The rapamycin-sensitive signal transduction pathway as a target for cancertherapy

The high frequency of mutations in cancer cells which result in altered cel l cycle regulation and growth signal transduction, conferring a proliferati ve advantage, indicates that many of these aberrant mechanisms may be strat egic targets for cancer therapy. The macrolide fungicide rapamycin, a natur al product with potent antimicrobial, immunosuppressant, and anti-tumor pro perties, inhibits the translation of key mRNAs of proteins required for cel l cycle progression from G(1) to S phase. Rapamycin binds intracellularly t o the immunophilin FK506 binding protein 12 (FKBP12), and the resultant com plex inhibits the protein kinase activity of a protein kinase termed mammal ian target of rapamycin (mTOR), The inhibition of mTOR, in turn, blocks sig nals to two separate downstream pathways which control the translation of s pecific mRNAs required for cell cycle traverse from G(1) to S phase. Blocki ng mTOR affects the activity of the 40S ribosomal protein S6 kinase (p70(s6 k)) and the function of the eukaryotic initiation factor 4E-binding protein -1 (4E-BP1), leading to growth arrest in the the G(1) phase of the cell cyc le. In addition to its actions on p70(s6k) and 4E-BP1, rapamycin prevents c yclin-dependent kinase activation, inhibits retinoblastoma protein (pRb) ph osphorylation, and accelerates the turnover of cyclin D1 that leads to a de ficiency of active cdk4/cyclin D1 complexes, all of which can inhibit cell cycle traverse at the G(1)/S phase transition. Both rapamycin and CCI-779, an ester analog of rapamycin with improved pharmaceutical properties and aq ueous solubility, have demonstrated impressive activity against a broad ran ge of human cancers growing in tissue culture and in human tumor xenograft models, which has supported the development of compounds targeting rapamyci n-sensitive signal-transduction pathways. CCI-779 has completed several pha se I clinical evaluations and is currently undergoing broad disease-directe d efficacy studies. The agent appears to be well tolerated at doses that ha ve resulted in impressive anti-tumor activity in several types of refractor y neoplasms. Important challenges during clinical development include the d efinition of a recommended dose range associated with optimal biological ac tivity and maximal therapeutic indices, as well as the ability to predict w hich tumors will be sensitive or resistant to CCI-779.