OPC 67683 is also a prodrug that requires in vivo activation by Rv354

An initial human phase I XL765 clinical study has demonstrated favorable toxicity and tolerability profiles with no established maximally tolerated dose. Several clinical trials are currently ongoing, including evaluation of XL765 as a single agent as well as in combination with other compounds. Our here support the development of XL765 based therapeutic strategies for testing in human MPNST Celecoxib clinical trials. However, it is critical to note that the anti MPNST effects secondary to PI3K/mTOR blockade reflected growth arrest rather than apoptotic cell death. These effects were found using either of the tested inhibitors, PI103 and XL765, and are in alignment with the effects of PI3K/mTOR dual inhibitors in several different tumor systems. Taking into account the established role of PI3K/AKT signaling in cellular survival, negating apoptosis directly through phosphorylation of apoptosisassociated downstream effectors or indirectly by modulating the transcription of critical proand anti survival molecules would suggest that a marked pro apoptotic Eumycetoma response secondary to the inhibition of this axis might be expected. However, as previously found and further exemplified in our study, apoptosis is not necessarily the primary response to PI3K/AKT inhibition, especially in cancer cells where marked apoptosis suppression can be the consequence of multiple genetic alterations. While targeting the highly proliferative state of locally advanced and/or metastatic MPNST is an attractive therapeutic stratagem, it might not be sufficient for disease eradication. Given that the anti MPNST effects of PI3K/ BAY 11-7082 mTOR inhibitors are cytostatic rather than cytotoxic diminishes enthusiasm for their use as single agents. Consequentially, identifying PI3K/mTOR blockade based therapeutic combinations having superior anti MPNST efficacy appears highly warranted. Examples of recent preclinical investigations of such an approach include combining dual PI3K/mTOR inhibitors with conventional chemotherapy, TRAIL, and EGFR blockade demonstrate enhanced effects as compared to when agents were used alone. While not yet evaluated in MPNST, such a strategy may have particular relevance in this context in that EGFR deregulation commonly occurs in these malignancies and is demonstrably contributory to their tumorigenic phenotype. EGFR blockade alone appears to exert only modest anti MPNST effects as observed in the preclinical MPNST setting, and a phase II clinical trial failed to demonstrate any objective responses to the EGFR inhibitor Tarceva in patients with relapsed MPNST. However, a recent study of combined EGFR blockade with mTOR inhibition resulted in additive anti proliferative, proapoptotic effects in MPNST cells in vitro and in vivo. Based on these findings, evaluating the impact of dual PI3K/mTOR inhibitors in combination with EGFR blockade might therefore be useful for identifying potential therapies for MPNST.