Pancreatic adenocarcinoma (PC) harbors frequent alterations in p16, resulting in cell cycle dysregulation. A phase I study of docetaxel and flavopiridol, a pan-cyclin-dependent kinase inhibitor, demonstrated encouraging clinical activity in PC. This phase II study was designed to further define the efficacy and toxicity of this regimen in patients with previously treated PC.
Patients with gemcitabine-refractory, metastatic PC were treated with docetaxel 35 mg/m(2) followed by flavopiridol 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Tumor measurements were performed every two cycles. A Simon two-stage design was used to evaluate the primary endpoint of response.
Ten patients were enrolled, and 9 were evaluable for response. No objective responses were observed; however, 3 patients (33%) achieved transient stable disease, with one of these patients achieving a 20% reduction in tumor size. Median survival was 4.2 months, with no patients alive at the time of analysis. Adverse events were significant, with 7 patients (78%) requiring >or=1 dose reduction for transaminitis (11%), grade 4 neutropenia (33%), grade 3 fatigue (44%), and grade 3 diarrhea (22%).
The combination of flavopiridol and docetaxel has minimal activity and significant toxicity in this patient population. These results reflect the challenges of treating patients with PC in a second-line setting where the risk/benefit equation is tightly balanced.
"Furthermore, a Phase I trial testing flavopiridol in combination with FOLFOX (a regime consisting of folinic acid, fluorouracil, and oxaliplatin) for advanced solid tumors demonstrated a complete response and three stable diseases for six patients with pancreatic cancer.37 However, a Phase II study in ten refractory metastatic pancreatic cancer patients demonstrated minimal activity and significant toxicity.38 Hence, it is an open question as to whether flavopiridol is simply not effective or it is only effective in a specific subpopulation as none of the patients in the aforementioned trials were genetically tested. "
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is the fourth biggest killer, and has one of the worst prognoses, of any cancer type. Approximately 95% of patients diagnosed with pancreatic cancer will not survive beyond 5 years post diagnosis, and these statistics have barely improved in over 40 years. Here, genomic changes in one particular patient with stage IV metastatic pancreatic cancer were explored to suggest a potential personalized treatment. In particular, exome sequencing of genomic DNA extracted from blood and the cancer biopsy was utilized with the aim of identifying mutational drivers of the cancer. This analysis revealed a splice site mutation in RBCK1 as the most promising driver of the cancer and a therapy based on a pan-cyclin-dependent kinase (pan-CDK) inhibitor, flavopiridol. This study suggests that drugs whose effectiveness is unclear for general populations of cancer sufferers should possibly be reconsidered for specific patients where the drug could be rationally argued to improve outcome.
OncoTargets and Therapy 05/2014; 7:655-62. DOI:10.2147/OTT.S45232 · 2.31 Impact Factor
"More than 20 small molecule inhibitors for CDKs are in clinical trials (for recent reviews see –). For example, Flavopiridol (Alvocidib) is in clinical development for the treatment of different metastatic cancers –. R-Roscovitine (Seliciclib, CYC202) inhibits CDK2, CDK7 and CDK9  and is also in clinical trials. To avoid side effects, high selectivity is desirable, though difficult to achieve as the ATP binding site of the human kinome is well conserved , . "
[Show abstract][Hide abstract] ABSTRACT: Cyclin-dependent kinases (CDKs) play a key role in the cell cycle and are important anti-cancer drug targets. The natural product fascaplysin inhibits CDK4 with surprising selectivity (IC(50) = 0.4 µM) compared to the close homolog CDK2 (IC(50) = 500 µM). Free energy calculations of the positively charged fascaplysin and an uncharged iso-electronic derivative in the CDK2 and CDK4 inhibitor complexes indicate that the positive charge of fascaplysin is crucial for selectivity. This finding will guide further improvements in the design of fascaplysin-based selective inhibitors for CDK4.
PLoS ONE 08/2012; 7(8):e42612. DOI:10.1371/journal.pone.0042612 · 3.23 Impact Factor
"Inhibition of CDK9 resulting in the removal of neutrophils from sites of inflammation could represent a rational and novel therapeutic approach to the treatment of chronic inflammatory disease. Flavopiridol (Alvocidib) in clinical trial as a treatment for cancers including pancreatic cancer  multiple myeloma  and recently Sekine et al  showed that flavopiridol was effective at reducing joint inflammation in the collagen-induced arthritis model, but did not discover the cellular target. These authors assumed that the effect was likely to be mediated by inhibition of lymphocyte proliferation or function and when this was shown not to be the cases they did not look at other cells. "
[Show abstract][Hide abstract] ABSTRACT: Neutrophils are the most abundant leukocyte and play a central role in the immune defense against rapidly dividing bacteria. However, they are also the shortest lived cell in the blood with a lifespan in the circulation of 5.4 days. The mechanisms underlying their short lifespan and spontaneous entry into apoptosis are poorly understood. Recently, the broad range cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to increase neutrophil apoptosis, implicating CDKs in the regulation of neutrophil lifespan. To determine which CDKs were involved in regulating neutrophil lifespan we first examined CDK expression in human neutrophils and found that only three CDKs: CDK5, CDK7 and CDK9 were expressed in these cells. The use of CDK inhibitors with differing selectivity towards the various CDKs suggested that CDK9 activity regulates neutrophil lifespan. Furthermore CDK9 activity and the expression of its activating partner cyclin T1 both declined as neutrophils aged and entered apoptosis spontaneously. CDK9 is a component of the P-TEFb complex involved in transcriptional regulation and its inhibition will preferentially affect proteins with short half-lives. Treatment of neutrophils with flavopiridol, a potent CDK9 inhibitor, increased apoptosis and caused a rapid decline in the level of the anti-apoptotic protein Mcl-1, whilst Bcl2A was unaffected. We propose that CDK9 activity is a key regulator of neutrophil lifespan, preventing apoptosis by maintaining levels of short lived anti-apoptotic proteins such as Mcl-1. Furthermore, as inappropriate inhibition of neutrophil apoptosis contributes to chronic inflammatory diseases such as Rheumatoid Arthritis, CDK9 represents a novel therapeutic target in such diseases.
PLoS ONE 01/2012; 7(1):e30128. DOI:10.1371/journal.pone.0030128 · 3.23 Impact Factor
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