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1.  Vulnerabilities of PTEN-p53-deficient prostate cancers to compound PARP/PI3K inhibition 
Cancer discovery  2014;4(8):896-904.
Prostate cancer (CaP) is the most prevalent cancer in males and treatment options are limited for advanced forms of the disease. Loss of the PTEN and p53 tumor suppressor genes is commonly observed in CaP, while their compound loss is often observed in advanced CaP. Here we show, that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the pro-survival signalling PI3K-AKT pathway limits the efficacy of a PARP-single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human CaP cell lines and in a Pten/p53 deficient mouse model of advanced CaP. Our findings therefore identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient CaP.
doi:10.1158/2159-8290.CD-13-0230
PMCID: PMC4125493  PMID: 24866151
PTEN; Prostate; PARP; PI3K; Senescence
2.  Serum glucose and risk of cancer: a meta-analysis 
BMC Cancer  2014;14:985.
Background
Raised serum glucose has been linked to increased risk of many solid cancers. We performed a meta-analysis to quantify and summarise the evidence for this link.
Methods
Pubmed and Embase were reviewed, using search terms representing serum glucose and cancer. Inclusion and exclusion criteria focused on epidemiological studies with clear definitions of serum glucose levels, cancer type, as well as well-described statistical methods with sufficient data available. We used 6.1 mmol/L as the cut-off for high glucose, consistent with the WHO definition of metabolic syndrome. Random effects analyses were performed to estimate the pooled relative risk (RR).
Results
Nineteen studies were included in the primary analysis, which showed a pooled RR of 1.32 (95% CI: 1.20 – 1.45). Including only those individuals with fasting glucose measurements did not have a large effect on the pooled RR (1.32 (95% CI: 1.11-1.57). A stratified analysis showed a pooled RR of 1.34 (95% CI: 1.02-1.77) for hormonally driven cancer and 1.21 (95% CI: 1.09-1.36) for cancers thought to be driven by Insulin Growth Factor-1.
Conclusion
A positive association between serum glucose and risk of cancer was found. The underlying biological mechanisms remain to be elucidated but our subgroup analyses suggest that the insulin- IGF-1 axis does not fully explain the association. These findings are of public health importance as measures to reduce serum glucose via lifestyle and dietary changes could be implemented in the context of cancer mortality.
doi:10.1186/1471-2407-14-985
PMCID: PMC4320469  PMID: 25526881
Glucose; Cancer; Metabolic syndrome; Meta-analysis; Diabetes
3.  Modification of the Association Between Obesity and Lethal Prostate Cancer by TMPRSS2:ERG  
Background
TMPRSS2:ERG is a hormonally regulated gene fusion present in about half of prostate tumors. We investigated whether obesity, which deregulates several hormonal pathways, interacts with TMPRSS2:ERG to impact prostate cancer outcomes.
Methods
The study included 1243 participants in the prospective Physicians’ Health Study and Health Professionals Follow-Up Study diagnosed with prostate cancer between 1982 and 2005. ERG overexpression (a TMPRSS2:ERG marker) was assessed by immunohistochemistry of tumor tissue from radical prostatectomy or transurethral resection of the prostate. Body mass index (BMI) and waist circumference, measured on average 1.3 years and 5.3 years before diagnosis, respectively, were available from questionnaires. Data on BMI at baseline was also available. We used Cox regression to calculate hazard ratios and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results
During a mean follow-up of 12.8 years, 119 men developed lethal disease (distant metastases or prostate cancer death). Among men with ERG-positive tumors, the multivariable hazard ratio for lethal prostate cancer was 1.48 (95% CI = 0.98 to 2.23) per 5-unit increase in BMI before diagnosis, 2.51 (95% CI = 1.26 to 4.99) per 8-inch increase in waist circumference before diagnosis, and 2.22 (95% CI = 1.35 to 3.63) per 5-unit increase in BMI at baseline. The corresponding hazard ratios among men with ERG-negative tumors were 1.10 (95% CI = 0.76 to1.59; P interaction = .24), 1.14 (95% CI = 0.62 to 2.10; P interaction = .09), and 0.78 (95% CI = 0.52 to 1.19; P interaction = .001).
