Journal
CLINICAL CANCER RESEARCH
Volume 21, Issue 3, Pages 602-610Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-0870
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Funding
- NIH [CA177909, P50CA083639, CA109298, P50CA098258, U54CA151668, UH2TR000943, CA016672, U54CA96300, U54CA96297]
- CPRIT [RP110595, RP120214]
- Ovarian Cancer Research Fund Program Project Development Grant
- Department of Defense grants [OC120547, OC093416]
- Betty Ann Asche Murray Distinguished Professorship
- RGK Foundation
- Gilder Foundation
- Judi A. Rees Ovarian Cancer Research Fund
- Chapman Foundation
- Meyer and Ida Gordon Foundation
- Blanton-Davis Ovarian Cancer Research Program
- Deutsche Forschungsgemeinschaft (DFG)
- Cancer Center Support Grant-funded Characterized Cell Line core, NCI [CA016672]
- NIH T32 training grant [CA101642]
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Purpose: We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy. Experimental Design: The medical records of patients with recurrent or progressive ovarian cancer were retrospectively queried for changes in platelet and CA-125 levels during primary therapy. In vitro coculture experiments and in vivo orthotopic models of human ovarian cancer in mice were used to test the effect of modulating platelet levels on tumor growth and responsiveness to docetaxel. Results: Thrombocytosis at the diagnosis of ovarian cancer was correlated with decreased interval to progression (P = 0.05) and median overall survival (P = 0.007). Mean platelet levels corrected during primary therapy and rose at recurrence. Contrary to treatment-responsive patients, in a cohort of patients refractory to primary therapy, platelet levels did not normalize during therapy. In A2780, HeyA8, and SKOV3-ip1 ovarian cancer cell lines, platelet coculture protected against apoptosis (P < 0.05). In orthotopic models of human ovarian cancer, platelet depletion resulted in 70% reduced mean tumor weight (P < 0.05). Compared with mice treated with docetaxel, mice treated with both docetaxel and platelet-depleting antibody had a 62% decrease in mean tumor weight (P = 0.04). Platelet transfusion increased mean aggregate tumor weight 2.4-fold (P < 0.05), blocked the effect of docetaxel on tumor growth (P = 0.55) and decreased tumor cell apoptosis. Pretransfusion aspirinization of the platelets blocked the growth-promoting effects of transfusion. Conclusions: Platelet-driven effects of chemotherapy response may explain clinical observations. (C) 2014 AACR.
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