Integrins as targets for cancer therapy

Biological implications and therapeutic opportunities

Integrins expressed by tumor and tumor-associated host cells mediate a diverse array of cellular effects resulting in tumor progression and metastasis. Important among these is the role integrins have in determining tumor cell survival. In the past few years studies have revealed new roles for unligated integrins in this process. Under some circumstances unligated integrins can induce tumor cell apoptosis through integrin-mediated death (IMD) by recruiting and activating caspase cleavage. Tumor cells that are resistant to IMD gain the ability to metastasize. In this case unligated integrins may promote cell survival, resulting in increased anchorage-independence and metastasis. These effects of unligated integrins may be clinically relevant and probably represent important factors in determining tumor cell sensitivity to integrin antagonists.

Crosstalk with growth factor receptors is required for many of the cancer-promoting effects of integrins. Recent studies have shown that certain growth factor receptors and oncogenes require specific integrins for their effects on tumorigenesis and metastasis. This suggests that it may be plausible to tailor the use of integrin antagonists in individual patients whose tumors are responsive to particular growth factors or oncogenes. Alternatively, the extracellular matrix (ECM) composition of the tumor microenvironment may have a vital role in determining the sensitivity of a tumor to integrin antagonists. This may partly explain the clinical responsiveness of patients with glioblastoma treated with cilengitide.

Cilengitide is an inhibitor of both αvβ3 and αvβ5 integrins, and it was selected in laboratory by screening a library of cyclic RGD peptides in a cell-free receptor assay for their capacity to inhibit integrins αvβ3 and αvβ5 but not αΙΙbβ3. In preclinical studies, cilengitide effectively inhibited angiogenesis and the growth of orthotopic glioblastoma. Importantly, the brain microenvironment was a crucial determinant of the susceptibility of tumors to cilengitide, as tumors that formed in the flank of these same mice were unaffected by treatment with this drug. In addition, high-grade glioblastomas abundantly express the ECM protein vitronectin, an integrin αvβ3 ligand, and this interaction affects tumor cell survival and invasion. Therefore, the relatively large quantity of vitronectin present in the brain microenvironment surrounding glioblastomas might explain why these tumors are susceptible to cilengitide treatment.

A phase I/II trial examined cilengitide in patients with newly diagnosed glioblastoma and met its primary end point with 69% of patients progression-free after 6 months. Importantly, this trial made the observation that patients with lowered expression of O-6-methylguanine-DNA methyltransferase, owing to promoter methylation, exhibited a higher rate (91%) of progression-free survival at 6 months. The MGMT promoter is a prognostic marker in patients with glioblastoma: tumors with unmethylated MGMT promoters indicate a lower probability of patient survival, as MGMT is thought to increase resistance to drugs such as temozolomide, which is a current standard therapy.

The favourable results obtained from these early clinical trials provided the impetus for a Phase III trial with cilengitide that began in October 2008. The CENTRIC trial will enroll approximately 500 patients and measure the effect of cilengitide on the survival of patients with MGMT promoter methylation in combination with temozolomide and radiotherapy. This is the first Phase III oncology trial carried out with any integrin antagonist. As a companion to the CENTRIC trial, the Phase II CORE trial will assess the efficacy of cilengitide in a large number of patients whose tumors have unmethylated MGMT promoters.

Currently, there are no validated biomarkers for clinically assessing the efficacy of anti-angiogenic therapies, including cilengitide. Although candidate markers are being investigated, including serum levels of VEGF, FGF and placental growth factor, as well as the abundance of circulating endothelial cells and their precursors, these markers have not yet consistently predicted tumor response. As a result, better vascular imaging techniques are being developed to monitor responsiveness to treatment. In particular, considerable effort has been expended on characterizing integrin antagonists for their ability to specifically deliver diagnostic agents to tumor cells and associated blood vessels. Some of these imaging agents have recently undergone evaluation in cancer patients.

Integrin-targeted therapeutics have recently proved beneficial in delivering chemotherapeutics, oncolytic viruses, pro-apoptotic peptides (such as TNF and TNF-related apoptosis-inducing ligand (TRAIL)) and radionucleotides to both tumor cells and the supporting vasculature.

Future studies will have to elucidate the factors responsible for tumor susceptibility to integrin-targeted therapeutics and these will ultimately influence how effective these agents are, wrote in the January 2010 issue of Nature Reviews Cancer Dr Jay S Desgrosellier of the Department of Pathology, San Diego Cancer Center, USA.