Mitchell E. Gross

Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone.

This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second‐line chemotherapy for taxane‐refractory, hormone‐refractory, prostate cancer (HRPC).

Phase II Study of Dasatinib in Patients with Metastatic Castration-Resistant Prostate Cancer

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)

Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years.

BACKGROUND Evolution of cryotherapy for prostate cancer is likely to result in parenchyma-sparing modifications adjacent to the urethra and neurovascular bundle. Results of initial series of focal therapy to minimize cryosurgery-related morbidity without compromising oncologic control have been encouraging, but limited in short-term outcomes. OBJECTIVE To retrospectively report (1) median 3.7-yr follow-up experience of primary focal cryotherapy for clinically unilateral prostate cancer with oncologic and functional outcomes, and (2) matched-pair analysis with contemporaneous patients undergoing radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS Over 8.5 yr (September 2002 to March 2011), focal cryoablation (defined as ablation of one lobe) was performed in 73 carefully selected patients with biopsy-proven, clinically unilateral, low-intermediate risk prostate cancer. All patients underwent transrectal ultrasound (TRUS) and Doppler-guided sextant and targeted biopsies at entry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Post-therapy follow-up included measuring prostate-specific antigen (PSA) level every 3-6 mo; TRUS biopsies at 6-12 mo and yearly, as indicated; and validated symptom questionnaires. Matched-pair analysis compared oncologic outcomes of focal cryotherapy and RP (matched for age, PSA, clinical stage, and biopsy Gleason score). RESULTS AND LIMITATIONS Complete follow-up was available in 70 patients (median follow-up: 3.7 yr; range: 1-8.5 yr). No patient died or developed metastases. Precryotherapy mean PSA was 5.9 ng/ml and Gleason score was 6 (n=30) or 7 (n=43). Postcryotherapy mean PSA was 1.6 ng/ml (70% reduction compared to precryotherapy; p<0.001). Of 48 patients undergoing postcryotherapy biopsy, 36 (75%) had negative biopsies; positive biopsy for cancer (n=12) occurred in the untreated contralateral (n=11) or treated ipsilateral lobe (n=1). Complete continence (no pads) and potency sufficient for intercourse were documented in 100% and 86% of patients, respectively. Matched-pair comparison of focal cryotherapy and RP revealed similar oncologic outcome, defined as needing salvage treatment. CONCLUSIONS Primary focal cryoablation for low-intermediate risk unilateral cancer affords encouraging oncologic and functional outcomes over a median 3.7-yr follow-up. Close surveillance with follow-up whole-gland biopsies is mandatory.

Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients Presented in part at the American Society of Clinical Oncology Multidisciplinary Prostate Cancer Symposium, February 17–19, 2005, Orlando, Florida; and the American Society of Clinical Oncology Multidisciplinary Prostate Cancer Symposium, February 24–26, 2006.

This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second‐line chemotherapy for taxane‐refractory, hormone‐refractory, prostate cancer (HRPC).

3-Dimensional Elastic Registration System of Prostate Biopsy Location by Real-Time 3-Dimensional Transrectal Ultrasound Guidance With Magnetic Resonance/Transrectal Ultrasound Image Fusion

PURPOSE 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

Detection of Androgen Receptor Mutations in Circulating Tumor Cells in Castration-Resistant Prostate Cancer

BACKGROUND Coding mutations in the AR (androgen receptor) gene have been identified in tissue samples from patients with advanced prostate cancer and represent a possible mechanism underlying the development of castration-resistant prostate cancer (CRPC). There is a paucity of tumor-derived tissue available for molecular studies of CRPC patients. Circulating tumor cells (CTCs) in the blood of CRPC patients represent a possible avenue for interrogating the disease of such patients. METHODS Circulating tumor cells were captured with the CellSearch Circulating Tumor Cell (CTC) Kit and with the CellSearch Profile Kit plus Qiagens AllPrep DNA/RNA Micro Kit for the measurement of the CTC count per 7.5 mL of blood and for the isolation of nucleic acids, respectively. The AR gene was amplified by the PCR, and mutation status and relative abundance were analyzed by applying Transgenomics WAVE denaturing HPLC technology followed by direct sequencing. RESULTS AR mutations were detected in 20 of 35 CRPC patients; 19 missense mutations, 2 silent mutations, 5 deletions, and 1 insertion were observed. The relative abundance of the mutants in the amplified products ranged from 5% to 50%. Many of the AR mutations were identified in surgical biopsies or at autopsy and were associated with resistance to androgen-directed therapies. CONCLUSIONS AR mutations can be identified in CTC-enriched peripheral blood samples from CRPC patients. This approach has the potential to open new perspectives in understanding CTCs and the mechanisms for tumor progression and metastasis in CRPC.

