PD0332991, a cdk4/6 inhibitor, induces tumor regression and extends survival in Atypical Teratoid Rhabdoid Tumor (ATRT) and Medulloblastoma mouse models.
Michelle Cook Sangar, Kyle Pedro, Sally H. Ditzler, Emily Girard, James Olson
Fred Hutchinson Cancer Research Center, Seattle, WA, USA
The cyclin dependent kinases 4 and 6 (cdk4/6)-cyclin D-INK4-retinoblastoma protein signaling pathway is frequently deregulated in cancer and has potential to be an important target in treatment of atypical teratoid rhabdoid tumors (ATRTs) and medulloblastomas. The vast majority of ATRTs have biallelic inactivating mutations in SMARCB1, which causes cell cycle progression by downregulation of p16INK4A and upregulation of cyclin D and E2Fs. Likewise, cyclin D expression is increased in most medulloblastomas and is a poor prognostic indicator. Since these pathway aberrations lead to increased activity of cdk4/6, we assessed efficacy of a cdk4/6 inhibitor in ATRT and medulloblastoma mouse models.
The efficacy of PD0332991, a specific inhibitor of cdk4/6, was investigated using patient-derived xenotransplant (PDX) mouse models of ATRT and medulloblastoma, generated using freshly resected tumor tissue from pediatric patients at Seattle Children’s Hospital or Children’s Oncology Group (COG) sites.
PD0332991 (150 mg/kg or 75 mg/kg) was administered daily by oral gavage. Efficacy was assessed by measuring the difference in tumor size (subcutaneous xenografts) or survival (orthotopic xenografts) in drug-treated as compared to vehicle-treated mice. Pharmacodynamic analyses involved investigation of the phosphorylation state of Rb protein and the extent of Ki67 positive staining using western blot analysis and immunohistochemistry.
PD0332991 treatment caused significant regression of subcutaneous ATRT and medulloblastoma tumors as compared to vehicle treatment. Rb phosphorylation at Ser780 was significantly reduced in drug-treated tumors. Likewise, Ki67, a marker of cell proliferation, was significantly reduced following drug treatment.
In each of 3 survival studies using orthotopic medulloblastoma models, all vehicle-treated mice (n=12-13) died, while all drug-treated mice (n=11-13) survived for the study duration (10-28 days). In the ATRT orthotopic mouse model, 13/17 drug-treated mice were alive at the end of the study (45 days) as compared to 1/17 vehicle-treated mice. There was no apparent toxicity associated with drug treatment.
Inhibition of cdk4/6 is a promising therapeutic strategy for both ATRTs and medulloblastomas. Treatment with PD0332991 resulted in significant tumor regression in subcutaneous tumor models and a highly significant survival advantage in orthotopic models. Pharmacodynamic analyses indicate that PD0332991 is engaging with cdk4/6 to inhibit phosphorylation of Rb at Ser780 and decrease proliferation in the tumors. Interestingly, while inhibition of cdk4/6 would be expected to have a cytostatic effect, several lines of evidence point towards a cytoreductive effect in vivo. The results of this study strongly support use of PD0332991 in a clinical trial for pediatric ATRT and medulloblastoma patients.