Phase I Assessment of New Mechanism-Based Pharmacodynamic Biomarkers for MLN8054, a Small-Molecule Inhibitor of Aurora A Kinase

被引：43

作者：

Chakravarty, Arijit ^{[1
]}

Shinde, Vaishali ^{[1
]}

Tabernero, Josep ^{[2
]}

Cervantes, Andres ^{[3
]}

Cohen, Roger B. ^{[4
]}

Dees, E. Claire ^{[5
]}

Burris, Howard ^{[6
]}

Infante, Jeffrey R. ^{[6
]}

Macarulla, Teresa ^{[2
]}

Elez, Elena ^{[2
]}

Andreu, Jordi ^{[2
]}

Rodriguez-Braun, Edith ^{[3
]}

Rosello, Susana ^{[3
]}

von Mehren, Margaret ^{[4
]}

Meropol, Neal J. ^{[4
]}

Langer, Corey J. ^{[4
]}

ONeil, Bert ^{[5
]}

Bowman, Douglas ^{[1
]}

Zhang, Mengkun ^{[1
]}

Danaee, Hadi ^{[1
]}

Faron-Yowe, Laura ^{[1
]}

Gray, Gary ^{[1
]}

Liu, Hua ^{[1
]}

Pappas, Jodi ^{[1
]}

Silverman, Lee ^{[1
]}

Simpson, Chris ^{[1
]}

Stringer, Bradley ^{[1
]}

Tirrell, Stephen ^{[1
]}

Veiby, Ole Petter ^{[1
]}

Venkatakrishnan, Karthik ^{[1
]}

Galvin, Katherine ^{[1
]}

Manfredi, Mark ^{[1
]}

Ecsedy, Jeffrey A. ^{[1
]}

机构：

[1] Millennium Pharmaceut Inc, Cambridge, MA 02139 USA

[2] Vall dHebron Univ Hosp, Barcelona, Spain

[3] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA

[4] Univ Valencia, Hosp Clin, Valencia, Spain

[5] UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA

[6] Sarah Cannon Res Inst, Nashville, TN USA

来源：

CANCER RESEARCH | 2011年 / 71卷 / 03期

关键词：

ADVANCED GASTRIC-CARCINOMA; MITOTIC ARREST; ANTIMITOTIC DRUGS; CANCER-PATIENTS; BREAST-CANCER; CELL-DIVISION; A KINASE; CHEMOTHERAPY; PACLITAXEL; APOPTOSIS;

D O I：

10.1158/0008-5472.CAN-10-1030

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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. Cancer Res; 71(3); 675-85. (C)2010 AACR.

引用

页码：675 / 685

页数：11

共 30 条

[1]

Albanell J, 2002, J CLIN ONCOL, V20, P110, DOI 10.1200/JCO.20.1.110

[2]

The Aurora/Ipi1p kinase family: regulators of chromosome segregation and cytokinesis [J].

Bischoff, JR ;

Plowman, GD .

TRENDS IN CELL BIOLOGY, 1999, 9 (11) :454-459

[3]

The cellular geography of aurora kinases [J].

Carmena, M ;

Earnshaw, WC .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (11) :842-854

[4]

Cheung CHA, 2009, EXPERT OPIN INV DRUG, V18, P379, DOI [10.1517/13543780902806392 , 10.1517/13543780902806392]

[5]

Dees EC, 2010, CANC CHEMOTHER 0707

[6]

Weekly administration of docetaxel and paclitaxel in metastatic or advanced breast cancer [J].

Eniu, A ;

Palmieri, FM ;

Perez, EA .

ONCOLOGIST, 2005, 10 (09) :665-685

[7]

Small Molecule Aurora Kinases Inhibitors [J].

Garuti, Laura ;

Roberti, Marinella ;

Bottegoni, Giovanni .

CURRENT MEDICINAL CHEMISTRY, 2009, 16 (16) :1949-1963

[8]

Cancer cells display intra- and interline variation profound following prolonged exposure to antimitotic drugs [J].

Gascoigne, Karen E. ;

Taylor, Stephen S. .

CANCER CELL, 2008, 14 (02) :111-122

[9]

Giet R, 1999, J CELL SCI, V112, P3591

[10]

MUTATIONS IN AURORA PREVENT CENTROSOME SEPARATION LEADING TO THE FORMATION OF MONOPOLAR SPINDLES [J].

GLOVER, DM ;

LEIBOWITZ, MH ;

MCLEAN, DA ;

PARRY, H .

CELL, 1995, 81 (01) :95-105

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