Abstract
The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure-effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues.
Highlights
The mitotic spindle is a validated anticancer target, against which many small-molecule inhibitors have been tested
In addition to measuring mitotic and apoptotic cell accumulation in patient skin and tumor biopsies, the pharmacodynamic marker panel included mitotic cell chromosome alignment and spindle bipolarity. The incorporation of these latter markers was critical, as the degree of chromosome alignment and spindle bipolarity decreases with Aurora A inhibition regardless of whether a cell undergoes prolonged mitotic arrest or a transient mitotic delay followed by mitotic slippage
Clinical trial design Two concurrent phase I trials were performed in patients with advanced solid tumors to evaluate the dose-limiting toxicities and maximum tolerated dose of MLN8054 administered orally for 7 to 21 consecutive days; clinical findings are described in detail elsewhere [24, 25]
Summary
The mitotic spindle is a validated anticancer target, against which many small-molecule inhibitors have been tested. In addition to measuring mitotic and apoptotic cell accumulation in patient skin and tumor biopsies, the pharmacodynamic marker panel included mitotic cell chromosome alignment and spindle bipolarity The incorporation of these latter markers was critical, as the degree of chromosome alignment and spindle bipolarity decreases with Aurora A inhibition regardless of whether a cell undergoes prolonged mitotic arrest or a transient mitotic delay followed by mitotic slippage. The goals of this phase I pharmacodynamic study were 2-fold, (i) to gain an understanding of the behavior of a new pharmacodynamic marker panel in a first-in-human clinical setting and (ii) to evaluate modulation of the Aurora A pathway in patient skin and tumor tissues with MLN8054 administration
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