Angiogenese und Tumorhypoxie beim Mammakarzinom: Fakten, Fragen und therapeutische Möglichkeiten

Zusammenfassung

Schon vor über 35 Jahren postulierte Judah Folkman als Pionier der Angiogeneseforschung, dass das Wachstum und die Metastasierung von Tumoren entscheidend von ihrer Blutgefäßversorgung abhängt. Seitdem ist der Wachstumsfaktor VEGF (Vascular Endothelial Growth Factor), der über seine Rezeptoren VEGFR-1 (Flt-1) und VEGFR-2 (KDR) wirkt, als Schlüsselmolekül der Angiogenese identifiziert worden. VEGF bewirkt das Aussprossen neuer Blutgefäße aus vorbestehenden Gefäßen in der Tumorumgebung. Diese Tumorblutgefäße sind abnormal und durch einen chaotischen Verlauf sowie eine unreife Struktur mit einer höheren Permeabilität charakterisiert. Dies bewirkt einen schlechteren Blutfluss, sodass beispielsweise Chemotherapeutika einen Tumor nicht in optimaler Dosierung erreichen können. Darüber hinaus induziert VEGF auch direkt die Tumorzell-Proliferation. VEGF wird von zahlreichen Tumoren und auch beim Mammakarzinom gebildet. Beim Mammakarzinom hat VEGF einen negativen prognostischen und prädiktiven Wert. In den letzten Jahren sind zahlreiche antiangiogen wirkende Substanzen (z. B. Antikörper, Rezeptor-Tyrosinkinase-Inhibitoren, lösliche Rezeptoren) gegen VEGF, seine Rezeptoren oder den VEGF-Signalweg entwickelt worden. Die am weitesten entwickelte Substanz ist Bevacizumab (Avastin®), ein monoklonaler humanisierter Antikörper gegen VEGF, der die Bindung des Liganden an seine Rezeptoren und somit die nachgeschaltete angiogene Signalwirkung verhindert. In Phase-III-Studien konnte die klinische Wirksamkeit von Bevacizumab in Kombination mit einer Chemotherapie (Paclitaxel bzw. Docetaxel) beim unvorbehandelten metastasierten Mammakarzinom (first line) gezeigt werden. In der klinischen Erprobung sind unter anderem auch sogenannte Multikinase-Inhibitoren (z. B. Sunitinib, Sorafenib), die verschiedene proangiogene Rezeptoren gleichzeitig hemmen. Trotz aller Fortschritte hat sich die klinische Umsetzung antiangiogener Therapiestrategien als schwieriger als erwartet herausgestellt. In der Zukunft wird es wichtig sein, diejenigen Patientinnen zu identifizieren, die maximal von einer bestimmten antiangiogenen Therapie profitieren. Neben der Identifikation geeigneter Tumoren und Erkrankungsstadien müssen auch prädiktive Biomarker entwickelt werden, die eine Vorhersage zulassen, welche Substanz bei einer Patientin optimal wirksam ist, sodass eine individualisierte maßgeschneiderte Therapie möglich ist. In den nächsten Jahren werden die Daten zahlreicher Studien zur Antiangiogenese verfügbar, die zum besseren Verständnis dieser Zusammenhänge beitragen könnten. Dabei kann uns insbesondere die translationale Forschung helfen, den klinischen Einsatz der antiangiogenen Therapien zu optimieren.

Abstract

More than 35 years ago Judah Folkman pioneered angiogenic research with his suggestion that blood vessel supply is critical for the growth and metastastic spread of tumor cells. Since then, numerous research efforts have resulted in the identification of vascular endothelial growth factor (VEGF) and its two receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR) as key molecules for neoangiogenesis in tumors. VEGF leads to the sprouting of new vessels from preexisting vessels in the vicinity of the tumor. Morphologically, these tumor vessels are characterized by undirected growth and an immature structure with increased permeability. This leads to diminished blood flow which can compromise the optimal perfusion and delivery of chemotherapeutic drugs to the tumor tissue. Moreover, VEGF directly induces tumor cell proliferation. VEGF is produced by numerous tumor entities, and also by breast cancers. In breast cancer, VEGF has been shown to have a negative prognostic and predictive value. Recently, antiangiogenic compounds, such as monoclonal antibodies, tyrosine kinase inhibitors and soluble receptors, have been developed to target VEGF, its receptors and the VEGF signalling pathway. The most advanced compound is Bevacizumab (Avastin®), a monoclonal, humanized antibody against VEGF, which blocks the binding of the ligand to its receptors and subsequent proangiogenic signalling cascades. In phase-III trials it was shown that the combination of Bevacizumab and chemotherapy (paclitaxel, docetaxel) is active in the 1st-line treatment of untreated metastastic breast cancer. Other compounds, such as sorafenib and sunitinib which target multiple proangiogenic receptors, are also undergoing clinical development. Despite a lot of progress in the research into molecular targeted therapies, the translation of research results into daily clinical practice has been more difficult than expected. In the future, it will be critical to identify those patients who could benefit most from antiangiogenic therapy. In addition to the identification of appropriate tumor entities and stages we need to identify predictive biomarkers that allow a prognosis about which compound will be active in a patient so as to facilitate an individual tailored molecular therapy. In the next couple of years data from several clinical trials will be available with results on the objective response rates to antiangiogenic therapies, which will contribute to a better understanding of the underlying mechanisms of these agents. Translational research will help to further define clinical settings for antiangiogenic therapies.

Schlüsselwörter

Mammakarzinom - Angiogenese - VEGF - Bevacizumab - zielgerichtete Therapie

Key words

breast cancer - angiogenesis - VEGF - bevacizumab - targeted therapy

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