Integrin Inhibitors Reaching the Clinic (2007)

Malignant cellular transformation is largely viewed as the consequence of autonomous cell genetic alterations, leading to the activation of oncogenes and the inactivation of tumor suppression genes and increasing genomic instability, which gives rise to a cell capable of limitless proliferation and survival, invasion, and metastasis. In addition, the formation of a tumor-associated vasculature—a process also referred to as tumor angiogenesis—has been recognized as an essential event promoting tumor progression. In the absence of tumor angiogenesis, tumors enter a state of dormancy, characterized by a balance between cell proliferation and apoptosis. During the last decade, significant advances have been made in the understanding of the tissue, cellular, and molecular events that regulate and mediate tumor angiogenesis. Many extracellular, cell surface, and intracellular molecules modulating angiogenesis have been identified and characterized, including growth factors and growth factor receptors, such as vascular endothelial growth factor (VEGF) and VEGF receptors; integrin and cadherin adhesion molecules; remodeling and guidance molecules and their receptors (eg, ephrin/Eph, angiopoietins/tyrosine kinase with Ig and EGF homology domains [Tie-2]); matrix-degrading enzymes (eg, matrix metalloproteinase [MMP] -9), signaling molecules, and transcription factors (eg, hypoxia inducible factor 1 alpha [HIF1 ]). Many of these molecules, in particular VEGF, have been or are being evaluated as novel therapeutic targets. Most recently, vascular integrin inhibition is being tested as antiangiogenic therapy. Integrins are heterodimer transmembrane receptors for the extracellular matrix composed of an alpha and beta subunit. Natural integrin ligands include laminin, fibronectin, and vitronectin, but they also include fibrinogen and fibrin, thrombospondin, MMP-2, and fibroblast growth factor 2. Integrins bind ligands by recognizing short amino acid stretches on exposed loops, particularly the arginine-glycine-aspartic acid (RGD) sequence. On ligation, integrins mediate complex signaling events, alone or in combination with growth factor receptors, regulating cell adhesion, proliferation, survival, and migration by activating canonical pathways, such as integrin-linked kinase (ILK), protein kinase B (PKB/Akt), mitogen-activated protein kinase (MAPK), Rac or nuclear factor kappa B (NFB). In resting vessels, integrins interact with the basal membrane, thereby maintaining vascular quiescence. During angiogenesis, they are essential for endothelial cell migration, proliferation, and survival. In preclinical studies, pharmacologic inhibition of integrin function efficiently suppressed angiogenesis and inhibited tumor progression. Of the 24 known integrin heterodimers, V 3 and V 5 were the first vascular integrins targeted to suppress tumor angiogenesis. These encouraging preclinical results stimulated researchers and industry to develop pharmacologic inhibitors of integrin function for clinical testing. Three classes of integrin inhibitors are currently in preclinical and clinical development: monoclonal antibodies targeting the extracellular domain of the heterodimer (eg, Vitaxin; MedImmune, Gaithersburg, MD), synthetic peptides containing an RGD sequence (eg, cilengitide; Merck KGaA, Darmstadt, Germany), and peptidomimetics (eg, S247; Pfizer, St Louis, MO), which are orally bioavailable nonpeptidic molecules mimicking the RGD sequence. In this issue of the Journal of Clinical Oncology, Nabors et al, on behalf of the New Approaches to Brain Tumor Therapy consortium, report on a phase I trial of cilengitide conducted in patients with recurrent glioma. Cilengitide (EMD 121974) is a cyclic RGD-motif containing peptide binding with high specificity to the V 3 and V 5 receptors. Glioblastoma, a highly vascularized and invasive tumor with microvascular proliferation as one of its hallmarks, is a logical target for such therapy. Overexpression of V 3 and V 5 has been shown in a majority of glioblastoma. In this trial, cilengitide was administered intravenously twice weekly at increasing doses up to 2,400 mg/m, without reaching dose-limiting toxicity. Overall tolerance was excellent, with occasional patients experiencing joint and bone pain. Thrombosis, thrombocytopenia, electrolyte imbalance, and anorexia were also reported. In five of the 51 patients, an objective response was observed. Sixteen other patients are reported as stable for a median duration of 5 months (range, 3 to 11 months). The pharmacokinetic profile was as reported previously, with no influence of comedications, in particular the frequent administration of enzymeinducing antiepileptic drugs. These results are intriguing for several reasons. First, despite a wide range of dosages, no clear pattern of toxicity could be determined. The absence of bleeding episodes is reassuring, as hemorrhage might have been expected with such a therapy and in this tumor type in particular. Second, objective and even long-lasting responses were seen, although mechanistically one would not necessarily expect measurable tumor reduction, but rather slowing of the growth curve. Due to the inherent heterogeneity of the patient and tumor population in phase I trials, the growth rate cannot be assessed in this trial. The authors refrain from reporting the progression-free survival rate at 3 or 6 months, which are commonly used surrogate end points in brain tumor trials. Third, responses were seen both at the lower dose levels (360 mg/m) as well as at the highest dose level tested (2,400 mg/m), allowing no conclusion to what dose is the most appropriate to be evaluated in future studies. Last, the authors are to be commended for having attempted to include correlative imaging end points in this study. However, imaging end points require careful standardization and a complex statistical analysis. Their data suggest that the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 13 MAY 1 2007