The
tumor environment is critical for
tumor maintenance and progression.
Integrins are a large family of
cell surface receptors mediating the interaction of
tumor cells with their microenvironment and play important roles in
glioma biology, including migration, invasion, angiogenesis and tumor stem cell anchorage. Here, we review preclinical and clinical data on
integrin inhibition in
malignant gliomas. Various pharmacological approaches to the modulation of
integrin signaling have been explored including
antibodies and
peptide-based agents.
Cilengitide, a
cyclic RGD-mimetic
peptide of αvβ3 and αvβ5
integrins is in advanced clinical development in
glioblastoma.
Cilengitide had only limited activity as a single agent in
glioblastoma, but, when added to standard
radiochemotherapy, appeared to prolong progression-free and overall survival in patients with newly diagnosed
glioblastomas and methylation of the promoter of the O⁶ methylguanine
methyltransferase (MGMT) gene. MGMT gene promoter methylation in turn predicts benefit from alkylating
chemotherapy. A phase III randomized clinical trial in conjunction with standard
radiochemotherapy in newly diagnosed
glioblastoma patients with MGMT gene promoter methylation has recently completed accrual (EORTC 26071-22072). A companion trial explores a dose-escalated regimen of
cilengitide added to
radiotherapy plus
temozolomide in patients without MGMT gene promoter methylation. Promising results in these trials would probably result in a broader interest in
integrins as targets for
glioma therapy and hopefully the development of a broader panel of anti-
integrin agents.