Conclusions
These results suggest that obesity is linked with poorer prostate cancer prognosis primarily in men with tumors harboring the gene fusion TMPRSS2:ERG.
doi:10.1093/jnci/djt332
PMCID: PMC3866157  PMID: 24292212
4.  Prostate-specific membrane antigen protein expression in tumor tissue and risk of lethal prostate cancer 
Background
Over-expression of prostate-specific membrane antigen (PSMA) in tumor tissue and serum has been linked to increased risk of biochemical recurrence in surgically treated prostate cancer patients, but no studies have assessed its association with disease-specific mortality.
Methods
We examined whether high PSMA protein expression in prostate tumor tissue was associated with lethal disease, and with tumor biomarkers of progression, among participants of two US-based cohorts (n=902, diagnosed 1983–2004). We used Cox proportional hazards regression to calculate multivariable hazard ratios (HR) and 95% confidence intervals (CI) of lethal prostate cancer, defined as disease-specific death or development of distant metastases (n=95). Partial Spearman rank correlation coefficients were used to correlate PSMA with tumor biomarkers.
Results
During an average 13 years of follow-up, higher PSMA expression at prostatectomy was significantly associated with lethal prostate cancer (age-adjusted HRQuartile(Q)4vs.Q1=2.42; p-trend<0.01). This association was attenuated and non-significant (multivariable-adjusted HRQ4vs.Q1=1.01; p-trend=0.52) after further adjusting for Gleason score and PSA at diagnosis. High PSMA expression was significantly (p<0.05) correlated with higher Gleason score and PSA at diagnosis, increased tumor angiogenesis, lower vitamin D receptor and androgen receptor expression, and absence of ERG expression.
Conclusions
High tumor PSMA expression was not an independent predictor of lethal prostate cancer in the current study. PSMA expression likely captures, in part, malignant features of Gleason grade and tumor angiogenesis.
Impact
PSMA is not a strong candidate biomarker for predicting prostate cancer-specific mortality in surgically treated patients.
doi:10.1158/1055-9965.EPI-13-0668
PMCID: PMC3893763  PMID: 24130224
prostate-specific membrane antigen; prostate cancer; tumor biomarkers; prognosis; angiogenesis
5.  Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer 
Nature biotechnology  2014;32(5):479-484.
Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.
doi:10.1038/nbt.2892
PMCID: PMC4034575  PMID: 24752078
6.  Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib 
Cancer discovery  2014;4(5):546-553.
Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole exome sequencing of a patient with a 14-month complete response on this trial revealed two simultaneous mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biological mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or “personalized”) medicine approaches to screen cancer patients for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.
doi:10.1158/2159-8290.CD-13-0353
PMCID: PMC4122326  PMID: 24625776
7.  Protein expression of PTEN, insulin-like growth factor I receptor (IGF1R), and lethal prostate cancer: a prospective study 
Background
Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality, and the potential effect modification by IGF1R, a direct activator of the PI3K pathway.
Methods
Protein expression in tumor were evaluated using tumor tissues obtained from 805 participants of the Physicians’ Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression, and its interaction with IGF1R, in relation to lethal prostate cancer (cancer-specific death or distant metastases).
Results
Low PTEN expression was associated with an increase risk of lethal prostate cancer (HR = 1.7, 95% CI: 0.98-3.2, P for trend = 0.04). The association was attenuated after adjustment for Gleason grade, tumor stage, and PSA at diagnosis. A significant negative interaction between PTEN and IGF1R was found (P for interaction = 0.03). Either reduction in PTEN or increase in IGF1R expression was sufficient to worsen prognosis. Models including PTEN and IGF1R expression offer additional predicting power to prostate cancer survival, comparing to those only including demographic and clinical factors.
Conclusions
Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF1R expression remains at normal level.
