Identification And Profiling Of Biomarkers And Surrogate Markers

Biomarkers and surrogate markers for anticancer activity of new drugs are becoming a prerequisite for clinical testing (81). Whereas surrogate markers (markers for disease progression/remission) can use well-established markers such as prostate-specific antigen for prostate cancer, biomarkers (indicators of drug activity) often must be newly developed and validated using animal models. Experiments by Bonasera et al. (82) suggested that use of 18F-labeled drugs in conjunction with positron emission tomography may be of limited value. Often immunohistochemical staining or Western blotting (see Tables 2, 4, and 5) are used to identify target activity and its inhibition in tumor tissue or other tissues. However, in a recent paper (83), peripheral blood leukocytes were used as a tissue source for p70S6 kinase (p70s6k), a downstream effector of mTOR, to monitor the effect of RAD001. Detailed biochemical profiling of mTOR signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs) indicated RAD001-dependent inhibition of p70s6k. RAD001 demonstrated dose-dependent anti-tumor activity in the CA20948 syngeneic rat pancreatic tumors with weekly administration schedules. Comparison of an optimal (5 mg/kg) vs a suboptimal

(0.5 mg/kg) RAD001 weekly treatment schedule, demonstrated that prolonged inactivation of p70s6k in PBMCs occurred only with the optimal dose. These data provide mechanistic support for the observed dose-dependent, anti-tumor efficacy of weekly treatment schedules. Supplemental experiments demonstrated that the assay could be applied to human PBMCs ex vivo, and this biomarker is currently being evaluated clinically. Taken together, these results demonstrate a correlation between the anti-tumor efficacy of intermittent RAD001 treatment schedules and prolonged p70s6k inactivation in PBMCs, and suggest that monitoring of PBMC-derived p70s6k activity levels could be used when assessing rapamycin treatment schedules in cancer patients.

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