Cyclin-dependent kinases as therapeutic targets: Examination of palbociclib (PD 0332991) and flavopiridol in human tumor primary culture microspheroids.
Author(s): Robert Alan Nagourney, Eknath A. Deo, Nilesh L. Vora, Milan Rohit Sheth, Paula J Bernard, Federico R Francisco, Steven S Evans; Rational Therapeutics, Long Beach, CA; Malcolm Todd Cancer Institute, Long Beach, CA; Todd Cancer Institiute, Long Beach, CA; UC Irvine Medical Center, Long Beach, CA
Abstract:
Background:
The cyclin dependent kinases (CDK) are a family of enzymes that mediate cell cycle progression. CDK dysregulation is a common event in human carcinogenesis, making CDK inhibition an attractive target for therapy. Palbociclib (PD) is a selective CDK 4/6 inhibitor, while flavopiridol (FL) is non-specific. CDK inhibitors are now in clinical trials.
Methods:
To examine the activity and compare the profiles of PD & FL, we used Ex Vivo Analyses of Programmed Cell Death (EVA/PCD) in human tumor primary cultures isolated from surgical specimens. After disaggregation, microspheroids, isolated by precise density centrifugation were exposed to PD or FL for 72 hours and drug induced cell death then measured by delayed-loss-of-membrane integrity and/or ATP content (luciferase).Dose response curves were interpolated to LC50 values. Twenty nine PD, 68 FL and 20-both specimens were studied.
Results:
PD & FL reveal activity in a broad array of tumors including upper GI, NSCLC, Breast, Ovary & Hematologic. No activity was observed for FL or PD in Head & Neck. Similar profiles were observed except in prostate where FL was more active than PD. Correlations by Pearson Moment revealed an R = 0.58 P<0.01 (2-tailed T).
Conclusions:
Findings confirm activity for the CDK inhibitors and suggest disease specific profiles. With culture conditions established, further analyses are now comparing PD with other classes of drugs, to examine combinations, synergy & sequence dependence, as will be reported. Supported in part by the Vanguard Cancer Foundation and the Memorial Medical Center Foundation.
Citation: J Clin Oncol 32, 2014 (suppl; abstr e13504)
http://abstracts.asco.org/144/AbstView_144_129973.html