Assessment of XXXX phosphorylation as a pharmacodynamic biomarker of @entity23902 inhibition.

@entity788 @entity4333 @entity522 @entity5 @entity73058 @entity23902 @entity136
PURPOSE: @entity23902 inhibitors, such as @entity73058 , are in clinical development in combination with cytotoxic agents for the treatment of solid @entity5 , including @entity788 . To maximize the likelihood of their clinical success, it is essential to optimize drug scheduling as well as pharmacodynamic biomarkers in preclinical models. EXPERIMENTAL DESIGN: We tested multiple schedules of administration of @entity136 and @entity73058 on the survival of @entity788 cells. Potential pharmacodynamic biomarkers including pChk1, pChk2, pHistone H3, and @entity522 were evaluated in vitro, followed by assessment of promising candidate biomarkers in vivo. We then went on to determine the contributions of @entity4333 and DNA damage to the mechanism(s) of induction of the identified biomarker, pS345 @entity23902 . RESULTS: @entity73058 given during and after or after @entity136 administration produced maximum chemosensitization. In vivo, @entity73058 significantly inhibited the growth of @entity788 xenografts in response to @entity136 . Of the biomarkers assessed, pS345 @entity23902 was most consistently increased in response to @entity136 and @entity73058 in @entity5 and normal tissues (hair follicles). pS345 @entity23902 induction in response to @entity136 and @entity73058 occurred in the presence of @entity4333 inhibition and in association with elevated yH2AX, suggesting that DNA damage is an underlying mechanism. CONCLUSIONS: @entity73058 sensitizes @entity788 to @entity136 in association with induction of pS345 @entity23902 . Together these data support the clinical investigation of @entity73058 with @entity136 in @entity788 under a dosing schedule in which @entity136 is administered concurrent with or before @entity73058 and in conjunction with skin biopsies to measure pS345 @entity23902 .
