text: The development of rapamycin as an anticancer agent began again in the 1990s with the discovery of temsirolimus (CCI-779). This novel soluble rapamycin derivative had a favorable toxicological profile in animals. More rapamycin derivatives with improved pharmacokinetics and reduced immunosuppressive effects have since then been developed for the treatment of cancer. These rapalogs include temsirolimus (CCI-779), everolimus (RAD001), and ridaforolimus (AP-23573) which are being evaluated in cancer clinical trials. Rapamycin analogs have similar therapeutic effects as rapamycin. However they have improved hydrophilicity and can be used for oral and intravenous administration. In 2012 National Cancer Institute listed more than 200 clinical trials testing the anticancer activity of rapalogs both as monotherapy or as a part of combination therapy for many cancer types.
  Rapalogs, which are the first generation mTOR inhibitors, have proven effective in a range of preclinical models. However, the success in clinical trials is limited to only a few rare cancers. Animal and clinical studies show that rapalogs are primarily cytostatic, and therefore effective as disease stabilizers rather than for regression. The response rate in solid tumors where rapalogs have been used as a single-agent therapy have been modest. Due to partial mTOR inhibition as mentioned before, rapalogs are not sufficient for achieving a broad and robust anticancer effect, at least when used as monotherapy.
  Another reason for the limited success is that there is a feedback loop between mTORC1 and AKT in certain tumor cells.  It seems that mTORC1 inhibition by rapalogs fails to repress a negative feedback loop that results in phosphorylation and activation of AKT. These limitations have led to the development of the second generation of mTOR inhibitors.