However, while monotherapy selleck chem Trichostatin A studies with several signal Inhibitors,Modulators,Libraries transduction inhibitors, including rapalogues, have shown only modest success in advanced breast cancers, preclinical data indicate that a combination of anti hormone and sig nal transduction inhibitors can provide significantly greater inhibition than either agent alone. Although breast cancers may become resistant to first line anti hormone treatment they often retain an active ER and will still respond to an alternative endocrine agent as a second line therapy, but longer term success is more likely to be achieved by also targeting up regulated growth factor path ways that can be independent Inhibitors,Modulators,Libraries from, or interactive with, ER signalling pathways.

Pre clinical data were supportive of the use of current mTOR antagonists alongside endocrine ther apy in breast cancer which resulted in a number of clinical trials using such combination therapies. One of the earliest phase 3 trials combined letrozole and temsirolimus and was used on advanced breast cancer but the trial had to be terminated early due to failure to demonstrate any Inhibitors,Modulators,Libraries benefit. Later studies have been more successful with very promising results obtained recently in advanced endo crine resistant disease where RAD001 was used in combination with the steroidal aromatase inhibitor exemestane or with tamoxifen in phase 2 3 trials. These have shown significant improvement in progression free survival from 4. 1 months with exemestane alone to 10. 6 months with a combination of exemestane and evero limus in the BOLERO 2 trial and an improved time to progression from 4.

5 months with tamoxifen Inhibitors,Modulators,Libraries alone to 8. 6 months with tamoxifen plus everolimus in the TAM RAD GINECO trial. These clinical findings indicated value for the allosteric mTOR inhibitors used alongside tamoxifen or aromatase inhibitors in advanced endocrine resistant tumours and there has been recent USA Food and Drug Administration approval for everolimus in combin ation with exemestane in ER HER2 metastatic breast cancer after non steroidal aromatase inhibitor failure. Nevertheless, Inhibitors,Modulators,Libraries there remains a group of patients who are initially refractory to everolimus anti hormone ther apy while others relapse at a later point during such treatment. It is feasible that these patients may gain more benefit from treatment with alternative mTOR inhibitors that, unlike rapalogues, are not re stricted to inhibition of only mTORC1 signalling.

It is thus interesting that several types of new mTOR inhibi tors are currently under development. The dual mTOR and PI3K inhibitors simultaneously block both the PI3K and mTOR signalling and, therefore, have the theoretical ad vantage of totally shutting down the PI3K Akt mTOR network. These have table 1 the possible drawback of asso ciation with greater toxicity but in early small clinical trials are reported to induce stable disease or partial re sponse.