Impact
PTEN and IGF1R expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer.
doi:10.1158/1055-9965.EPI-13-0349
PMCID: PMC3818474  PMID: 23983239
Prostate cancer; PTEN; Tumor biomarker; Survival; Interaction
8.  Blood Levels of Saturated and Monounsaturated Fatty Acids as Markers of De Novo Lipogenesis and Risk of Prostate Cancer 
American Journal of Epidemiology  2013;178(8):1246-1255.
De novo lipogenesis has been implicated in prostate carcinogenesis, and blood levels of specific saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) could reflect activity of this pathway. We used gas chromatography to measure blood SFA and MUFA levels in prediagnostic samples from 476 incident prostate cancer cases (1982–1995) in the Physicians' Health Study and an equal number of controls matched on age and smoking status. Five tagging polymorphisms in the fatty acid synthase (FASN) gene (rs1127678, rs6502051, rs4246444, rs12949488, and rs8066956) were related to blood SFA and MUFA levels. Conditional logistic regression was used to estimate the rate ratios, with 95% confidence intervals, of prostate cancer across quintiles of blood fatty acid levels. The polymorphisms rs6502051 and rs4246444 were associated with lower levels of 14:1n-5, 16:1n-7, and 18:1n-9. Blood levels of 16:1n-7 were associated with higher prostate cancer incidence, with rate ratios for men in increasing quintiles of 1.00, 1.40, 1.35, 1.44, and 1.97 (95% confidence interval: 1.27–3.06; Ptrend = 0.003). Furthermore, 16:1n-7 levels were positively related to incidence of high-grade (Gleason score ≥7) tumors (rate ratioQ5–Q1 = 3.92; 95% confidence interval: 1.72–8.94) but not low-grade tumors (rate ratioQ5–Q1 = 1.51; 95% confidence interval: 0.87–2.62) (Pheterogeneity = 0.02). Higher activity of enzymes involved in de novo lipogenesis, as reflected in blood levels of 16:1n-7, could be involved in the development of high-grade prostate cancer.
doi:10.1093/aje/kwt136
PMCID: PMC3792734  PMID: 23989197
biomarkers; epidemiology; fatty acids; nutrition; prostate cancer
9.  Integrative analysis of 1q23.3 copy number gain in metastatic urothelial carcinoma 
Purpose
Metastatic urothelial carcinoma (UC) of the bladder is associated with multiple somatic copy number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic UC treated with platinum-based chemotherapy.
Experimental Design
We obtained overall survival (OS) and array DNA copy number data from metastatic UC patients in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by Nanostring nCounter to identify transcripts from the region that are associated with copy number gain. In addition, expression data from an independent cohort was used to identify candidate genes.
Results
Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in the both cohorts (adjusted HR 2.96; 95% CI, 1.35 to 6.48; P = 0.01 and adjusted HR 5.03; 95% CI 1.43-17.73; P < 0.001). The F11R, PFDN2, PPOX, USP21 and DEDD genes, all located on 1q23.3, were closely associated with poor outcome.
Conclusions
1q23.3 copy number gain displayed association with poor survival in two cohorts of metastatic UC. The identification of the target of this copy number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of poor risk UC patients. Prospective validation of the survival association is necessary to demonstrate clinical relevance.
doi:10.1158/1078-0432.CCR-13-0759
PMCID: PMC3975677  PMID: 24486590
10.  The fat side of Prostate Cancer 
Biochimica et biophysica acta  2013;1831(10):1518-1532.
