Integrins in Cancer 


Integrins are modular heterodimeric members of a large family of mammalian cell surface proteins responsible for the attachment of cells to the extracellular matrix (ECM) through their respective binding to different ECM components. Integrin family members are highly conserved in structure, function, spatial-temporal expression, and in many cases - tissue localization across mammalian species. There are eight beta subunits that selectively pair with eighteen alpha subunits to create 24 known integrin heterodimers.

The α5β1 and α3β1 integrin heterodimers are responsible for the attachment of cells to the extracellular matrix (ECM) through their specific binding to fibronectin and laminin, respectively. In non-cancerous tissues, these two integrin subtypes are found “ligated” to their cognate ECM ligand(s). Often these two integrins are found to be expressed only at the basement membrane (basolateral) side of the epithelium of non-cancerous tissues where integrin ligation to ECM is thought to promote survival signaling while negatively regulating cell cycle progression through contact inhibition. When detached from the ECM in non-cancerous tissues, typically a result of injury, integrins in healthy non-adherent epithelial cells signal to initiate a specialized form of apoptosis termed “anoikis”. In a separate but related process commonly referred to as integrin-mediated cell death (IMCD), unligated integrins on healthy adherent cells promote apoptosis.

It is now becoming apparent that tumor cells expressing unligated integrins are capable of circumventing anoikis and IMCD, and instead utilize these integrins to support invasion, metastasis, and epithelial-mesenchymal transition – all hallmarks of cancers of epithelial origin. As such, the presence of active, unligated integrins in non-cancerous tissues is atypical and therefore, non-cancerous cells may be spared from oncolysis by VAX014. The likely exception to this is limited only to those healthy yet episodic biologic events requiring transient cell migration, such as neo-angiogenesis and wound healing.

In the context of solid tumors, the prevalence and role of both the α3β1 and α5β1 integrin sub-types in tumor tissue has been well documented and identified as potential prognostic factors and tumor-selective targets. Examples include melanoma, breast, lung, urothelial, and colorectal carcinoma(s). In addition, the critical role of α5β1 in neo-angiogenesis makes it widely present in tumor neo-vasculature. Given the various established role(s) of integrins in cancer, several integrin-targeted oncology agents have been developed but have yet to unlock the therapeutic potential of this approach to treating solid tumors.

VAX014 is differentiated from other integrin-targeted oncology agents because the invasin targeting component recognizes and kills only those cells whose α3β1 and α5β1 integrins are found "un-ligated" to their cognate extracellular matrix (ECM) binding partners. In contrast, most first generation integrin-targeted therapeutics are unable to distinguish between ligated and un-ligated integrins.  In the context of normal tissues, α3β1 and α5β1 integrins are bound (ligated) to their respective ECM partners, laminin and fibronectin.  Disruption of integrin-ECM binding and the presence of un-ligated integrins in normal tissues, typically a result of injury, results in rapid apoptosis-like programmed cell death through a process termed "anoikis​".  In cancer, aberrant survival signals received as a result of various oncogenic mutations converge to override anoikis, allowing tumor cells to survive detachment from ECM, a critical feature of epithelial-mesenchymal transition, cell migration, tumor metastasis and cancer progression.  Therefore, because normal cells cannot survive anoikis due to un-ligated α3β1 and α5β1 integrins but cancer cells can, these un-ligated α3β1 and α5β1 integrins represent attractive tumor-selective pharmacological targets with the potential to have minimal off-target toxicity.  ​​​​​