Westhoff Mike-Andrew, Karpel-Massler Georg, Brühl Oliver, Enzenmüller Stefanie, La Ferla-Brühl Katia, Siegelin Markus D, Nonnenmacher Lisa, Debatin Klaus-Michael
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
Department of Neurosurgery, University Medical Center Ulm, Ulm, Germany ; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY USA.
Mol Cell Ther. 2014 Oct 27;2:32. doi: 10.1186/2052-8426-2-32. eCollection 2014.
Members of the PI3K/Akt/mTor signaling cascade are among the most frequently altered proteins in cancer, yet the therapeutic application of pharmacological inhibitors of this signaling network, either as monotherapy or in combination therapy (CT) has so far not been particularly successful. In this review we will focus on the role of PI3K/Akt/mTOR in two distinct tumors, Glioblastoma multiforme (GBM), an adult brain tumor which frequently exhibits PTEN inactivation, and Neuroblastoma (NB), a childhood malignancy that affects the central nervous system and does not harbor any classic alterations in PI3K/Akt signaling. We will argue that inhibitors of PI3K/Akt signaling can be components for potentially promising new CTs in both tumor entities, but further understanding of the signal cascade's complexity is essential for successful implementation of these CTs. Importantly, failure to do this might lead to severe adverse effects, such as treatment failure and enhanced therapy resistance.
PI3K/Akt/mTor信号级联的成员是癌症中最常发生改变的蛋白质之一，然而，该信号网络的药理学抑制剂作为单一疗法或联合疗法（CT）的治疗应用迄今为止并不特别成功。在这篇综述中，我们将聚焦PI3K/Akt/mTOR在两种不同肿瘤中的作用，即多形性胶质母细胞瘤（GBM），一种常表现出PTEN失活的成人大脑肿瘤，以及神经母细胞瘤（NB），一种影响中枢神经系统且PI3K/Akt信号通路无任何经典改变的儿童恶性肿瘤。我们将论证，PI3K/Akt信号通路抑制剂可以成为这两种肿瘤实体中潜在有前景的新联合疗法的组成部分，但进一步了解信号级联的复杂性对于成功实施这些联合疗法至关重要。重要的是，不这样做可能会导致严重的不良反应，如治疗失败和增强的治疗抗性。
