A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapy

Abstract

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.

Keywords: Cancer; Glioblastoma; Neuroblastoma; PI3K; Pharmacological inhibitors; Signaling cascade.

Figure 1

The PI3K/Akt/mTOR signaling cascade. Simplified schemata of the PI3K/Akt/mTOR signaling cascade. While indisputable involved at several levels, directly as well as indirectly with cell survival, other important functions of this signaling network are also highlighted here. Key molecules which have been implicated in cancer or have been selected as potential therapeutic targets are: 1. Receptor tyrosine kinases, such as EGFR, IGFR and ALK, often overexpressed or activated by mutations in many different cancers, including glioblastoma and neuroblastoma. These transmembrane proteins are apical of several interconnected signaling cascades. 2. PI3K, phosphatidylinositol 3'-OH kinase, a lipid kinase, predominately consisting of a p110 catalytic and a p85 regulatory subunit, of which the former has been found to be mutationally activated in certain cancers. 3. PTEN, phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P ₃] phosphatase and tensin homologue, is a phosphatase that counters PI3K-mediated phosphorylation and as such functions as a negative regulator of the PI3K/Akt/mTOR signaling cascade. It is among the most frequently inactivated, either by mutation or promoter methylation, proteins in cancer. 4. The serine/threonine kinase Akt, v-akt murine thymoma viral oncogene homologue (Protein Kinase B), is often considered the central downstream mediator of PI3K signaling, as it phosphorylates a diverse array of targets that are involved in all key functions of this pathway. 5. mTOR, mammalian target of Rapamycin, depending on its complex partners, can either be up- or downstream of Akt. It is frequently found to be associated with the process of autophagy, which depending on the context, can be either a survival strategy or a form of cell death. (modified from [33]).

Figure 2

Potential tumor-specific differences in therapeutic end points. Although inhibition of PI3K/Akt/mTOR signaling is a feasible approach in both glioblastoma and neuroblastoma, the molecular background of those two malignancies is very different. While glioblastoma exhibits amplification of HER1/EGFR with coexpression of the activated EGFRvIII variant [53], their main feature with regards to the PI3K signaling network is the frequent inactivation of PTEN [11]. In contrast, neuroblastoma does not exhibit any frequent mutation within the PI3K/Akt/mTOR signaling cascade, but often displays overexpression of several receptor tyrosine kinases [42, 43]. Interestingly, our own data suggest that the downstream effectors that need to be inhibited to chemosensitize these tumors to chemotherapy are different. Glioblastoma is sensitized for doxorubicin-induced apoptosis via blocking DNA-PK activation, i.e. DNA repair [24], while in neuroblastoma this seems to be mediated at the level of mitochondria via VDAC1 [5]. It remains to be seen whether this is an isolated phenomenon, due to low numbers of cell lines investigated, or whether different arms of the PI3K network have a different weighting dependent on the malignancy.

Figure 3

Possible future treatment schedule. A possible complex combination therapy that consists of a cell death inducer and several sensitizer that all target individual components of the PI3K signaling cascade. 1. Take out the cancer cells' ability to move, thus preventing invasion and metastasis, extending the therapeutic window. Continue blocking this arm throughout therapy. 2. Block the DNA repair mechanisms prior to treatment. Importantly do not affect cell cycle progression, thus making cancer cells amenable to most standard treatments. 3. Administer chemo- or radiotherapy. 4. Block the survival pathways mediated by PI3K signaling in the cancer cells stressed by treatment. If, as outlined in Figure 2, details of key mediators are know, e.g. DNA-PK in glioblastoma (4.1), or VDAC1 in neuroblastoma (4.2), target these, otherwise Akt seems the most promising target. 5. Finally, block growth factor receptors to maximize cell cycle arrest, thus preventing a cancer repopulation by the cells that escaped treatment-induced apoptosis. Point 5 might appear superfluous, as 3 and 4 should already block proliferation, however, this inhibition should also target cells that have activated additional signaling cascades or have (epi)genetically escaped sensitivity to treatment.