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Integrin Inhibitors Reaching the Clinic

Multidisciplinary Oncology Center, University of Lausanne Hospitals, Lausanne, Switzerland

Curzio Ruegg

Multidisciplinary Oncology Center, University of Lausanne Hospitals, and the Swiss Institute for Experimental Cancer Research, National Center of Competence in Research Molecular Oncology, Epalinges, Lausanne, Switzerland

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.¹ 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.² 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 [HIF-1]).³ Many of these molecules, in particular VEGF, have been or are being evaluated as novel therapeutic targets.⁴ 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 (NF-B). 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.⁵ In preclinical studies, pharmacologic inhibition of integrin function efficiently suppressed angiogenesis and inhibited tumor progression. Of the 24 known integrin heterodimers, Vß3 and Vß5 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.⁵

In this issue of the Journal of Clinical Oncology, Nabors et al,⁶ 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 Vß3 and Vß5 receptors.⁷ Glioblastoma, a highly vascularized and invasive tumor with microvascular proliferation as one of its hallmarks, is a logical target for such therapy. Overexpression of Vß3 and Vß5 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/m², 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 enzyme-inducing 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/m²) as well as at the highest dose level tested (2,400 mg/m²), 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.⁸ Their data suggest that the relative cerebral blood flow may be an adequate surrogate marker.⁸ A correlation of the reduction in cerebral blood flow and the area under the concentration curve could be demonstrated for nonprogressing patients at 16 weeks, but not the 8-week time point.⁶

The optimal dose of cilengitide to be carried forward for future testing has not yet been determined, and higher doses may be of lesser importance than the administration schedule and exposure duration. The results of a randomized phase II trial in patients with recurrent glioblastoma comparing a flat dose of 500 mg of cilengitide with a higher dose of 2,000 mg are awaited. However, even higher doses may not be sufficient to effectively block integrin receptors for a biologic effect due to its short plasma half-life of only 2.5 to 3 hours. The tested administration schedule of a twice-weekly short infusion is mainly based on empirical grounds and practicability. As an alternative, continuous infusion of cilengitide using a pump system is currently being tested in a phase I trial at the University of Chicago (Chicago, Illinois). Another unanswered question remains the optimal duration of therapy. Two responding patients received cilengitide therapy for 1 and 2 years, respectively. However, there may even be a rationale to continue therapy in progressing patients, as angiogenesis and tumor growth and invasiveness may have been slowed by the integrin inhibition. Additional information on the growth rate, before and after cilengitide discontinuation, may be of interest.

As for all other antiangiogenic drugs currently in clinical testing, the development of integrin inhibitors faces many concerns. The first concern is the target itself—is Vß3 (or Vß5) a good one? Preclinical results and emerging clinical evidence suggests so. However, additional integrins (eg, 1ß1, 2ß1, 5ß1, and 6ß4) have been associated with angiogenesis in experimental models, and additional inhibitors, such as volociximab (an anti-5ß1 monoclonal antibody), are currently being tested in the clinic.⁵ A second concern is about combination therapies. Antiangiogenic drugs are unlikely to function as single agents, and preclinical evidence shows that integrin inhibitors may be most effective in combination with chemotherapy agents and in particular with radiotherapy.⁹ The rationale for combining cilengitide with radiotherapy is further strengthened by the observation that Vß3 expression in endothelial cells is upregulated with radiation.⁹ A phase II trial of cilengitide in addition to temozolomide and radiotherapy in patients with newly diagnosed glioblastoma has completed accrual in April 2006, and initial results are expected for the American Society of Clinical Oncology in spring 2007. A third concern relates to monitoring of angiogenesis. While the efficacy of conventional anticancer therapy is commonly evaluated by measuring its effect on response rate and survival, these end points may be inadequate for antiangiogenic drugs, which act primarily on vessels and only indirectly on tumor cells. To assess the effects on the tumor vasculature independent of the overall antitumor activity and clinical response, it would be of great value to be able to quantify tumor angiogenesis in patients in a noninvasive and reliable manner. Many approaches have been proposed and investigated such as soluble molecules, circulating endothelial cells/precursors, and imaging-based techniques, but to date, there is still no validated marker or method available for predicting benefit from antiangiogenic agents in clinical oncology.^10,11 It will be essential in future clinical trials with integrin antagonists, and any other antiangiogenic drugs, to associate clinical testing with studies aimed at identifying molecular, biologic, or functional correlative parameters of angiogenesis or antiangiogenic activity.

