Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma.
Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.
Raje
N
N
Division of Hematologic Malignancies, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA. nraje@partners.org
Hideshima
T
T
Mukherjee
S
S
Raab
M
M
Vallet
S
S
Chhetri
S
S
Cirstea
D
D
Pozzi
S
S
Mitsiades
C
C
Rooney
M
M
Kiziltepe
T
T
Podar
K
K
Okawa
Y
Y
Ikeda
H
H
Carrasco
R
R
Richardson
P G
PG
Chauhan
D
D
Munshi
N C
NC
Sharma
S
S
Parikh
H
H
Chabner
B
B
Scadden
D
D
Anderson
K C
KC
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000037:antagonists & inhibitors; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D047309:Flavones / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D011719:Pyrazines / Q000627:therapeutic use; D016160:Retinoblastoma Protein / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001897:Boronic Acids; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D047309:Flavones; D015850:Interleukin-6; C520467:P276-00; D011719:Pyrazines; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D000069286:Bortezomib; D020169:Caspases