this review we provide an overview of recent encouraging preclinical findings, we discuss the apparent disagreement between preclinical and clinical results, and we consider new opportunities to exploit the potential of integrin adhesion complexes as targets for cancer therapy.

Keywords: cancer; clinical trial; extracellular matrix; integrin; therapy.

FIGURE 1

Schematic overview illustrating four factors that could contribute to the lack of clinical efficacy for integrin targeting therapeutics. These include (A). sequestration by tumor-derived extracellular vesicles (TEVs): integrin therapeutics bind integrins on TEVs instead of the tumor itself; (B). Different integrin expression at different stages: integrin expression can change as the tumor progresses and thereby influence target availability; (C). Opposing roles of integrins: Integrins exert tumor promoting effects but may also drive, as yet poorly understood, metastasis suppressing signals. Inhibition of integrins could therefore potentially be disadvantageous; (D). Integrins redundancy: inhibition of one integrin can be compensated by expression of other integrins.

FIGURE 2

Schematic overview of novel integrin targeting liposomal like drug delivery approaches. (A). cRGD decorated cationic liposomes; (B). Liposomes decorated with a combination of LPS and RGD peptides; (C). DGEA decorated liposomes; (D). Gel coated liposomes decorated with PR-b.

FIGURE 3

Schematic overview of alternative therapy delivery approaches making use of integrins. (A). Priming dendritic cells for vaccination; (B). Arming T cells with bispecific antibodies; (C). Targeting Photothermal Ablation Therapy; (D). Drug targeting through Covalent Molecular Conjugates.