Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 3

Implementing Mechanism-Relevant Biomarkers for Assessing Upstream and Downstream Responses to Aurora A Inhibition

Mark Manfredi, Ph.D.
Millennium Pharmaceuticals Inc.

Aurora A kinase localizes and functions at centrosomes and is essential for cells to progress normally through mitosis. The Aurora A gene is frequently amplified and protein overexpressed in human cancers of diverse origin. Using MLN8054, a selective Aurora A kinase small molecule inhibitor, we characterized the early and late events following Aurora A inhibition in cultured tumor cells. This work was critical in identifying mechanistic biomarkers to be used preclincally and clinically. In cells, MLN8054 inhibits Aurora A autophosphorylation on threonine 288 and Aurora A-mediated phosphorylation and localization of TACC3 to the mitotic spindles. MLN8054 treatment results in mitotic spindle defects followed by a delay in prometaphase, which can be detected using markers of mitosis. Following prolonged treatment, cells undergo apoptosis and other terminal outcomes. We have evaluated these diverse markers in xenograft tumor tissue sections using automated immunofluorescent microscopy. Using oral dosing and osmotic minipumps we establish the PK/PD/Efficacy relationship in order to guide clinical development of MLN8054. These markers and techniques are currently being used in skin and tumor biopsies from MLN8054 phase I studies.

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