i hate that you can no longer list links but came across this:
These results suggest that increased PI3-kinase pathway activity results in resistance to erlotinib treatment in GBMs, even in tumors that show amplification and/or overexpression of EGFR. These results also prompt the question of whether increased PKB/Akt phosphorylation/activity is the causal downstream effector of PI3-kinase-mediated resistance, or whether it merely represents a marker for increased PI3-kinase activity, and the erlotinib resistance is conferred by other PI3-kinase effectors. We are using three Exelixis compounds in these studies: XL147 (PI3K inhibitor), XL765 (PI3K/mTOR inhibitor) and XL418 (PKB/S6K inhibitor). Although previous data suggest that dual PI3-kinase/mTOR inhibition is required to inhibit the proliferation of GBM tumor cells (Fan et al., 2006), this concept needs to be validated.
Recent pre-clinical work from Dr. Haas-Kogan’s laboratory has investigated the anti-neoplastic effects of dual PI3K/mTOR inhibitors as single agents and in combination with radiation and temozolomide. The dual inhibitor XL765 showed significant cytotoxic activity in vitro against a panel of primary glioma and neuroblastoma cell lines independent of their genetic backgrounds. These results demonstrate that in orthotopic models, XL765 + radiation have additive effects in vitro and XL765 + temozolomide have synergistic anti-tumor activity in vitro and in vivo (Prasad G, Sottero T, Yang X, Mueller S, James CD, Weiss WA, et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro-oncology. 2011;13(4):384-92).
Our work with XL765 (Sanofi-Aventis/Exelixis) exemplifies our commitment to tranlating our laboratory findings into clinical practice for patients with pediatric and brain tumors. The pre-clinical results from our laboratory combined with ongoing adult trials have led to a Phase 1 clinical study within the Pediatric Brain Tumor Consortium (PBTC) that Drs. Haas-Kogan and Mueller will co-chair. This will be the first test of this type of agent in pediatric patients, and would pave the way for future combination studies of dual PI3K/mTOR inhibitors in pediatric brain tumors and in neuroblastoma.
I pulled the following quote from another location in Dr Hass-Kogan's research site on pediatric GBM. Her research may be worth following due to the comparative nature of her ongoing research.
She's not too hard on the eyes, either...
"We are using various signaling inhibitors, including XL765 (PI3K/mTOR inhibitor from Exelixis/Sanofi-Aventis) and BEZ235 (PI3K/mTOR inhibitor from Novartis)."