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Proffered Abstract (Plenary Session): Predictive Determinants of Tumor Response to Cytotoxic Therapies

Circulating endothelial cells as a therapeutic marker for docetaxel treatment and combination therapy of docetaxel and thalidomide in a human prostate cancer model

NCI, Bethesda, MD, European Institute of Oncology, Milan, Italy, European Institue of Oncology, Milan, Italy

Abstract

PR-10

The field of anti-angiogenic therapy has developed rapidly in last decade and the pace has been accelerated when the FDA approved bevacizumab in 2004, the first selective anti-angiogenesis therapy approved for treatment of human cancer. Because anti-angiogenic agents do not target tumor cells directly, the efficacy of these drugs often are difficult to be detected by the traditional therapeutic endpoints utilized for cytotoxic regimens. Hence, a good therapeutic biomarker for anti-angiognic drugs is urgently needed.Circulating endothelial cells (CEC) has been tested for this purpose and has shown good promise. An increased level of circulating endothelial cells were found in patients with a wide range of cancers, compared to healthy controls. However, there are conflicted publications about the effects of drug treatment on CEC levels. Some drugs have been shown to decrease CEC levels in patients with cancer, while other anti-angiogenic drugs have increased CEC levels. Furthermore, it has become clear that a combination regimen of an anti-angiogenic agents and chemotherapies will be needed to treat patients with cancer. While chemotherapy itself has been shown to affect CEC levels in patients, it is still unclear whether CEC serve a good therapeutic marker to detect the efficacy of an anti-angiogenic drug when it is used in combination with chemotherapy drugs.We tested CEC as a therapeutic marker in a human prostate cancer model. We treated PC3 xenograft tumors with either docetaxel alone or docetaxel/thalidomide combination therapy and tested the CEC levels at the different time points before or during treatments. The results showed that shortly after the treatment, docetaxel dramatically increased dead CEC level to 2.6 fold and the combination of docetaxel and thalidomide further augmented it to 4.3 fold, suggesting that anti-angiogenic drugs may enhance the cytotoxicity of chemotherapy drugs against vascular endothelial cells. At a later time point, Thalidomide reduced viable CEC level by 18% while docetaxel decreased it by 61%. The combination treatment further diminished the viable CEC level by 75%, indicating that anti-angiogenic drugs may inhibit the proliferation and differentiation of bone marrow derived endothelial progenitor cells.