Prostate cancer (PCa) metabolism appears to be unique in comparison with other type of solid cancers. Normal prostate cells mainly rely on glucose oxidation to provide precursors for the synthesis and secretion of citrate, resulting in an incomplete Krebs cycle and minimal oxidative phosphorylation for energy production. In contrast, during transformation, PCa cells no longer secrete citrate and they reactivate the Krebs cycle as energy source. Moreover, primary PCas do not show increased aerobic glycolysis and therefore they are not efficiently detectable with 18F-FDG-PET. However, increased de novo lipid synthesis, strictly intertwined with deregulation in classical oncogenes and oncosuppressors, is an early event of the disease. Up-regulation and increased activity of lipogenic enzymes (including fatty acid synthase and choline kinase) occurs throughout PCa carcinogenesis and correlates with worse prognosis and poor survival. Thus, lipid precursors such as acetate and choline have been successfully used as alternative tracers for PET imaging. Lipid synthesis intermediates and FA catabolism also emerged as important players in PCa maintenance. Finally, epidemiologic studies suggested that systemic metabolic disorders including obesity, metabolic syndrome, and diabetes as well as hypercaloric and fat-rich diets might increase the risk of PCa. However, how metabolic disorders contribute to PCa development and whether dietary lipids and de novo lipids synthesized intra-tumor are differentially metabolized still remains unclear. In this review, we examine the switch in lipid metabolism supporting the development and progression of PCa and we discuss how we can exploit its lipogenic nature for therapeutic and diagnostic purposes.
doi:10.1016/j.bbalip.2013.03.010
PMCID: PMC3766375  PMID: 23562839
prostate cancer; lipid metabolism; fatty acids; imaging; metabolic diseases
12.  Gleason Grade Progression Is Uncommon 
Cancer research  2013;73(16):5163-5168.
Gleason grade is universally used for pathologic scoring the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well-differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate Specific Antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high grade tumors. We studied 1,207 Physicians’ Health Study and Health Professionals Follow-up Study participants diagnosed with prostate cancer 1982–2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982–1/1993), 19.9% stage ≥T3, to the latest (5/2000–12/2004), 3% stage T3, none T4. The proportion of Gleason score ≥8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (p=0.04) suggests the relationship between grade and stage varies by time period. As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance.
doi:10.1158/0008-5472.CAN-13-0427
PMCID: PMC3775342  PMID: 23946472
prostate cancer; Gleason score; dedifferentiation
13.  5α-reductase Inhibitors and Risk of High-grade or Lethal Prostate Cancer 
JAMA internal medicine  2014;174(8):1301-1307.
Importance
5α-reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear.
Objective
To determine the association between 5ARI use and development of high-grade or lethal prostate cancer.
Design, Setting, and Participants
Prospective observational study of 38,058 men followed for prostate cancer diagnosis and outcomes between 1996–2010 in the Health Professionals Follow-up Study.
Exposure
Use of 5ARIs between 1996–2010.
Main Outcome Measures
Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing.
Results
During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high-grade (Gleason 8–10), 1238 were Gleason grade 7, and 1600 were low-grade (Gleason 2–6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (HR 0.77; 95% CI, 0.65–0.91). 5ARI users had a reduced risk of Gleason 7 (HR 0.67; 95% CI, 0.49–0.91) and low-grade (Gleason 2–6) prostate cancer (HR 0.74; 95% CI, 0.57–0.95). 5ARI use was not associated with risk of high-grade (Gleason 8–10, HR 0.97; 95% CI, 0.64–1.46) or lethal disease (HR 0.99; 95% CI, 0.58–1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use 0.95; 95% CI, 0.92–0.99), localized (HR 0.95; 95% CI, 0.90–1.00), and low-grade disease (HR 0.92; 95% CI, 0.85–0.99). There was no association for lethal, high-grade, or grade 7 disease.
Conclusions and Relevance
While 5ARI use was not associated with developing high-grade or lethal prostate cancer, they were associated with a reduction in low-grade, Gleason 7 and overall prostate cancer. Since the number of patients with high-grade or lethal prostate cancer in our cohort was limited, we cannot rule out potential risk of harm with 5ARI use.
doi:10.1001/jamainternmed.2014.1600
PMCID: PMC4122627  PMID: 24887392
14.  FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder 
Cancer Medicine  2014;3(4):835-844.
While fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle-invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle-invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin-fixed paraffin-embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild-type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle-invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon.
doi:10.1002/cam4.262
PMCID: PMC4303151  PMID: 24846059
Biomarker; bladder cancer; FGFR3; metastatic urothelial carcinoma; muscle-invasive urothelial carcinoma; targeted therapy
15.  Selenoprotein P Genetic Variants and mRNA Expression, Circulating Selenium and Prostate Cancer Risk and Survival 
The Prostate  2012;73(7):700-705.
