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1.  Androgenic Biomarker Profiling in Human Matrices and Cell Culture Samples Using High Through put, Electrospray Tandem Mass Spectrometry 
The Prostate  2014;74(7):722-731.
A high throughput, high pressure liquid chromatographic (HPLC) method with triple quadrupole mass spectral detection (LC/MS/MS) was validated for the measurement of 5 endogenous androgens in human plasma and serum and applied to various in vivo and in vitro study samples to pursue a better understanding of the interrelationship of the androgen axis, intracrine metabolism, and castration-recurrent prostate cancer (CaP).
A Shimadzu HPLC system interfaced with a Sciex QTRAP 5500 mass spectrometer with electrospray ionization was used with inline column-switching. Samples were liquid/liquid extracted and chromatographed on a Luna C18(2) column at 60°C with a biphasic gradient using a 15-min run time.
The method was validated for five androgens in human plasma and serum, and applied to four sets of samples. Plasma (n = 188) and bone marrow aspirate (n = 129) samples from patients with CaP, who received abiraterone acetate plus prednisone for up to 945 days (135 weeks), had undetectable androgens after 8 weeks of treatment. Plasma dehydroepiandrosterone (DHEA) concentrations were higher in African Americans than Caucasian Americans with newly diagnosed CaP. Analysis of prostate tumor tissue homogenates demonstrated reproducible testosterone (T) and dihydrotestosterone (DHT) concentrations with a minimal sample size of ~1.0–2.0 mg of tissue. Finally, cell pellet and media samples from the LNCaP C4-2 cell line showed conversion of T to DHT.
The proposed LC/MS/MS method was validated for quantitation of five endogenous androgens in human plasma and serum, and effectively profiles androgens in clinical specimens and cell culture samples.
PMCID: PMC4335642  PMID: 24847527
androgen axis; prostate cancer; testosterone; dihydrotestosterone; steroid 5α-reductase; LC/MS/MS
2.  Molecular Classification of Prostate Cancer Progression: Foundation for Marker driven-Treatment of Prostate Cancer 
Cancer discovery  2013;3(8):849-861.
Recently, many therapeutic agents for prostate cancer (PCa) have been approved that target the androgen receptor and/or the prostate tumor microenvironment. Each of these therapies has modestly increased patient survival. However, if a better understanding as to when in the course of PCa progression specific therapies should be applied, and what biomarkers would indicate when resistance arises, survival due to these therapies would almost certainly improve. Thus, applying the armamentarium of therapeutic agents in the right sequences in the right combination at the right time is a major goal in prostate cancer treatment. For this to occur, an understanding of prostate cancer evolution during progression is required. In this review, we discuss the current understanding of PCa progression, but challenge the prevailing view by proposing a new model of PCa progression, with the goal of improving biologic classification and treatment strategies. We use this model to discuss how integrating clinical and basic understanding of PCa will lead to better implementation of molecularly-targeted therapeutics and improve patient survival.
PMCID: PMC3926428  PMID: 23811619
3.  Glucocorticoid Receptor Confers Resistance to Anti-Androgens by Bypassing Androgen Receptor Blockade 
Cell  2013;155(6):1309-1322.
The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a novel mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
PMCID: PMC3932525  PMID: 24315100
4.  Modeling A Lethal Prostate Cancer Variant with Small Cell Carcinoma Features 
Small-cell prostate carcinoma (SCPC) morphology predicts for a distinct clinical behavior, resistance to androgen ablation, and frequent but short responses to chemotherapy. We sought to develop model systems that reflect human SCPC and can improve our understanding of its biology.
Experimental Design
We developed a set of CRPC xenografts and examined their fidelity to their human tumors of origin. We compared the expression and genomic profiles of SCPC and large cell neuroendocrine carcinoma (LCNEC) xenografts to those of typical prostate adenocarcinoma xenografts. Results were validated immunohistochemically in a panel of 60 human tumors.
The reported SCPC and LCNEC xenografts retain high fidelity to their human tumors of origin and are characterized by a marked upregulation of UBE2C and other mitotic genes in the absence of AR, retinoblastoma (RB1) and cyclin D1 (CCND1) expression. We confirmed these findings in a panel of CRPC patients' samples. In addition, array comparative genomic hybridization of the xenografts showed that the SCPC/LCNEC tumors display more copy number variations than the adenocarcinoma counterparts. Amplification of the UBE2C locus and microdeletions of RB1 were present in a subset, but none displayed AR nor CCND1 deletions. The AR, RB1, and CCND1 promoters showed no CpG methylation in the SCPC xenografts.
