Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer.

VT-464 is a novel, nonsteroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. This study evaluates the anticancer activity of VT-464 compared with abiraterone (ABI) in castrate-resistant prostate cancer cell lines and xenograft models that are enzalutamide (ENZ)-responsive (C4-2) or ENZ-resistant (MR49C, MR49F). In vitro, androgen receptor (AR) transactivation was assessed by probasin luciferase reporter, whereas AR and AR-regulated genes and steroidogenic pathway enzymes were assessed by Western blot and/or qRT-PCR. The MR49F xenograft model was used to compare effects of oral VT-464 treatment to vehicle and abiraterone acetate (AA). Steroid concentrations were measured using LC-MS chromatography. VT-464 demonstrated a greater decrease in AR transactivation compared with ABI in C4-2 and both ENZ-resistant cell lines. At the gene and protein level, VT-464 suppressed the AR axis to a greater extent compared with ABI. Gene transcripts StAR, CYP17A1, HSD17B3, and SRD5A1 increased following treatment with ABI and to a greater extent with VT-464. In vivo, intratumoral androgen levels were significantly lower after VT-464 or AA treatment compared with vehicle, with the greatest decrease seen with VT-464. Similarly, tumor growth inhibition and PSA decrease trends were greater with VT-464 than with AA. Finally, an AR-antagonist effect of VT-464 independent of CYP17A1 inhibition was observed using luciferase reporter assays, and a direct interaction was confirmed using an AR ligand binding domain biolayer interferometry. These preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism.

Evolving landscape and novel treatments in metastatic castrate-resistant prostate cancer.

Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease. Further understanding of the biology of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.

Novel non-AR therapeutic targets in castrate resistant prostate cancer.

Castrate resistant prostate cancer (CRPC) remains a disease with significant morbidity and mortality. The recent approval of abiraterone and enzalutamide highlight the improvements which can be made targeting the androgen receptor (AR) axis. Nonetheless, resistance inevitably develops and there is continued interest in targeting alternate pathways which cause disease resistance and progression. Here, we review non-AR targets in CRPC, with an emphasis on novel agents now in development. This includes therapeutics which target the tumour microenvironment, the bone metastatic environment, microtubules, cellular energetics, angiogenesis, the stress response, survival proteins, intracellular signal transduction, DNA damage repair and dendritic cells. Understanding the hallmarks of prostate cancer resistance in CRPC has led to the identification and development of these new targets. We review the molecular rationale, as well at the clinical experience for each of these different classes of agents which are in clinical development.

Point-of-care clinical documentation: assessment of a bladder cancer informatics tool (eCancerCareBladder): a randomized controlled study of efficacy, efficiency and user friendliness compared with standard electronic medical records.

OBJECTIVE: To compare the use of structured reporting software and the standard electronic medical records (EMR) in the management of patients with bladder cancer. The use of a human factors laboratory to study management of disease using simulated clinical scenarios was also assessed. DESIGN: eCancerCare(Bladder) and the EMR were used to retrieve data and produce clinical reports. Twelve participants (four attending staff, four fellows, and four residents) used either eCancerCare(Bladder) or the EMR in two clinical scenarios simulating cystoscopy surveillance visits for bladder cancer follow-up. MEASUREMENTS: Time to retrieve and quality of review of the patient history; time to produce and completeness of a cystoscopy report. Finally, participants provided a global assessment of their computer literacy, familiarity with the two systems, and system preference. RESULTS: eCancerCare(Bladder) was faster for data retrieval (scenario 1: 146 s vs 245 s, p=0.019; scenario 2: 306 vs 415 s, NS), but non-significantly slower to generate a clinical report. The quality of the report was better in the eCancerCare(Bladder) system (scenario 1: p<0.001; scenario 2: p=0.11). User satisfaction was higher with the eCancerCare(Bladder) system, and 11/12 participants preferred to use this system. LIMITATIONS: The small sample size affected the power of our study to detect differences. CONCLUSIONS: Use of a specific data management tool does not appear to significantly reduce user time, but the results suggest improvement in the level of care and documentation and preference by users. Also, the use of simulated scenarios in a laboratory setting appears to be a valid method for comparing the usability of clinical software.

Small incidentally discovered testicular masses in infertile men--is active surveillance the new standard of care?

PURPOSE: The management of small, incidental testicular masses found on scrotal ultrasound is controversial. Although these neoplasms are classically treated with surgical excision, ultrasound surveillance has been proposed as an alternative to surgery. MATERIALS AND METHODS: We reviewed our experience of ultrasound surveillance for small testicular masses at Mount Sinai Hospital Fertility Clinic from 2001 to 2008, offered to all patients with subcentimeter, incidentally discovered hypoechoic testicular lesions. Patient age, semen parameters, the size and growth of the lesion on serial ultrasounds, need for surgery and pathological diagnosis were collected in a database. RESULTS: Of 4,418 patients evaluated 46 (1%) met the study inclusion criteria. Mean age was 35 years, and 39 patients (85%) presented with infertility. Semen analysis revealed azoospermia, oligospermia and normospermia in 15, 18 and 7 patients, respectively, and was unavailable in 6. Mean ultrasound followup was 253 days and mean number of ultrasounds was 2.8. Mean lesion diameter was 4.3 mm (range 1 to 10). There were 38 patients with serial ultrasound followup only with a mean growth of 0.5 mm per year (95% CI -2.2-3.3). Three patients underwent immediate surgery and 5 underwent surgery following a period of ultrasound followup. Indications for surgery were interval growth in 2 patients and patient choice in 6. Larger size (p = 0.02) and presence of vascular flow (p <0.01) were associated with intervention. One patient underwent radical orchiectomy for pure seminoma identified due to interval growth from 3 to 6 mm at 3 months. The other 7 masses excised with partial orchiectomy were benign. CONCLUSIONS: Ultrasound surveillance of small (less than 1 cm) incidental testicular masses is a safe alternative to immediate surgical removal.

Is 24-hour urinary calcium a surrogate marker for dietary calcium intake?

OBJECTIVES: To determine whether the 24-hour urinary excretion of calcium was a reliable surrogate marker for dietary calcium intake. Although dietary calcium intake has been negatively correlated with the risk of recurrent calcium-based stones, detailed dietary histories are not routinely evaluated in most patients with recurrent stone formation. METHODS: The dietary records and corresponding 24-hour urine collections of 68 randomly selected women with a history of calcium-based renal stones and two or more outpatient clinic visits were studied. Subjects were excluded if they had conditions or took medications affecting calcium absorption or excretion. Multivariate regression analysis was performed on the most recent set of data per patient with 24-hour urinary calcium as the dependent variable. Independent variables included age, weight, and dietary calcium, sodium, potassium, magnesium, fiber, and animal protein. Regression analysis was performed on the differences between the first and last visits for dietary and urinary data. Using tertiles, the positive predictive value of 24-hour urinary calcium for the respective dietary intake tertiles was calculated. RESULTS: The regression model on absolute values showed all dietary parameters to have squared partial correlation coefficients of less than 0.3 (P = 0.015, R2 = 0.264). In the second regression analysis, the model did not significantly explain the variance (P = 0.656). The positive predictive value of a mean 24-hour urinary calcium level less than 3.75 mmol/L for calcium intake less than 585 mg/day was 45%. CONCLUSIONS: The results of the present study revealed that the 24-hour urinary calcium cannot be used as a surrogate marker for dietary intake of calcium. A detailed dietary history is needed for all women with recurrent stone formation for proper assessment and potential modification of calcium intake to reduce recurrences.