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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Prof. Dr. Pia Wülfing
Universitätsklinikum Münster
Albert-Schweitzer-Straße 33
48149 Münster
Email: pia.wuelfing@ukmuenster.de
