The collection of tissue samples was approved and supervised by the Re search Ethics

In preclinical studies, IHC staining of mouse skin biopsies looking at Rb phosphoryl ation at serine 807 and serine 811 demonstrated strong pretreatment Rb phosphorylation followed by a time dependent loss of Rb phosphorylation, with a partial loss at 2 hours post treatment selleck chemicals阻害剤 and complete loss of Rb phosphorylation at 4 hours post treatment, The lack of inhibition of phospho Rb observed in our trial may be due to the timing of the posttreatment skin biopsy, as the nonclinical data from mice clearly showed a time dependent effect. Skin biopsies were obtained 4 hours post treatment, on the basis of mouse data, and this may not be the optimal time point in patients. Our trial enrolled subjects with a variety of solid tumors who were heavily pretreated, as is typical in a phase 1 study population.<br><br> Early PET CT scan analysis, as a bio marker for SD, did not show any correlation between tumor metabolic changes and treatment with dinaciclib. Analysis of tumor response using RECIST buy Lenalidomide criteria also showed no objective responses among the subjects in this study. However, at least 10 subjects achieved prolonged SD for at least 4 cycles of treatment, with one subject demonstrating prolonged SD while re ceiving treatment for 12 cycles. Therefore, treatment with dinaciclib may have the ability to delay disease progression in this and other studies, may be affected by dosing schedules and or drug exposure. The pan CDK inhibi tor flavopiridol was originally studied in 3 phase 1 trials using 2 different schedules.<br><br> No objective responses were observed in a trial of 55 patients using a 1 hour daily infu sion for 5 days, 3 days, or 1 day in a 21 day cycle, However, two trials evaluated flavopiridol with a 72 hour continuous infusion given every 2 weeks, and this sched ule resulted LY2228820 ic50 in one PR in a patient with renal cancer in a study of 76 patients, and one CR in a patient with gastric cancer in a trial of 38 patients, The CDK1, CDK2, and CDK4 inhibitor PHA793887 did not show any object ive responses in a first in human study in solid tumor patients, whereas one PR was observed with the CDK1, CDK2, CDK4, CDK5, and CDK9 inhibitor AT7519 in a patient with metastatic NSCLC, Orally bioavailable CDK inhibitors include the CDK1 and CDK2 inhibitor AZD5438, the CDK1, CDK2, CDK7, and CDK9 inhibi tor seliciclib, and the CDK4 and CDK6 inhibitor PD0332991.<br><br> Phase 1 trials of these agents report one PR in a patient with testicular cancer among 33 patients treated with PD0332991, and one PR in a patient with hepatocellular carcinoma among 56 patients treated with seliciclib, No responses were observed in 3 phase 1 trials of AZD5438 or in a separate trial of seliciclib, The identification of biomarkers may help to stratify patients into specific in some subjects with solid tumors. However, given the small sample size of 48 treated subjects, no clear correl ation was observed between day 1 day 15 ex vivo lympho cyte proliferation inhibition and day 22 PET CT analysis SUVmax, or between day 22 PET CT response and the duration of SD. The lack of a correlation could be due to the great heterogeneity among subjects baseline characteristics in terms of tumor types, disease stage, and the number of prior chemotherapy regimens.