Simultaneous targeting of Src kinase and receptor tyrosine kinase results in synergistic inhibition of renal cell carcinoma proliferation and migration.

There have been recent improvements in the treatment for metastatic renal cell carcinoma (RCC) with receptor tyrosine kinase (RTK) inhibitors being one of newer treatment options. We hypothesized that simultaneous targeting of Src kinase and the RTK may have synergistic effects to further improve therapies on metastatic RCC. The effects of Src kinase inhibitor saracatinib and multiple RTK inhibitor sunitinib on RCC cell line (ACHN) and Caki-1 were studied. Saracatinib alone or in combination with sunitinib inhibited the migration of ACHN and Caki-1 cells in vitro. Activation of migration related components FAK, P130Cas and Paxillin were blocked by saracatinib at 0.05- to 3-µM concentrations. Combined treatment resulted in improved growth inhibition, greater loss of the S phase cell population and decreased clonogenic colony formation compared to sunitinib alone in the metastatic Caki-1 line. Molecular studies in Caki-1 showed that saracatinib alone and in combination with sunitinib inhibited phosphorylation of the cell progression regulator c-Myc in a dose-dependent manner. Sunitinib alone or in combination suppressed cyclin-D1 expression with the combination showing greater dose-dependent effect. Sunitinib inhibited vascular endothelial growth factor (VEGF) secretion through the inhibition of STAT3 signaling and VEGF biosynthesis. HIF1-α expression in normoxic and hypoxic conditions in Caki-1 cells was inhibited by either saracatinib or sunitinib when administered alone, however, a greater reduction occurred when these compounds were given in combination. Targeting Src kinase and RTK simultaneously with saracatinib and sunitinib resulted in 70-80% blockade of RCC cell migration, synergistic inhibition of cell growth and reduction of acquired drug resistance in Caki-1 cells. The results show promise for combination targeted therapy of RCC.

Objective measurement of quality of life changes after ACE Malone using the FICQOL survey.

PURPOSE: There is little objective data demonstrating improved quality of life after a Malone antegrade continence enema (ACE) despite the dramatic subjective improvements seen by physicians and caretakers. METHODS: We utilized the FICQOL survey, a reliable and valid instrument for measuring the impact of fecal incontinence and constipation on quality of life (FICQOL) of caregivers and children with spina bifida. Between 2002 and 2009, 23 families were evaluated prospectively before and after an ACE procedure. Items on the survey were compared with Wilcoxon rank sum or signed rank test. RESULTS: After an ACE Malone the mean number of bowel movements (BM) per day decreased along with a decrease in number of accidents per week from 3.9 to 0.3. There was no change in the time committed to bowel care. The percentage of patients taking oral laxatives decreased from 44% to 6%. Both parent and child were less often prevented from leaving the house and the caretakers' bother, anxiety and depression due to bowel care decreased. Although factors regarding the child's social issues and parent's employment improved, the changes were not statistically significant. CONCLUSIONS: Among patients with spina bifida and fecal incontinence who underwent the ACE procedure at our institution, a significant improvement in fecal incontinence and QOL scores was observed using a validated instrument, FICQOL. Without changing the amount of time necessary for bowel care, the ACE procedure decreases the families' worries and anxieties and allows them to leave home with the confidence that their child will not have leakage of stool.

Aberrant activation of androgen receptor in a new neuropeptide-autocrine model of androgen-insensitive prostate cancer.

Treatment of advanced prostate cancer with androgen deprivation therapy inevitably renders the tumors castration-resistant and incurable. Under these conditions, neuroendocrine differentiation of prostate cancer (CaP) cells is often detected and neuropeptides released by these cells may facilitate the development of androgen independence. Exemplified by gastrin-releasing peptide (GRP), these neuropeptides transmit their signals through G protein-coupled receptors, which are often overexpressed in prostate cancer, and aberrantly activate androgen receptor (AR) in the absence of androgen. We developed an autocrine neuropeptide model by overexpressing GRP in LNCaP cells and the resultant cell line, LNCaP-GRP, exhibited androgen-independent growth with enhanced motility in vitro. When orthotopically implanted in castrated nude mice, LNCaP-GRP produced aggressive tumors, which express GRP, prostate-specific antigen, and nuclear-localized AR. Chromatin immunoprecipitation studies of LNCaP-GRP clones suggest that GRP activates and recruits AR to the cognate promoter in the absence of androgen. A Src family kinase (SFK) inhibitor, AZD0530, inhibits androgen-independent growth and migration of the GRP-expressing cell lines, and blocks the nuclear translocation of AR, indicating the involvement of SFK in the aberrant activation of AR and demonstrating the potential use of SFK inhibitor in the treatment of castration-resistant CaP. In vivo studies have shown that AZD0530 profoundly inhibits tumor metastasis in severe combined immunodeficient mice implanted with GRP-autocrine LNCaP cells. This xenograft model shows autocrine, neuropeptide- and Src kinase-mediated progression of androgen-independent CaP postcastration, and is potentially useful for testing novel therapeutic agents.

Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer.

BACKGROUND: It has been demonstrated that Agent Orange exposure increases the risk of developing several soft tissue malignancies. Federally funded studies, now nearly a decade old, indicated that there was only a weak association between exposure and the subsequent development of prostate cancer. Because Vietnam War veterans are now entering their 60s, the authors reexamined this association by measuring the relative risk of prostate cancer among a cohort of men who were stratified as either exposed or unexposed to Agent Orange between the years 1962 and 1971 and who were followed during the interval between 1998 and 2006. METHODS: All Vietnam War era veterans who receive their care in the Northern California Veteran Affairs Health System were stratified as either exposed (n=6214) or unexposed (n=6930) to Agent Orange. Strata-specific incidence rates of prostate cancer (International Classification of Diseases, 9th Revision code 185.0) were calculated. Differences in patient and disease characteristics (age, race, smoking history, family history, body mass index, finasteride exposure, prebiopsy prostate-specific antigen (PSA) level, clinical and pathologic stage, and Gleason score) were assessed with chi-square tests, t tests, a Cox proportional hazards model, and multivariate logistic regression. RESULTS: Twice as many exposed men were identified with prostate cancer (239 vs 124 unexposed men, respectively; odds ratio [OR], 2.19; 95% confidence interval [95% CI], 1.75-2.75). This increased risk also was observed in a Cox proportional hazards model from the time of exposure to diagnosis (hazards ratio [HR], 2.87; 95% CI, 2.31-3.57). The mean time from exposure to diagnosis was 407 months. Agent Orange-exposed men were diagnosed at a younger age (59.7 years; 95% CI, 58.9-60.5 years) compared with unexposed men (62.2 years; 95% CI, 60.8-63.6 years), had a 2-fold increase in the proportion of Gleason scores 8 through 10 (21.8%; 95% CI, 16.5%-27%) compared with unexposed men (10.5%; 95% CI, 5%-15.9%), and were more likely to have metastatic disease at presentation than men who were not exposed (13.4%; 95% CI, 9%-17.7%) than unexposed men (4%; 95% CI, 0.5%-7.5%). In univariate analysis, distribution by race, smoking history, body mass index, finasteride exposure, clinical stage, and mean prebiopsy PSA were not statistically different. In a multivariate logistic regression model, Agent Orange was the most important predictor not only of developing prostate cancer but also of high-grade and metastatic disease on presentation. CONCLUSIONS: Individuals who were exposed to Agent Orange had an increased incidence of prostate cancer; developed the disease at a younger age, and had a more aggressive variant than their unexposed counterparts. Consideration should be made to classify this group of individuals as 'high risk,' just like men of African-American heritage and men with a family history of prostate cancer.

Medical and surgical palliative care of patients with urological malignancies.

PURPOSE: Urological malignancies are relatively common and patients often live many years with disease. There are many effective medical and surgical palliative treatments, although few comprehensive guidelines have been published. We reviewed the various palliative treatments available for the 3 most common urological malignancies, namely prostate cancer, bladder cancer and renal cancer. MATERIALS AND METHODS: A literature search of the last 15 years was performed using MEDLINE/PubMed. In addition, relevant journals were targeted for specific information related to this review. Our clinical experience was combined with the current literature to create guidelines for palliative care. RESULTS: Several effective treatments are available for the palliative care of patients with prostate, bladder or renal cancer. Options in palliative care are varied with regard to invasiveness, morbidity, risks and benefits. The algorithms described provide a framework to a sequential approach to achieving palliation. Urologists are central to initiating care and referrals to improve outcomes in these patients. CONCLUSIONS: Palliative care includes disease directed treatment as well as functional, psychosocial and spiritual support. Disease directed therapy and palliative care should be provided simultaneously throughout illness. Improved quality of care and quality of life as well as physician satisfaction are frequent outcomes of this approach. Supportive care begins at initial diagnosis and it should be flexible to meet the changing needs of patients with cancer and their families.