Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells.

Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 α (HIF-1α) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1α target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1α inhibition attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth.

Racial disparities in the association between variants on 8q24 and prostate cancer: a systematic review and meta-analysis.

Recent studies implicate single nucleotide polymorphisms (SNPs) within the 8q24 region as a risk factor for prostate cancer (PCa). New developments suggest that 8q24 encodes regulators of the nearby MYC gene, a known oncogene. In order to better understand the implications of SNPs in this region, we performed meta-analyses, stratified by race, of seven SNPs and one microsatellite marker previously identified as risk loci on the 8q24 region of the genome. In addition, we reviewed the literature examining the possible associations between these polymorphisms and clinicopathological features of PCa. The results of the meta-analyses indicate that rs6983267, rs1447295, rs6983561, rs7837688, rs16901979, and DG8S737 are significantly associated with a higher risk for PCa for at least one race, whereas the variants rs13254738 and rs7000448 are not. The degree of association and frequency of the causative allele varied among men of different races. Though several studies have demonstrated an association between certain 8q24 SNPs and clinicopathological features of the disease, review of this topic revealed conflicting results.

Multi-institutional Study of Outcomes After Pediatric Heart Transplantation: Candidate Gene Polymorphism Analysis of ABCC2.

OBJECTIVES: Earlier studies have indicated that the pharmacokinetics of mycophenolic acid (MPA) is influenced by polymorphisms of ABCC2, which encodes for the membrane transporter MRP2. The ABCC2 rs717620 A allele has been associated with enterohepatic recirculation of MPA, and our previous work had correlated the discontinuance of MPA with this allele in pediatric heart transplant patients. Therefore, we hypothesized that the ABCC2 rs717620 A allele would be associated with poorer outcomes including rejection with hemodynamic compromise (RHC), graft failure, and death in the pediatric heart transplant (PHTx) population receiving MPA. METHODS: PHTx recipients from 6 institutions in the Pediatric Heart Transplantation Study (PHTS) from the period of 1993-2009, receiving MPA therapy, were genotyped for ABCC2 rs717620. Genotyping was accomplished by direct sequencing. Demographic and outcome data were limited to the data routinely collected as part of the PHTS and included RHC and mortality. RESULTS: Two hundred ninety patients were identified who received MPA at some point post transplantation, of which 200 carried the GG genotype, 81 carried the AG genotype, and 9 carried the AA genotype. Follow-up time after transplantation was 6 years. RHC occurred in 76 patients and 18 patients died. In the 281 patients followed up more than 1 year, late RHC (>1 year post transplantation) occurred in 42 patients. While both RHC and late RHC were associated with the ABCC2 rs717620 GG genotype (hazard ratios: 1.80 and 4.57, respectively, p<0.05) in all patients, this association was not significant in PHTx patients receiving only MPA as the antiproliferative agent from the time of transplant (n=142). CONCLUSIONS: ABCC2 rs717620 polymorphisms varied within racial groups. As a candidate gene assessment, the ABCC2 rs717620 AG and AA genotypes may be associated with improved, rather than poorer, RHC in PHTx patients receiving MPA therapy. ABCC2 rs717620 polymorphisms should be included in any expanded pharmacogenomic analysis of outcomes after pediatric heart transplantation.

Bcl-2 family of proteins as therapeutic targets in genitourinary neoplasms.

INTRODUCTION: Overexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including those of the genitourinary tract. Inhibitors that target prosurvival Bcl-2 proteins are in preclinical and clinical development. The objective of this review is to assess the involvement of Bcl-2 proteins as well as the preclinical and clinical activity of Bcl-2 inhibitors under evaluation for genitourinary neoplasms. MATERIALS AND METHODS: PubMed was used with both medical subject heading terms and free search to identify the relevant literature. Information on clinical trials was obtained using http://Clincaltrials.gov, EU Clinical Trials Register, and meeting abstracts of the American Society of Clinical Oncology. RESULTS: To date, 2 Bcl-2 inhibitors have been evaluated in clinical trials for genitourinary tumors (oblimersen and AT-101 (R-(-)-gossypol)). Both agents demonstrated some success in early stages of development, but their clinical activity did not meet expectations. Preclinical studies are under way for other Bcl-2 inhibitors including ABT-737, HA14-1, and Bcl-2 homology 3 inhibitors. CONCLUSION: Antiapoptotic Bcl-2 proteins are potential molecular targets in genitourinary cancers. Bcl-2 inhibitors might be effective as single agents or in combination with conventional therapies. However, the biology of the Bcl-2 family in genitourinary cancers remains poorly understood and robust preclinical studies are needed to inform clinical development. Such studies should aim to identify: (1) pharmacodynamic markers that could help guide patient selection for treatment with Bcl-2 inhibitors, and (2) optimal combinations of Bcl-2 inhibitors with other anticancer agents for future clinical investigation.

Transporter pharmacogenetics: transporter polymorphisms affect normal physiology, diseases, and pharmacotherapy.

Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable inter-individual variation in physiology and pharmacotherapy. The purpose of this review is to provide a broad overview of how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. Given that there are thousands of published papers related to the interplay between transporter genetics and medicine, this review will provide examples that exemplify the broader focus of the literature.

Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia.

PURPOSE: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. EXPERIMENTAL DESIGN: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. RESULTS: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 µmol/L; K(i) = 11.7 µmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. CONCLUSIONS: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.

Prostate cancer genomic signature offers prognostic value.

Previous attempts to link prostate cancer progression to genetic alterations have been unsuccessful, and consequently, there is still no reliable predictor of prognosis for men with this disease. A recent study by Taylor et al., published in Cancer Cell, assesses copy number alterations, mutations, and transcriptomes in 218 tumors and 12 prostate cancer cell lines and xenografts. Their analysis identifies frequencies of ERG alterations, 8p loss and 8q gain similar to previous findings. It also reveals novel genetic factors in prostate cancer progression, including the androgen receptor coactivator, NCOA2, which serves as an oncogene in about 11% of tumors, and a deletion at chromosome 3p14, which was associated with TMPRSS-ERG fusion. The copy number alteration data demonstrates six distinct subgroups of prostate cancer with considerable variation in time to biochemical relapse. Classification of prostate cancer into these genetic subgroups may help clinicians predict the likelihood of disease progression in newly diagnosed men, ultimately guiding treatment decisions and therapy development.