PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

Abstract

The high recurrence rate and the low overall survival in ovarian cancer suggest that a more specific therapeutic approach in addition to conventional treatment is required. Translational and clinical research is investigating new molecular targets in order to find an alternative way to affect tumor growth and to minimize the overlap of toxicity of antiblastic agents. Given its implication in many cellular activities including regulation of cell growth, motility, survival, proliferation, protein synthesis, autophagy, transcription, as well as angiogenesis, PI3K/AKT/mTOR is one of the most investigated intracellular signaling pathways. A dis-regulation of this pathway has been shown in several tumors, including ovarian cancer. In this setting, mTor proteins represent a potential target for inhibitors, which could ultimately play a pivotal role in counteracting cellular proliferation. Recently, mTor inhibitors have been approved in the treatment of pancreatic neuroendocrine tumors, mantle cell lymphoma and renal cancer. Clinical trials have assessed the safety of these drugs in ovarian cancer patients. Ongoing phase I and II studies are evaluating the oncologic outcome of mTor inhibitor treatment and its effect in combination with conventional chemotherapy and target agents.

Zusammenfassung

Die hohe Rückfallquote und die allgemeine niedrige Gesamtüberlebensrate beim Ovarialkrebs weisen darauf hin, dass neben der herkömmlichen Behandlung zusätzlich eine spezifischere Therapie benötigt wird. In der translationalen und klinischen Forschung wird derzeit nach alternativen molekularen Zielstrukturen gesucht, die einerseits das Tumorwachstum aufhalten und andererseits die überlappende Toxizität von wachstumshemmenden Wirkstoffe minimieren könnten. Da PI3K/AKT/mTOR viele Zellfunktionen steuern, u. a. die Regulierung des Zellwachstums, Motilität, Überleben, Proliferation, Proteinsynthese, Autophagozytose, Transkription und Angiogenese, gehören sie zu den meist untersuchten intrazellulären Signalwegen. Eine Deregulierung dieses Signalweges wurde bei einigen Tumoren festgestellt, darunter auch für das Ovarialkarzinom. Vor diesem Hintergrund könnten mTor-Proteine potenzielle Ziele für Inhibitoren sein, die dann eine Schlüsselrolle bei der Hemmung der Zellproliferation spielen könnten. Vor Kurzem wurden mTor-Inhibitoren zur Behandlung von neuroendokrinen Tumoren der Bauchspeicheldrüse, Mantelzell-Lymphomen und Nierenkrebs zugelassen. Klinische Studien haben die Sicherheit dieser Medikamente in Patientinnen mit Eierstockkrebs untersucht. Aktuell werden Phase-I und -II-Studien durchgeführt, um die onkologischen Ergebnisse nach einer Behandlung mit mTOR-Inhibitoren und die Auswirkungen dieser Therapie in Kombination mit konventioneller Chemotherapie und Target-Wirkstoffen zu bewerten.

Key words

everolimus - mTOR inhibitors - ovarian cancer - target therapy - temsirolimus - PI3K/AKT/mTOR

Schlüsselwörter

Everolimus - mTOR-Inhibitoren - Ovarialkarzinom - gezielte Therapie - Temsirolimus - PI3K/AKT/mTOR

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