PIASy-mediated repression of the androgen receptor is independent of sumoylation

PIASy, a member of the protein inhibitor of activated STAT (PIAS) family, represses the transcriptional activity of the androgen receptor (AR). In this report, we investigate the mechanism of PIASy-mediated repression of AR. We show that AR binds to the RING-finger like domain of PIASy. PIASy contains two transcriptional repression domains, RD1 and RD2. RD1, but not RD2, is required for PIASy-mediated repression of AR. We show that the RD1 domain binds HDAC1 and HDAC2 and that HDAC activity is required for PIASy-mediated AR repression. PIAS proteins possess small ubiquitin-related modifier (SUMO) E3 ligase activity. Conjugation of SUMO-1 to AR has been implicated in the regulation of AR activity. We examine if the SUMO ligase activity of PIASy is required for PIASy to repress AR. We show that a mutant PIASy, defective in promoting sumoylation, retains the ability to repress AR transcription. In addition, mutation of all the known sumoylation acceptor sites of AR does not affect the transrepression activity of PIASy on AR. Our results suggest that PIASy may repress AR by recruiting histone deacetylases, independent of its SUMO ligase activity.

Once-daily dasatinib: expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer.

OBJECTIVES To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC. METHODS Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase). RESULTS The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia. CONCLUSIONS Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC.

Rapid Phenotypic and Genomic Change in Response to Therapeutic Pressure in Prostate Cancer Inferred by High Content Analysis of Single Circulating Tumor Cells

Timely characterization of a cancers 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.

Prospective evaluation of 18F-NaF and 18F-FDG PET/CT in detection of occult metastatic disease in biochemical recurrence of prostate cancer.

Purpose This study aimed to perform a prospective evaluation of 18F-NaF and 18F-FDG PET/CT in the detection of occult metastatic disease in men with prostate cancer and biochemical relapse. Methods Thirty-seven men with prostate-specific antigen (PSA) relapse (median, 3.2 ng/mL; range, 0.5–40.2 ng/mL) after definitive therapy for localized prostate cancer [26 radical prostatectomy (RP), 11 external beam radiation therapy] and negative conventional imaging underwent 18F-FDG and 18F-NaF PET/CT on 2 separate days within the same week. Studies were interpreted by 2 experienced radiologists in consensus for abnormal uptake suspicious for metastatic disease. The reference standard was a combination of imaging and clinical follow-up. Rank of PSA values for positive and negative PET/CT was compared using analysis of variance adjusting for primary therapy. Association between PSA and scan positivity in patients with RP was evaluated using Wilcoxon rank sum test. Results Result of the 18F-FDG PET/CT scan was positive for nodal disease in 2 patients. True-positive detection rate for occult osseous metastases by 18F-NaF PET/CT was 16.2%. Median PSA levels for positive versus negative PET/CT scans were 4.4 and 2.9 ng/mL, respectively, with the difference marginally significant in prostatectomized men (P = 0.072). Percentages of patients with either 18F-NaF– or 18F-FDG–positive PET/CT in RP and external beam radiation therapy were 10% (n = 10) and undefined (n = 0) for a PSA of 2 ng/mL or less, 29% (n = 7) and 50% (n = 2) for PSA greater than 2 ng/mL but 4 ng/mL or less, 60% (n = 5) and 40% (n = 5) for PSA greater than 4 ng/mL but 10 ng/mL or less, and 25% (n = 4) and 25% (n = 4) for PSA greater than 10 ng/mL, respectively. Conclusions In biochemical relapse of prostate cancer, 18F-NaF PET/CT is useful in the detection of occult osseous metastases, whereas the yield of 18F-FDG PET/CT is relatively limited. 18F-NaF PET/CT positivity tends to associate with increasing PSA level in prostatectomized men and may occur in lower PSA ranges than conventionally recognized.