Emmanuel S Antonarakis

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (109)741.45 Total impact

  • M Nakazawa · C Lu · Y Chen · C J Paller · M A Carducci · M A Eisenberger · J Luo · E S Antonarakis
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    ABSTRACT: We previously showed that pre-treatment detection of androgen receptor splice variant-7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) is associated with resistance to abiraterone and enzalutamide, but not to taxane chemotherapies. Here, we conducted serial measurements of AR-V7 and evaluated patterns of longitudinal AR-V7 dynamics over the course of multiple sequential therapies. Metastatic prostate cancer patients treated at Johns Hopkins with AR-directed therapies or taxane chemotherapies underwent serial liquid biopsies for CTC-based AR-V7 analysis at baseline, during therapy, and at progression. We used a CTC enrichment platform followed by multiplexed reverse-transcription polymerase chain reaction analysis to detect full-length androgen receptor and AR-V7 transcripts. Patients selected for inclusion in this report were those who provided ≥4 CTC samples, at least one of which was AR-V7-positive, over the course of ≥2 consecutive therapies. We identified 14 patients who received a total of 37 therapies and contributed 70 CTC samples for AR-V7 analysis during a median follow-up period of 11 months. Three patients remained AR-V7-positive during the entire course of therapy. The remainder underwent transitions in AR-V7 status: there were 8 instances of 'conversions' from AR-V7-negative to positive status (during treatment with first-line ADT, abiraterone, enzalutamide, and docetaxel), and 6 instances of 'reversions' from AR-V7-positive to negative status (during treatment with docetaxel and cabazitaxel). AR-V7 is a dynamic marker, and transitions in AR-V7 status may reflect selective pressures on the tumor exerted by therapeutic interventions. While 'conversions' to AR-V7-positive status were observed with both AR-directed therapies and taxane chemotherapies, 'reversions' to AR-V7-negative status only occurred during taxane therapies. Serial blood-based AR-V7 testing is feasible in routine clinical practice, and may provide insights into temporal changes in tumor evolution. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Annals of Oncology 06/2015; DOI:10.1093/annonc/mdv282 · 6.58 Impact Factor
  • Benjamin L Maughan · Emmanuel S Antonarakis
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    ABSTRACT: Metastatic prostate cancer is an incurable disease that is treated with a variety of hormonal therapies targeting various nodes of the androgen receptor (AR) pathway. Invariably patients develop resistance and become castration resistant. Common treatments for castration-resistant disease include novel hormonal therapies, such as abiraterone and enzalutamide, chemotherapy, immunotherapy and radiopharmaceuticals. As this disease generally remains incurable, understanding the molecular underpinnings of resistance pathways is critical in designing therapeutic strategies to delay or overcome such resistance. Areas covered: This review will explore the resistance mechanisms relevant to hormonal agents, such as AR-V7 expression and others, as well as discussing new approaches being developed to treat patients with castration-resistant prostate cancer that take advantage of these new insights. A literature search was performed to identify all published clinical trials related to androgen therapy mechanisms of drug resistance in metastatic castration-resistant prostate cancer. Expert opinion: Androgen therapy resistance mechanisms are varied, and include modification of all nodes in the androgen signaling pathway. The optimal treatment for men with relapsed metastatic castration-resistant prostate cancer is uncertain at this time. The authors recommend using available clinical data to guide treatment decision making until more specific biomarkers are clinically available.
    Expert Opinion on Pharmacotherapy 06/2015; 16(10):1-17. DOI:10.1517/14656566.2015.1055249 · 3.09 Impact Factor
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    ABSTRACT: Correlative human studies suggest that the pleiotropic cytokine interleukin-6 (IL-6) contributes to the development and/or progression of prostate cancer. However, the source of IL-6 production in the prostate microenvironment in patients has yet to be determined. The cellular origin of IL-6 in primary and metastatic prostate cancer was examined in formalin-fixed, paraffin-embedded (FFPE) tissues using a highly sensitive and specific chromogenic in situ hybridization (CISH) assay that underwent extensive analytical validation. Quantitative RT-PCR (q-RT-PCR) showed that benign prostate tissues often had higher expression of IL-6 mRNA than matched tumor specimens. CISH analysis further indicated that both primary and metastatic prostate adenocarcinoma cells do not express IL-6 mRNA. IL-6 expression was highly heterogeneous across specimens and was nearly exclusively restricted to the prostate stromal compartment - including endothelial cells and macrophages among other cell types. The number of IL-6-expressing cells correlated positively with the presence of acute inflammation. In metastatic disease, tumor cells were negative in all lesions examined and IL-6 expression was restricted to endothelial cells within the vasculature of bone metastases. Finally, IL-6 was not detected in any cells in soft tissue metastases. These data suggest that, in prostate cancer patients, paracrine rather than autocrine IL-6 production is likely associated with any role for the cytokine in disease progression. Copyright © 2015, American Association for Cancer Research.