Modeling human prostate carcinoma with xenografts allows in-depth and detailed studies of its underlying biology. The detailed clinical annotation of the donor tumors enables associations of anticipated relevance to be made. Futures studies in the xenografts will address the functional significance of the findings.
PMCID: PMC3923417  PMID: 22156612
castration resistance prostate cancer; small cell neuroendocrine carcinoma; retinoblastoma; UBE2C; cyclin D1
5.  A New Therapy Paradigm for Prostate Cancer Founded on Clinical Observations 
Efficacy equivalent to that reported in other common adult solid tumors considered to be chemotherapy-sensitive has been reported with Docetaxel in patients with castrate-resistant prostate cancer. However, in contrast to other cancers, the expected increase in efficacy with the use of chemotherapy in earlier disease states has not been reported to date in prostate cancer. On the basis of these observations, we speculated that the therapy development paradigm used successfully in other cancers may not apply to the majority of prostate cancers. Several lines of supporting clinical and experimental observations implicate the tumor microenvironment in prostate carcinogenesis and resistance to therapy.
We conclude that a foundation to guide the development of therapy for prostate cancer is required. The therapy paradigm we propose accounts for the central role of the tumor microenvironment in bone and, if correct, will lead to microenvironment-targeted therapy.
PMCID: PMC3891669  PMID: 20145177
6.  Randomized Phase 3 Trial of Abiraterone Acetate in Men with Metastatic Castration-Resistant Prostate Cancer and No Prior Chemotherapy 
The New England journal of medicine  2012;368(2):138-148.
Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy. Many mCRPC patients never receive chemotherapy and thus cannot benefit from abiraterone acetate; we evaluated this agent in mCRPC patients who had not received chemotherapy.
In this double-blind study, 1088 patients were randomized 1:1 to abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. Co-primary end points were radiographic progression-free survival (rPFS) and OS. Secondary end points measured clinically relevant landmarks of mCRPC progression. Patient-reported outcomes included pain progression and quality of life.
The study was unblinded after a planned interim analysis (IA) at 43% of OS events. Treatment with abiraterone acetate-prednisone resulted in a 57% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.43; 95% confidence interval [CI]: 0.35 to 0.52; P<0.001; 13% OS events IA) and an estimated 25% decrease in the risk of death (HR, 0.75; 95% CI: 0.61 to 0.93; P=0.009; 43% OS events IA). Secondary end points supported superiority of abiraterone acetate-prednisone: time to cytotoxic chemotherapy initiation, opiate use for cancer-related pain, prostate-specific antigen progression (all P<0.001) and performance status deterioration (P=0.005). Self-reported time to pain progression and patient functional status degradation favored abiraterone acetate-prednisone (P=0.05 and P=0.003). Grade 3/4 mineralocorticoid-related adverse events and liver function test abnormalities were more common with abiraterone acetate-prednisone.
Abiraterone acetate produces OS and rPFS benefits, as well as significant delays in clinical deterioration and initiation of chemotherapy, in mCRPC.
PMCID: PMC3683570  PMID: 23228172
Abiraterone acetate; prednisone; metastatic castration-resistant prostate cancer; androgen; CYP17
7.  Integrated Hedgehog signaling is induced following castration in human and murine prostate cancers 
The Prostate  2012;73(2):10.1002/pros.22550.
The interplay between androgen and Hedgehog (Hh) signaling pathways may be associated with prostate cancer progression and resistance to therapy.
Tissue microarrays from prostatectomy specimens were derived from 53 patients treated preoperatively with androgen ablation (AA) with or without chemotherapy, and from 26 stage- and grade-matched controls. A previously characterized androgen-regulated human prostate cancer xenograft was used to conduct parallel murine studies. Expression of markers of interest was determined on both untreated and castrated tumors.
Four-month exposure to AA or AA with chemotherapy led to a uniform increase in Hh signaling as compared to controls, paired with an inverse trend of androgen receptor (AR) and CYP17 expression in clinically derived specimens. Changes in the expression profiles of Hh signaling were observed in the epithelium and stroma, in response to genotoxic stress of androgen ablation and chemotherapy. A reduced expression of KI67and increased bcl2 expression was observed in the malignant epithelial compartment.
To our knowledge, this is the first clinical evidence that Hh signaling is induced by AA or the combination of AA and chemotherapy and, by inference, contributes to castrate-resistant progression of prostate cancer as supported by parallel human and murine studies. These data are in agreement with previous reports that implicate Hh signaling in castrate-resistant progression of prostate cancer. Based on these findings, we are pursuing parallel clinical and murine investigations to determine if Hh signaling inhibition combined with AA will be more effective than AA alone.
PMCID: PMC3878994  PMID: 22753310
Prostate cancer; preoperative treatment; Hedgehog signaling; resistance to treatment; androgen ablation
8.  Recurrent seminomas: Clinical features and biologic implications 
Urologic oncology  2010;30(4):10.1016/j.urolonc.2010.05.011.
Certain patients with seminoma and clinically atypical phenotypes—visceral metastases, elevated levels of βhuman chorionic gonadotropin (βHCG), and/or recurrent disease— have a poor prognosis. The primary goal of this pilot study was to characterize the clinical characteristics and treatment profile of these rare patients. We also wished to test whether these tumors expressed any specific biomarkers that might distinguish them as a unique subtype of seminoma.
Materials and methods
We retrospectively identified 25 patients with a history of seminoma plus visceral metastases, βHCG levels >200 mU/ml, and/or recurrent disease. We reviewed these patients’ histories for treatment efficacy and clinical outcome. Tissue samples were available from 6 of those patients, and we studied them for expression of the markers OCT 3/4, PLAP, CD30, TRA-1-60, c-kit, and gp200. We compared our results with the expression of those markers in tissue samples from mixed seminoma/embryonal carcinomas and classic seminomas.
Our analysis suggested that certain chemotherapeutic regimens (such as ifosfamide, paclitaxel, and cisplatin) are efficacious for the treatment of patients with these atypical seminomas. Further, specimens from the atypical seminomas generally had staining profiles that resembled those of classic seminomas and the seminoma components in mixed germ-cell tumors, but the profiles differed from those of the embryonal carcinoma components in the same mixed germ-cell tumors.
Although these atypical seminomas tend to be resistant to chemotherapy, they may still respond to certain chemotherapeutic regimens. Our pilot immunohistochemical study also suggested that the unique phenotypes associated with these atypical seminomas do not result from any relationship with embryonal carcinomas. More study is needed to confirm these initial findings.
PMCID: PMC3856193  PMID: 20822932
Seminoma; Testicular neoplasms; Embryonal carcinoma; TRA-1-60; gp200
9.  Phase II Study of Abiraterone Acetate Plus Prednisone in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer Demonstrating Radiographic Flare Discordant With Serologic Measures of Response 
Abiraterone is an oral inhibitor of CYP17, essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with CRPC without prior exposure to chemotherapy or CYP17 targeted therapy, and assessed the frequency of interpretation of bone scans discordant with PSA and clinical response.
Patients and Methods
33 patients received abiraterone acetate 1000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating “disease progression” in the context of a ≥50% decline in PSA, with scan improvement 3 months later.
A ≥ 50% PSA decline at week 12 was confirmed in 22/33 (67%) patients. PSA declines of ≥ 50% were seen in 26 (79%) patients. Undetectable PSA levels (≤ 0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression are 63 and 71 weeks, respectively. Twenty three patients were evaluable for bone scan flare. Progression was indicated in the radiologist's report in 12/23 (52 %), and 10/12 subsequently showed improvement. As prospectively defined, bone scan flare was observed in 10/23 (43.5%) evaluable patients or 10/33 (30%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports.
Clinical response to abiraterone acetate plus prednisone was frequent and durable in men with metastatic CRPC progressing on hormonal therapy with over half of patients on therapy > 1 year. Further investigation is needed to clarify the potential confounding effect of the frequently occurring bone scan flare phenomena on patient management and interpretation of clinical trial results.
PMCID: PMC3657705  PMID: 21632851
abiraterone acetate; castration-resistant prostate cancer; CRPC; hormone-resistant prostate cancer; therapy; efficacy
10.  Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone 
Journal of Clinical Oncology  2011;30(6):637-643.
Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow–infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations.
Patients and Methods
This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues.
Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression.
The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.
PMCID: PMC3295561  PMID: 22184395
11.  Activation of Beta-Catenin Signaling in Androgen Receptor–Negative Prostate Cancer Cells 
Clinical Cancer Research  2012;18(3):726-736.
To study Wnt/beta-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the beta-catenin–androgen receptor (AR) interaction.
Experimental Design
We performed beta-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of beta-catenin–mediated transcription), and sequenced the beta-catenin gene in MDA PCa 118a, MDA PCa 118b, MDA PCa 2b, and PC-3 prostate cancer (PCa) cells. We knocked down beta-catenin in AR-negative MDA PCa 118b cells and performed comparative gene-array analysis. We also immunohistochemically analyzed beta-catenin and AR in 27 bone metastases of human CRPCs.
Beta-catenin nuclear accumulation and TOP-flash reporter activity were high in MDA PCa 118b but not in MDA PCa 2b or PC-3 cells. MDA PCa 118a and 118b cells carry a mutated beta-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA PCa 118b cells with downregulated beta-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant beta-catenin. Finally, we found nuclear localization of beta-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher’s exact test), suggesting that reduced AR expression enables Wnt/beta-catenin signaling.
We identified a previously unknown downstream target of beta-catenin, HAS2, in PCa, and found that high beta-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone-metastatic PCa. These findings may guide physicians in managing these patients.
PMCID: PMC3271798  PMID: 22298898
beta-catenin; prostate cancer; androgen receptor; hyaluronan synthase
12.  Androgen Deprivation Therapy and Cardiovascular Risk 
Nephro-urology monthly  2012;5(1):653-654.
PMCID: PMC3614327  PMID: 23577326
Androgen Antagonists; Androgens; Prostatic Neoplasms; Cardiovascular system
13.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 number, NCT00638690.)
PMCID: PMC3471149  PMID: 21612468
14.  Persistent, Biologically Meaningful Prostate Cancer After 1 Year of Androgen Ablation and Docetaxel Treatment 
Journal of Clinical Oncology  2011;29(18):2574-2581.
Clinicians are increasingly willing to treat prostate cancer within the primary site in the presence of regional lymph node or even limited distant metastases. However, no formal study on the merits of this approach has been reported. We used a preoperative clinical discovery platform to prioritize pathways for assessment as therapeutic targets and to test the hypothesis that the primary site harbors potentially lethal tumors after aggressive treatment.
Patients and Methods
Patients with locally advanced or lymph node–metastatic prostate cancer underwent 1 year of androgen ablation and three cycles of docetaxel therapy, followed by prostatectomy. All specimens were characterized for stage by accepted criteria. Expression of select molecular markers implicated in disease progression and therapy resistance was determined immunohistochemically and compared with that in 30 archived specimens from untreated patients with high-grade prostate cancer. Marker expression was divided into three groups: intracellular signaling pathways, stromal-epithelial interaction pathways, and angiogenesis.
Forty patients were enrolled, 30 (75%) of whom underwent prostatectomy and two (5%) who underwent cystoprostatectomy. Twenty-nine specimens contained sufficient residual tumor for inclusion in a tissue microarray. Immunohistochemical analysis showed increased epithelial and stromal expression of CYP17, SRD5A1, and Hedgehog pathway components, and modulations of the insulin-like growth factor I pathway.
A network of molecular pathways reportedly linked to prostate cancer progression is activated after 1 year of therapy; biomarker expression suggests that potentially lethal cancers persist in the primary tumor and may contribute to progression.
PMCID: PMC3138635  PMID: 21606419
15.  Mitosis Phase Enrichment with Identification of Mitotic Centromere-Associated Kinesin As a Therapeutic Target in Castration-Resistant Prostate Cancer 
PLoS ONE  2012;7(2):e31259.
The recently described transcriptomic switch to a mitosis program in castration-resistant prostate cancer (CRPC) suggests that mitotic proteins may be rationally targeted at this lethal stage of the disease. In this study, we showed upregulation of the mitosis-phase at the protein level in our cohort of 51 clinical CRPC cases and found centrosomal aberrations to also occur preferentially in CRPC compared with untreated, high Gleason–grade hormone-sensitive prostate cancer (P<0.0001). Expression profiling of chemotherapy-resistant CRPC samples (n = 25) was performed, and the results were compared with data from primary chemotherapy-naïve CRPC (n = 10) and hormone-sensitive prostate cancer cases (n = 108). Our results showed enrichment of mitosis-phase genes and pathways, with progression to both castration-resistant and chemotherapy-resistant disease. The mitotic centromere-associated kinesin (MCAK) was identified as a novel mitosis-phase target in prostate cancer that was overexpressed in multiple CRPC gene-expression datasets. We found concordant gene expression of MCAK between our parent and murine CRPC xenograft pairs and increased MCAK protein expression with clinical progression of prostate cancer to a castration-resistant disease stage. Knockdown of MCAK arrested the growth of prostate cancer cells suggesting its utility as a potential therapeutic target.
PMCID: PMC3281954  PMID: 22363599
16.  Morphologic Characterization of Preoperatively Treated Prostate Cancer: Toward a Post-Therapy Histologic Classification 
European urology  2009;57(6):1030-1038.
Preoperative treatment of prostate cancer (PCa) changes morphology of residual tumors so that the Gleason score is no longer valid.
To codify morphologic features of preoperatively treated PCa and identify potential classifiers predictive of outcome.
Design, setting, and participants
We performed a detailed morphologic evaluation of specimens obtained from 115 patients with high-risk PCa who had preoperative androgen ablation, alone or in combination with chemotherapy.
Included hierarchical clustering analysis of morphologic characteristics, associations with other pathologic parameters, and univariate and multivariate analyses in search for associations with disease outcome.
Results and limitations
Based on hierarchical clustering analysis, we categorized pretreated prostate cancer in three morphologically distinct groups: group A, characterized by a predominance of cell clusters, cell cords, and isolated cells; group B tumors, by intact and fused small glands; and group C tumors by any degree of cribriform growth pattern or intraductal tumor spread.
Univariate analysis identified associations between this grouping, pathologic tumor stage (p < 0.01) and residual tumor volume (p < 0.001). Presence of intraductal spread or cribriform pattern in biopsies was associated with group C tumors. The presence of cribriform or intraductal spread morphology and positive surgical margins were stronger predictors of biochemical relapse than pathologic stage on multivariate analysis. The number of specimens evaluated in this study was limited, and a prospective validation is warranted along with molecular studies to validate the proposed morphologic classifier.
If validated, this classification will introduce uniformity in the selection of tissue samples for biomarker studies, facilitate the comparison of trials among different institutions, and may provide a new prognostic tool for preoperatively treated PCa.
PMCID: PMC2962710  PMID: 19853370
17.  Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study 
Lancet  2010;375(9724):1437-1446.
MDV3100 is a rationally-designed androgen receptor antagonist that blocks androgen receptor (AR) binding, nuclear translocation, and co-activator recruitment more effectively than the androgen receptor antagonists currently in use. MDV3100 is also unique in that it prevents DNA binding, induces apoptosis, and has no agonist activity when AR is overexpressed. Because growth of castration-resistant prostate cancer (CRPC) appears to depend upon continued androgen receptor signaling, we hypothesized that MDV3100 could be effective therapy for men with CRPC. Antitumor activity and safety were assessed in a phase 1-2 trial.
Eligible patients with progressive metastatic CRPC were enrolled in cohorts of 3-6 patients. Once the safety of a dose was established, cohorts were expanded to include at least 12 chemotherapy-naïve and 12 post-chemotherapy treated patients.
140 patients were treated with doses ranging from 30 to 600 mg daily. Positron emission tomography (PET) imaging to assess androgen receptor blockade showed decreased 18-fluorodihydrotestosterone binding at dosages of 60 mg/day and above. Antitumor effects were observed at all dosages including declines in serum PSA of 50% or more in 56% of patients, responses in soft tissue, stabilized bone disease, and conversion from unfavourable to favourable circulating tumour cell counts. The median time to progression was 47 weeks for radiological progression. The maximal tolerated dose for sustained treatment (>28 days) was 240 mg and the most common adverse event was dose-dependent fatigue, which generally resolved following dose reduction.
Encouraging antitumor activity on all outcomes assessed was observed for MDV3100 in both chemotherapy-naïve and post-chemotherapy patients with CRPC, establishing that patients with CRPC are not uniformly hormone-refractory. A phase 3 trial in patients with progressive disease after docetaxel treatment is underway.
