Purpose: Antiproliferative and antiosteoclastic activity from preclinical models show potential for dasatinib, an oral SRC and SRC family kinase inhibitor, as a targeted therapy for patients with prostate cancer. This phase II study investigated the activity of dasatinib in patients with metastatic castration-resistant prostate cancer (CRPC). Experimental Design: Chemotherapy-naive men with CRPC and increasing prostate-specific antigen were treated with dasatinib 100 or 70 mg twice daily. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), and markers of bone metabolism. Following Prostate Cancer Working Group 2 guidelines, lack of progression according to Response Evaluation Criteria in Solid Tumor and bone scan was determined and reported at 12 and 24 weeks. Results: Forty-seven patients were enrolled and received dasatinib (initial dose 100 mg twice daily, n = 25; 70 mg twice daily, n = 22), of whom 41 (87%) had bone disease. Lack of progression was achieved in 20 (43%) patients at week 12 and in 9 (19%) patients at week 24. Of 41 evaluable patients, 21 (51%) patients achieved ≥40% reduction in urinary N-telopeptide by week 12, with 33 (80%) achieving some level of reduction anytime on study. Of 15 patients with elevated urinary N-telopeptide at baseline, 8 (53%) normalized on study. Of 40 evaluable patients, 24 (60%) had reduction in bone alkaline phosphatase at week 12 and 25 (63%) achieved some reduction on study. Dasatinib was generally well tolerated and treatment-related adverse events were moderate. Conclusions: This study provides encouraging evidence of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC. (Clin Cancer Res 2009;15(23):7421–8)

Interferon (IFN) treatment induces tyrosine phosphorylation and nuclear translocation of Stat1 (signal transducer and activator of transcription) to activate or repress transcription. We report here that a member of the protein inhibitor of activated STAT family, PIASy, is a transcriptional corepressor of Stat1. IFN treatment triggers the in vivo interaction of Stat1 with PIASy, which represses Stat1-mediated gene activation without blocking the DNA binding activity of Stat1. An LXXLL coregulator signature motif located near the NH ₂ terminus of PIASy, although not involved in the PIASy–Stat1 interaction, is required for the transrepression activity of PIASy. Our studies identify PIASy as a transcriptional corepressor of Stat1 and suggest that different PIAS proteins may repress STAT-mediated gene activation through distinct mechanisms.

We determined the accuracy of the novel Urostation 3-dimensional transrectal ultrasound system (Koelis, La Tranche, France) for image based mapping biopsies in a prostate phantom. The system is capable of 1) registering the 3-dimensional location of each biopsy track in the 3-dimensional prostate volume data and 2) performing elastic image fusion of transrectal ultrasound with magnetic resonance imaging. We used 3 CIRS-053 prostate phantoms containing 3 hypoechoic lesions to perform ultrasound guided biopsy and 3 CIRS-066 phantoms (Computerized Imaging Reference Systems, Norfolk, Virginia) containing 3 isoechoic but magnetic resonance imaging visible lesions to perform magnetic resonance fusion guided biopsy. Three targeted biopsies were done per lesion. Each biopsy tract was injected with gadolinium based magnetic resonance contrast mixed with india ink. Phantoms were then subjected to 1 mm slice magnetic resonance imaging and serial step sectioning to assess the accuracy of targeted biopsy. A total of 27 ultrasound guided biopsies were targeted into 9 hypoechoic lesions. All 27 biopsies (100%) successfully hit the target lesion. For hypoechoic lesions mean ± SD procedural targeting error was 1.52 ± 0.78 mm and system registration error was 0.83 mm, resulting in an overall error of 2.35 mm. Of the 27 magnetic resonance fusion biopsies 24 (84%) hit the lesion. For isoechoic lesions mean procedural targeting error was 2.09 ± 1.28 mm, resulting in an overall error of 2.92 mm. The novel, computer assisted, 3-dimensional transrectal ultrasound biopsy localization system achieved encouraging accuracy with less than 3 mm error for targeting hypoechoic and isoechoic lesions. The ability to register actual biopsy trajectory and perform elastic magnetic resonance/ultrasound image fusion is a significant advantage for future focal therapy application.

Timely characterization of a cancer's evolution is required to predict treatment efficacy and to detect resistance early. High content analysis of single Circulating Tumor Cells (CTCs) enables sequential characterization of genotypic, morphometric and protein expression alterations in real time over the course of cancer treatment. This concept was investigated in a patient with castrate-resistant prostate cancer progressing through both chemotherapy and targeted therapy. In this case study, we integrate across four timepoints 41 genome-wide copy number variation (CNV) profiles plus morphometric parameters and androgen receptor (AR) protein levels. Remarkably, little change was observed in response to standard chemotherapy, evidenced by the fact that a unique clone (A), exhibiting highly rearranged CNV profiles and AR+ phenotype was found circulating before and after treatment. However, clinical response and subsequent progression after targeted therapy was associated with the drastic depletion of clone A, followed by the sequential emergence of two distinct CTC sub-populations that differed in both AR genotype and expression phenotype. While AR- cells with flat or pseudo-diploid CNV profiles (clone B) were identified at the time of response, a new tumor lineage of AR+ cells (clone C) with CNV altered profiles was detected during relapse. We showed that clone C, despite phylogenetically related to clone A, possessed a unique set of somatic CNV alterations, including MYC amplification, an event linked to hormone escape. Interesting, we showed that both clones acquired AR gene amplification by deploying different evolutionary paths. Overall, these data demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the multi-scale analysis of fluid biopsies to quantify and monitor disease evolution in individual patients.