title: Phase I assessment of new mechanism-based pharmacodynamic biomarkers for MLN8054, a small-molecule inhibitor of Aurora A kinase.
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.
authors.affiliation: Millennium Pharmaceuticals Inc., Cambridge, Massachusetts 02139, USA.
authors.forename: Arijit
authors.initials: A
authors.lastname: Chakravarty
authors.forename: Vaishali
authors.initials: V
authors.lastname: Shinde
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Andres
authors.initials: A
authors.lastname: Cervantes
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.forename: Elena
authors.initials: E
authors.lastname: Elez
authors.forename: Jordi
authors.initials: J
authors.lastname: Andreu
authors.forename: Edith
authors.initials: E
authors.lastname: Rodriguez-Braun
authors.forename: Susana
authors.initials: S
authors.lastname: Rosello
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.forename: Bert
authors.initials: B
authors.lastname: ONeil
authors.forename: Douglas
authors.initials: D
authors.lastname: Bowman
authors.forename: Mengkun
authors.initials: M
authors.lastname: Zhang
authors.forename: Hadi
authors.initials: H
authors.lastname: Danaee
authors.forename: Laura
authors.initials: L
authors.lastname: Faron-Yowe
authors.forename: Gary
authors.initials: G
authors.lastname: Gray
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Jodi
authors.initials: J
authors.lastname: Pappas
authors.forename: Lee
authors.initials: L
authors.lastname: Silverman
authors.forename: Chris
authors.initials: C
authors.lastname: Simpson
authors.forename: Bradley
authors.initials: B
authors.lastname: Stringer
authors.forename: Stephen
authors.initials: S
authors.lastname: Tirrell
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Veiby
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: Katherine
authors.initials: K
authors.lastname: Galvin
authors.forename: Mark
authors.initials: M
authors.lastname: Manfredi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ecsedy
mesh_terms: D064127:Aurora Kinases; D001552:Benzazepines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism*; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D001552:Benzazepines; D014408:Biomarkers, Tumor; C518940:MLN8054; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases