Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted, most likely with temozolomide.
The PI3K/Akt/mTOR pathway is activated in the majority of pancreatic cancers, and inhibition of this pathway has antitumor effects in preclinical studies. We performed a multi-institutional, single-arm, phase II study of RAD001(everolimus), an oral inhibitor of mTOR, in patients who experienced treatment failure on first-line therapy with gemcitabine. Not effective as a single agent – needs to be used in combination with CT
The mTOR kinase is the catalytic subunit of two functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an immunosuppressant and anti-cancer agent. Here, we find that Torin1, a highly potent and selective ATP-competitive mTOR inhibitor that directly inhibits both complexes, impairs cell growth and proliferation to a far greater degree than rapamycin.
Effective medical therapy for persistent/recurrent medullary thyroid carcinoma (MTC) is not available, yet. Everolimus (RAD001) is a Rapamycin derivative, a potent mTOR pathway inhibitor. RAD001 has been employed in several clinical studies demonstrating antiproliferative and apoptotic effects in human tumors, both in vitro and in vivo, also in combination with somatostatin analogs. Results suggest Afinitor might be a useful treatment in combination with octreotide
After RCC, what next for Afinitor? Preclinical data suggest that mTOR may be a good target for breast cancer therapy, especially in tumors with Akt activation resulting from either growth factor dependency or loss of PTEN function.
The mammalian target of rapamycin (mTOR) is a serine threonine kinase implicated in cellular response to nutrients and growth factor signaling. mTOR functions downstream of phosphatidylinositol 3’-kinase (PI3K) and AKT and is abnormally activated in a number of different tumor types. mTOR inhibitors are consequently increasingly recognized as an important new therapeutic class of agents in the treatment of cancer. Two mTOR inhibitors or rapalogs – temsirolimus and everolimus – have undergone phase III trials in renal cell carcinoma (RCC), and temsirolimus has entered clinical oncology practice after it was approved by the US Food and Drug Administration for use in RCC. mTOR inhibitors are also under clinical investigation in a broad variety of other solid tumors. Both temsirolimus and everolimus are now approved in advanced RCC.