Background
Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions.
Methods
The Physicians’ Health Study (PHS) is a prospective cohort of 22,071 US physicians; we utilized a nested case-control study of 1,352 PCa cases and 1,382 controls. We assessed four SNPs capturing common variation within the SEPP1 locus. In a subset of men (n=80), we evaluated SEPP1 mRNA expression in tumors.
Results
Two SNPs were significantly associated with PCa risk. For rs11959466, each T allele increased risk (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02,1.69; ptrend=0.03). For rs13168440, the rare homozygote genotype decreased risk compared to the common homozygote (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with plasma selenium; increasing selenium levels were associated with decreased PCa risk only among men with the minor allele (pinteraction=0.01). SEPP1 expression was significantly lower in men with lethal PCa than long-term survivors.
Conclusions
SEPP1 genetic variation was associated with PCa incidence; replication of these results in an independent dataset is necessary. These findings further support a causal link between selenium and PCa, and suggest that the effect of selenium may differ by genetics.
doi:10.1002/pros.22611
PMCID: PMC3640488  PMID: 23129481
genetic variation; selenium; prostate cancer
16.  Animal models of human prostate cancer: The Consensus Report of the New York Meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee 
Cancer research  2013;73(9):2718-2736.
Animal models, particularly mouse models, play a central role in the study of the etiology, prevention and treatment of human prostate cancer (PCa). While tissue culture models are extremely useful in understanding the biology of PCa, they cannot recapitulate the complex cellular interactions within the tumor microenvironment that play a key role in cancer initiation and progression. The NCI Mouse Models of Human Cancers Consortium convened a group of human and veterinary pathologists to review the current animal models of PCa and make recommendations regarding the pathological analysis of these models. Over 40 different models with 439 samples were reviewed including genetically engineered mouse models, xenograft, rat and canine models. Numerous relevant models have been developed over the last 15 years and each approach has strengths and weaknesses. Analysis of multiple genetically engineered models has shown that reactive stroma formation is present in all the models developing invasive carcinomas. In addition, numerous models with multiple genetic alterations display aggressive phenotypes characterized by sarcomatoid carcinomas and metastases, which is presumably a histological manifestation of epithelial-mesenchymal transition. The significant progress in development of improved models of PCa has already accelerated our understanding the complex biology of PCa and promises to enhance development of new approaches to prevention, detection and treatment of this common malignancy.
doi:10.1158/0008-5472.CAN-12-4213
PMCID: PMC3644021  PMID: 23610450
prostate cancer; animal models; transgenic; pathology; genetically engineered mice; xenograft
17.  A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis 
EMBO Molecular Medicine  2014;6(4):519-538.
5′AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63–78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63–78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.
doi:10.1002/emmm.201302734
PMCID: PMC3992078  PMID: 24497570
AMPK direct activation; androgen signaling inhibitors; de novo lipogenesis; MT 63–78; prostate cancer
18.  Metformin, an Adjunct Antineoplastic Therapy, Divergently Modulates Tumor Metabolism and Proliferation, Interfering with Early Response Prediction Using 18F-FDG PET Imaging 
Over the last several years epidemiological data has emerged which suggests that the anti-diabetic drug metformin (MET), an AMP-activated protein kinase (AMPK) activator, improves progression free survival in multiple cancers; more than 30 clinical trials are underway to confirm this finding. We postulated that the role of AMPK as a central cellular energy sensor would result in opposite effects on glucose uptake and proliferation, suggesting different roles for 18F-FDG and 18F-FLT in assessing its effectiveness as an anti-neoplastic agent.
