Table 4.

Functional categories most significantly overrepresented among genes whose changed expression level following treatment with ES-285 correlates with increasing dose

Blood samplesSkin biopsies
Functional categoryEASE scoreFunctional categoryEASE score
(A) All dose levelsCell proliferation0.00003Cell cycle0.001
Cell cycle0.0001Mitotic cell cycle0.003
G2-M transition of mitotic cell cycle0.005Cell proliferation0.009
Protein catabolism0.01Nuclear division0.02
S phase of mitotic cell cycle0.01Biological process unknown0.03
G1-S transition of mitotic cell cycle0.01M phase0.03
Antiapoptosis0.02Telomere maintenance0.04
Negative regulation of cell cycle0.02Coenzyme and prosthetic group metabolism0.04
Mitotic cell cycle0.02S phase of mitotic cell cycle0.04
DNA replication0.02Mitosis0.05
Regulation of CDK activity0.03Amino acid biosynthesis0.05
Ubiquitin cycle0.03M phase of mitotic cell cycle0.05
(B) 128 mg/m2 or higherCell proliferation0.02Actin filament0.01
Cell cycle0.04Amino acid metabolism0.02
Obsolete cellular component0.04Calmodulin binding0.02
Cytoplasm0.06Amino acid and derivative metabolism0.02
Cytoskeletal protein binding0.08Enzyme inhibitor activity0.03
Sulfotransferase activity0.08Actin cytoskeleton0.03
Transferase activity0.09Nitrogen compound metabolism0.03
Amine metabolism0.10Amine metabolism0.03
Obsolete molecular function0.10Cell adhesion0.03
Cell growth and/or maintenance0.11Phosphate transport0.04
Transferase activity0.12Collagen0.04
Protein phosphatase regulator activity0.13Cell adhesion molecule binding0.05
Phosphatase regulator activity0.13Cadherin binding0.05
Cytoskeleton0.13Enzyme regulator activity0.05
Cell organization and biogenesis0.14Structural molecule activity0.07
Physiologic process0.17Inorganic anion transport0.07
Regulation of cell cycle0.18Calcium ion binding0.07
Regulation of cell proliferation0.18Promyelocytic leukemia body0.07
Actin binding0.19Anion transport0.07

NOTE: (A) All dose levels. (B) 128 mg/m2 or higher. Functional categories are ranked by the degree of their overrepresentation based on a variant of the one-tailed Fisher exact probability (EASE score). Categories most highly overrepresented are at the top. A (top row): all dose levels. Correlation of change in gene expression with dose administered by ANOVA (P < 0.05). Full gene lists are shown in Supplementary Table S1.4 B (bottom row): 128 mg/m2 or higher. The list of all genes from blood samples was filtered to only include genes with <1.5-fold change in expression in all five lower dose levels (4–64 mg/m2) and >1.5-fold change in expression in at least two of three higher dose levels (128, 200, and 256 mg/m2). The list of all genes from skin biopsies was filtered to include genes with <1.5-fold change in expression in three of five lower dose levels and >1.5-fold change in expression in at least two of three higher dose levels. Full gene lists are shown in Supplementary Table S3.4

Abbreviation: CDK, cyclin-dependent kinase.