In conclusion, the trial by the New Approaches to Brain Tumor Therapy investigators is the first demonstration of a clinically measurable antitumor activity with the administration of an integrin inhibitor. This opens novel perspectives for combination therapy not only in malignant glioma, but also in many other tumor types, for which dependence on Vß3 and Vß5 has been suggested, as integrin-mediated cell adhesion, angiogenesis, proliferation, and migration is a ubiquitous phenomenon. However, as this is only one among many redundant mechanisms of (tumor) angiogenesis, it is likely that such a strategy will work best in combination with other agents, and only in a subgroup of tumor types. It is possible that this class of agents also works best in the adjuvant setting before metastases formation occurs. Future clinical studies will tell.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Roger Stupp, Merck KGaA; Curzio Ruegg, Merck KGaA Stock: N/A Honoraria: N/A Research Funds: Roger Stupp, Merck KGaA Testimony: N/A Other: N/A

AUTHOR CONTRIBUTIONS

Conception and design: Roger Stupp, Curzio Ruegg

Data analysis and interpretation: Roger Stupp, Curzio Ruegg

Manuscript writing: Roger Stupp, Curzio Ruegg

Final approval of manuscript: Roger Stupp, Curzio Ruegg

ACKNOWLEDGMENTS

Our laboratory work is supported by grants from the Swiss National Science Foundation (FNS), National Center for Competence in Research Molecular Oncology, a research instrument of the FNS; Oncosuisse; the Medic Foundation; the Fondazione San Salvatore; Roche Research Foundation; and Novartis Foundation.

REFERENCES

1. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57-70, 2000[CrossRef][Medline]

2. Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15-18, 2002[Medline]

3. Carmeliet P: Angiogenesis in life, disease and medicine. Nature 438:932-936, 2005[CrossRef][Medline]

4. Ferrara N, Kerbel RS: Angiogenesis as a therapeutic target. Nature 438:967-974, 2005[CrossRef][Medline]

5. Alghisi GC, Ruegg C: Vascular integrins in tumor angiogenesis: Mediators and therapeutic targets. Endothelium 13:113-135, 2006[CrossRef][Medline]

6. Nabors LB, Mikkelsen T, Rosenfeld S, et al: Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 25:1651-1657, 2007[Abstract/Free Full Text]

7. Smith J: Cilengitide (Merck). Curr Opin Investig Drugs 4:741-745, 2003[Medline]

8. Akella NS, Twieg DB, Mikkelsen T, et al: Assessment of brain tumor angiogenesis inhibitors using perfusion magnetic resonance imaging: Quality and analysis results of a phase I trial. J Magn Reson Imaging 20:913-922, 2004[CrossRef][Medline]

9. Abdollahi A, Griggs DW, Zieher H, et al: Inhibition of alpha(v)beta3 integrin survival signaling enhances antiangiogenic and antitumor effects of radiotherapy. Clin Cancer Res 11:6270-6279, 2005[Abstract/Free Full Text]

10. Jubb AM, Oates AJ, Holden S, et al: Predicting benefit from anti-angiogenic agents in malignancy. Nat Rev Cancer 6:626-635, 2006[CrossRef][Medline]

11. Ruegg C, Meuwly JY, Driscoll R, et al: The quest for surrogate markers of angiogenesis: A paradigm for translational research in tumor angiogenesis and anti-angiogenesis trials. Curr Mol Med 3:673-691, 2003[CrossRef][Medline]

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