During cancer progression malignant cells undergo epithelial-mesenchymal transitions (EMTs) and mesenchymal-epithelial transitions (METs) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTCs) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer (BC). We show that the majority (>80%) of these CTCs in patients with metastatic CRPC co-express epithelial proteins such as EpCAM, CK, and E-cadherin, mesenchymal proteins, including vimentin, N-cadherin, and O-cadherin, and the stem cell marker CD133. Equally, we find that over 75% of CTCs from women with metastatic BC co-express cytokeratin, vimentin, and N-cadherin. The existence and high frequency of these CTCs co-expressing epithelial, mesenchymal, and stem-cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

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Purpose: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer. Experimental Design: Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m 2 every 21days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity. Results:Thirty-one patients were enrolled over three docetaxel dose levels (8 at . Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95 % CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy. Conclusions:The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m 2 . Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.Despite recent favorable declines in prostate cancer mortality, prostate cancer in 2008 remains a common cause of cancer death worldwide (1). Docetaxel and prednisone was U.S. Food and Drug Administration approved in 2004 for the palliative management of men with castration-resistant metastatic prostate cancer, based on improved survival, pain, and qualityof-life responses and tolerability compared with mitoxantrone and prednisone (2). As a result of this clinical activity in men with metastatic castration-resistant prostate cancer, docetaxel has become the standard by which experimental therapeutics are being compared against or added to, with the intent of improving on both quantity and quality of life for men with advanced prostate cancer.Prostate cancer commonly metastasizes to bone, using a number of homing receptors and signaling molecules to interact, adapt to, and grow in this microenvironment (3). One such paracrine and autocrine signaling molecule that plays an important role in metastatic prostate cancer progression is endothelin (4 -6). Endothelin-1 levels are increased in advanced prostate cancer and endothelin-1 acts as a mitogen for osteoblasts and prostate cancer cells through its interaction with the endothelin-A receptor (4). In addition to its proangiogenic and vasoconstricting activities important in the maintenance of vasomotor tone, endothelin additionall...

In men with mCRPC, percutaneous sampling of osseous metastases for genomic profiling is possible, but use of zoledronic acid for more than 1 year may reduce the yield of adequate tissue for RNA isolation. Sampling large low-attenuating lesions at their periphery maximizes yield.