Methods
Colon cancer cell lines HT29 (human) and MC26 (murine) were treated for 24 or 72hrs with a range of MET (0–10mM). Western blotting was used to study the activation of AMPK after MET treatment. Glucose uptake and cell proliferation were measured by cell retention studies with either 18F-FDG or 18F-FLT. EdU (a thymidine analogue) and Annexin-Propidium Iodine flow cytometry were performed to determine cell cycle S-phase and apoptotic changes. In vivo 18F-FDG and 18F-FLT PET images were acquired before and 24hrs after MET treatment on HT29 tumor bearing mice.
Results
After 24hrs of MET incubation, phosphorylated AMPK increased several fold in both cell lines while total AMPK was unchanged. In cell retention studies, 18F-FDG uptake increased whereas 18F-FLT retention decreased significantly in both cell lines. Cells in S-phase decreased 36% in HT29 and 33% in MC26 cells following MET therapy. Apoptosis increased 10.5× and 5.8×, in HT29 and MC26 cells, respectively after 72hrs of incubation with MET. PET imaging showed increased 18F-FDG uptake (mean SUV: 0.71±0.03 and 1.29±0.11 pre and post MET therapy, p<0.05) and decreased 18F-FLT uptake (mean SUV: 1.18±0.05 and 0.89±0.01 pre and post MET therapy, p<0.05) in HT29 tumor bearing mice.
Conclusion
MET, through activation of the AMPK pathway, exerts a dose dependent increase in tumor glucose uptake while decreasing cell proliferation in human and murine colon cancer cells. Thus, changes in 18F-FDG uptake post MET treatment may be misleading; 18F-FLT imaging is a promising alternative that correlates with tumor response.
doi:10.2967/jnumed.112.107011
PMCID: PMC3703242  PMID: 23376854
Metformin; AMPK; Tumor metabolic imaging; Proliferation imaging
19.  Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention 
Cancer discovery  2012;3(1):44-51.
Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5α-reductase inhibitors (5-ARI) have yielded encouraging yet ultimately confounding results. Using a pre-clinical mouse model of high-grade prostatic intraepithelial neoplasia (HG-PIN) induced by PTEN loss, we observed unprecedented deteriorating effects of androgen deprivation, where surgical castration or MDV3100 treatment accelerated disease progression of the otherwise stable HG-PIN to invasive castration-resistant prostate cancer (CRPC). As an alternative, targeting the PI3K signaling pathway via either genetic ablation of PI3K components or pharmacological inhibition of PI3K pathway reversed the PTEN loss-induced HG-PIN phenotype. Finally, concurrent inhibition of PI3K and MAPK pathways was effective in blocking the growth of PTEN-null CRPC. Together, these data have revealed the potential adverse effects of anti-androgen chemoprevention in certain genetic contexts (such as PTEN loss) while demonstrating the promise of targeted therapy in the clinical management of this complex and prevalent disease.
doi:10.1158/2159-8290.CD-12-0262
PMCID: PMC3546223  PMID: 23258246
20.  A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer 
Nature genetics  2013;45(7):747-755.
Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten-loss driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed upon deletion of either Trp53 or Lrf together with Pten, leading to the development of castration resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1-XIAP/SRD5A1 as a predictive and actionable signature for CRPC. Importantly, we show that combined inhibition of XIAP, SRD5A1, and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates stratification of patients and the development of tailored and innovative therapeutic treatments.
doi:10.1038/ng.2650
PMCID: PMC3787876  PMID: 23727860
21.  The Ubiquitin Specific Protease USP2a Prevents Endocytosis-Mediated EGFR Degradation 
Oncogene  2012;32(13):10.1038/onc.2012.188.
