Development of cell-cycle checkpoint therapy for solid tumors.
Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available. For instance, palbociclib (PD0332991) is a first-in-class, oral, highly selective inhibitor of CDK4/6 and, in combination with letrozole (Phase II; PALOMA-1) or with fulvestrant (Phase III; PALOMA-3), it has significantly prolonged progression-free survival, in patients with metastatic estrogen receptor-positive, HER2-negative breast cancer, in comparison with that observed in patients using letrozole, or fulvestrant alone, respectively. In this review, we provide an overview of the current compounds available for cell-cycle checkpoint protein-directed therapy for solid tumors.
Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan ketamura@ncc.go.jp.
Kenji
K
Tamura
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D018572:Disease-Free Survival; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D065171:Estrogen Receptor Antagonists / Q000008:administration & dosage; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D000077289:Letrozole; D058990:Molecular Targeted Therapy / Q000379:methods* / Q000639:trends; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D014230:Triazoles / Q000008:administration & dosage
D047072:Aromatase Inhibitors; D064096:Aurora Kinase A; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases; D004958:Estradiol; D065171:Estrogen Receptor Antagonists; D000077267:Fulvestrant; D000077289:Letrozole; D009570:Nitriles; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D014230:Triazoles; C508053:ERBB2 protein, human; C499349:WEE1 protein, human; C576917:AURKA protein, human
CDK4/6 inhibitor; aurora kinase; cell-cycle check-point; cyclin-dependent kinase; palbociclib; polo-like kinase