PMCID: PMC2948179  PMID: 20398925
18.  Selenium and Vitamin E: Cell Type– and Intervention-Specific Tissue Effects in Prostate Cancer 
Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation.
Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 μg of selenium, 400 IU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided.
The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [CI] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% CI = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance (difference = 21.3%; 95% CI = 0.7 to 41.8; P = .051).
We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis-generating engine. We have also identified cell type– and zone-specific tissue effects of interventions with selenium and vitamin E that may have clinical implications.
PMCID: PMC2734116  PMID: 19244175
19.  Candidate pathways and genes for prostate cancer: a meta-analysis of gene expression data 
BMC Medical Genomics  2009;2:48.
The genetic mechanisms of prostate tumorigenesis remain poorly understood, but with the advent of gene expression array capabilities, we can now produce a large amount of data that can be used to explore the molecular and genetic mechanisms of prostate tumorigenesis.
We conducted a meta-analysis of gene expression data from 18 gene array datasets targeting transition from normal to localized prostate cancer and from localized to metastatic prostate cancer. We functionally annotated the top 500 differentially expressed genes and identified several candidate pathways associated with prostate tumorigeneses.
We found the top differentially expressed genes to be clustered in pathways involving integrin-based cell adhesion: integrin signaling, the actin cytoskeleton, cell death, and cell motility pathways. We also found integrins themselves to be downregulated in the transition from normal prostate tissue to primary localized prostate cancer. Based on the results of this study, we developed a collagen hypothesis of prostate tumorigenesis. According to this hypothesis, the initiating event in prostate tumorigenesis is the age-related decrease in the expression of collagen genes and other genes encoding integrin ligands. This concomitant depletion of integrin ligands leads to the accumulation of ligandless integrin and activation of integrin-associated cell death. To escape integrin-associated death, cells suppress the expression of integrins, which in turn alters the actin cytoskeleton, elevates cell motility and proliferation, and disorganizes prostate histology, contributing to the histologic progression of prostate cancer and its increased metastasizing potential.
The results of this study suggest that prostate tumor progression is associated with the suppression of integrin-based cell adhesion. Suppression of integrin expression driven by integrin-mediated cell death leads to increased cell proliferation and motility and increased tumor malignancy.
PMCID: PMC2731785  PMID: 19653896
20.  Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms 
The Journal of Clinical Investigation  2008;118(8):2697-2710.
In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor–negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer–induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor–null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.
PMCID: PMC2447924  PMID: 18618013
21.  Four cycles of paclitaxel and carboplatin as adjuvant treatment in early-stage ovarian cancer: a six-year experience of the Hellenic Cooperative Oncology Group 
BMC Cancer  2006;6:228.
Surgery can cure a significant percentage of ovarian carcinoma confined to the pelvis. Nevertheless, there is still a 10–50% recurrence rate. We administered paclitaxel/carboplatin as adjuvant treatment in early-stage ovarian carcinoma.
Patients with stages Ia or Ib, Grade 2 or 3 and Ic to IIb (any grade) were included. Patients were treated with 4 cycles of Paclitaxel 175 mg/m2 and Carboplatin [area under the curve (AUC) 6 (Calvert Formula)] every 3 weeks.
Sixty-nine patients with no residual disease following cytoreductive surgery and minimal or modified surgical staging were included in this analysis. Grade 3 or 4 neutropenia occured in 29.9% of patients, while neutropenic fever was reported in 4.5%. Neurotoxicity (all Grade 1 or 2) was reported in 50% of cases. Median follow-up was 62 months. 5-year overall survival (OS) and relapse-free survival (RFS) were: 87% (95% confidence intervals [CI]: 78–96) and 79% (95% CI: 69–89), respectively. Significantly fewer patients with stages Ic-IIb and tumor grade 2 or 3 achieved a 5-year RFS than patients with only one of these two factors (73% vs 92%, p = 0.03).
Paclitaxel/Carboplatin chemotherapy is a safe and effective adjuvant treatment in early-stage ovarian carcinoma. Patients with stages Ic-IIb and tumor grade 2 or 3 may benefit from more extensive treatment.
PMCID: PMC1592509  PMID: 16999858

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