Ubiquitination of EGFR is required for down-regulation of the receptor by endocytosis. Impairment of this pathway results in constitutively active EGFR, which is associated with carcinogenesis, particularly in lung cancer. We previously demonstrated that the deubiquitinating enzyme USP2a has oncogenic properties. Here we show a new role for USP2a as a regulator of EGFR endocytosis. USP2a localizes to early endosomes and associates with EGFR, stabilizing the receptor, which retains active downstream signaling. HeLa cells transiently expressing catalytically active but not mutant USP2a show increased plasma membrane-localized EGFR, as well as decreased internalized and ubiquitinated EGFR. Conversely, USP2a silencing reverses this phenotype. Importantly, USP2a prevents the degradation of mutant in addition to wild type EGFR. Finally, we observed that USP2a and EGFR proteins are coordinately over-expressed in non-small cell lung cancers. Taken together, our data indicate that USP2a antagonizes EGFR endocytosis and thus amplifies signaling activity from the receptor. Our findings suggest that regulation of deubiquitination could be exploited therapeutically in cancers over-expressing EGFR.
doi:10.1038/onc.2012.188
PMCID: PMC3866888  PMID: 22710717
USP2a; DUB; EGFR; endocytosis
22.  Blood and tissue biomarkers in prostate cancer: state of the art 
The Urologic clinics of North America  2010;37(1):131-Contents.
doi:10.1016/j.ucl.2009.11.006
PMCID: PMC3784983  PMID: 20152526
prostate cancer; tissue biomarkers; blood biomarkers; molecular pathology
23.  THE TMPRSS2:ERG REARRANGEMENT, ERG EXPRESSION, AND PROSTATE CANCER OUTCOMES: A COHORT STUDY AND META-ANALYSIS 
Background
Whether the genomic rearrangement TMPRSS2:ERG has prognostic value in prostate cancer is unclear.
Methods
Among men with prostate cancer in the prospective Physicians’ Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random effects models to estimate associations between rearrangement status and outcomes.
Results
The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence, and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence (HR: 0.99; 95% CI: 0.78-1.26) or lethal disease (HR: 0.93; 95% CI: 0.61-1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis (RR≥T3 vs. T2: 1.23; 95% CI: 1.16-1.30) but not with biochemical recurrence (RR: 1.00; 95% CI: 0.86-1.17) or lethal disease (RR: 0.99; 95% CI: 0.47-2.09).
Conclusions
These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy.
Impact
This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy.
doi:10.1158/1055-9965.EPI-12-0042
PMCID: PMC3671609  PMID: 22736790
TMPRSS2:ERG; prostate cancer; gene fusion; biomarker; prognosis
24.  SMAD4–dependent barrier constrains prostate cancer growth and metastatic progression 
Nature  2011;470(7333):269-273.
Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression1. Here,we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP–SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment con-firmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.
doi:10.1038/nature09677
PMCID: PMC3753179  PMID: 21289624
25.  Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications 
Purpose
More than 1,300,000 prostate needle biopsies are performed annually in the U.S. with up to 16% incidence of isolated high-grade prostatic intraepithelial neoplasia (HGPIN). HGPIN has low predictive value for identifying prostate cancer (PCA) on subsequent needle biopsies in PSA screened populations. In contemporary series, PCA is detected in about 20% of repeat biopsies following a diagnosis of HGPIN. Further, discrete histological subtypes of HGPIN with clinical implication in management have not been characterized. The TMPRSS2-ERG gene fusion that has recently been described in PCA has also been demonstrated to occur in a subset of HGPIN. This may have significant clinical implications given that TMPRSS2-ERG fusion PCA is associated with a more aggressive clinical course.
Experimental Design
In this study we assessed a series of HGPIN lesions and paired PCA for the presence of TMPRSS2-ERG gene fusion.
Results
Fusion positive HGPIN was observed in 16% of the 143 number of lesions, and in all instances the matching cancer shared the same fusion pattern. 60% of TMPRSS2-ERG fusion PCA had fusion negative HGPIN.
Conclusions
Given the more aggressive nature of TMPRSS2-ERG PCA, the findings of this study raise the possibility that gene fusion positive HGPIN lesions are harbingers of more aggressive disease. To date, pathological, molecular and clinical parameters do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. Our results suggest that the detection of isolated TMPRSS2-ERG fusion HGPIN would improve the positive predictive value of finding TMPRSS2-ERG fusion PCA in subsequent biopsies.
doi:10.1158/1078-0432.CCR-07-5194
PMCID: PMC3717517  PMID: 18519767

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