A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma

Abstract

The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 kinase alpha and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and PI3 kinase alpha in malignant glioma.

Rapamycin and mTOR kinase inhibitors

“…The cytostatic property of the compound was attributed to its ability to inhibit both p110α and mTOR. PI-103 treatment of mice also reduced the size of established tumor xenografts at doses that produced no observable toxicity [86]. These results suggest that dualspecificity PI3K/mTOR inhibitors, or use of a PI3K inhibitor in combination with rapamycin, might be a viable therapeutic option for the treatment of certain cancers.…”

“…Although this dual specificity limits the use of PI-103 as a probe to study mTOR function, PI-103 has proved to be useful as an experimental compound in cancer research. PI-103 was found to be the most active compound in a group of ten isoform-selective PI3K inhibitors that were evaluated for the ability to block the proliferation of glioma cells in vitro [86]. The cytostatic property of the compound was attributed to its ability to inhibit both p110α and mTOR.…”

The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

“…Although it has been shown earlier that PI-103 has an anti-proliferative effect on GBM cells as a single agent (Fan et al, 2007) or in combination with the epidermal growth factor receptor inhibitor erlotinib (Fan et al, 2006), and that it enhances tumor radiosensitivity (Prevo et al, 2008), no study has so far addressed the potential interaction between chemotherapeutic agents and PI-103. This is of particular interest for GBM, for which the current standard of care is still considered to be a surgical resection of the tumor mass, a frequently unsuccessful and difficult procedure (Stupp et al, 2006).…”

“…For example, class I PI3K inhibitors, such as the pyridinylfuranopyrimidine inhibitor PI-103, are considered as promising candidates for such an approach (Ihle and Powis, 2009;Maira et al, 2009). Although PI-103 has been shown to block proliferation (Fan et al, 2006(Fan et al, , 2007 and to enhance the efficacy of radiotherapy (Prevo et al, 2008), its potential as a chemosensitizer has so far not been addressed. Therefore, in this study, we investigated the effect of PI-103 in combination with DNA-damaging drugs in GBM.…”

PDK1-driven Myc signaling regulates cellular response to mTOR inhibitors

“…These findings point to significant concerns as these inhibitors are being tested in clinical trials in various human tumors. 12,13 One would expect that this compensatory activation of Myc signaling, if validated in the primary tumors, may eventually lead to acquired resistance and patient relapse.…”