    06/2015; DOI:10.1158/2326-6066.CIR-15-0013
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    ABSTRACT: We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown. To investigate whether AR-V7-positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men. We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men. We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates, PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone). Of 37 taxane-treated patients enrolled, 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7-positive and AR-V7-negative men (41% vs 65%; P = .19). Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7-positive and AR-V7-negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7-positive men, whereas outcomes did not differ by treatment type in AR-V7-negative men. In AR-V7-positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003). Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7-positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7-negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell-based AR-V7 detection may serve as a treatment selection biomarker in CRPC.
    06/2015; DOI:10.1001/jamaoncol.2015.1341
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    ABSTRACT: BACKGROUND New therapies are being explored as therapeutic options for men with biochemically recurrent prostate cancer (BRPC) who wish to defer androgen deprivation therapy. MPX is pulverized muscadine grape (Vitis rotundifolia) skin that contains ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro.METHODS In the phase I portion of this phase I/II study, non-metastatic BRPC patients were assigned to increasing doses of MPX (Muscadine Naturals. Inc., Clemmons, NC) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Initial dose selection was based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. The primary endpoint was the recommended phase II dosing regimen.RESULTSThe cohort (n = 14, 71% Caucasian, 29% black) had a median follow-up of 19.2 (6.2–29.7) months, median age of 61 years, and median Gleason score of 7. Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 eructation. No other related adverse events were reported and one patient reported improvement of chronic constipation. Six of 14 patients came off study for disease progression (five metastatic, one rising PSA) after exposure for a median of 15 months. One patient came off for myasthenia gravis that was unrelated to treatment. Seven patients remain on study. The lack of dose-limiting toxicities led to the selection of 4,000 mg/d as the highest dose for further study. Median within-patient PSADT increased by 5.3 months (non-significant, P = 0.17). No patients experienced a maintained decline in serum PSA from baseline.CONCLUSION These data suggest that 4,000 mg of MPX is safe, and exploratory review of a lengthening in PSADT of a median of 5.3 months supports further exploration of MPX. Both low-dose (500 mg) and high-dose (4,000 mg) MPX are being further investigated in a randomized, multicenter, placebo-controlled, dose-evaluating phase II trial. Prostate 9999: XX–XX, 2015. © 2015 Wiley Periodicals, Inc.
    The Prostate 05/2015; DOI:10.1002/pros.23024 · 3.57 Impact Factor
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    ABSTRACT: Prostate-specific membrane antigen (PSMA) is a recognized target for imaging prostate cancer. Here we present initial safety, biodistribution, and radiation dosimetry results with [(18)F]DCFPyL, a second-generation fluorine-18-labeled small-molecule PSMA inhibitor, in patients with prostate cancer. Biodistribution was evaluated using sequential positron-emission tomography (PET) scans in nine patients with prostate cancer. Time-activity curves from the most avid tumor foci were determined. The radiation dose to selected organs was estimated using OLINDA/EXM. No major radiotracer-specific adverse events were observed. Physiologic accumulation was observed in known sites of PSMA expression. Accumulation in putative sites of prostate cancer was observed (SUVmax up to >100, and tumor-to-blood ratios up to >50). The effective radiation dose from [(18)F]DCFPyL was 0.0139 mGy/MBq or 5 mGy (0.5 rem) from an injected dose of 370 MBq (10 mCi). [(18)F]DCFPyL is safe with biodistribution as expected, and its accumulation is high in presumed primary and metastatic foci. The radiation dose from [(18)F]DCFPyL is similar to that from other PET radiotracers.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 04/2015; 17(4). DOI:10.1007/s11307-015-0850-8 · 2.87 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e1089-e1090. DOI:10.1016/j.juro.2015.02.1960 · 3.75 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e1090. DOI:10.1016/j.juro.2015.02.1961 · 3.75 Impact Factor
  • Daniel L Suzman · Emmanuel S Antonarakis
    Journal of Clinical Oncology 03/2015; 33(10). DOI:10.1200/JCO.2014.60.1419 · 18.43 Impact Factor
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    ABSTRACT: Background:Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel.Methods:We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel.Results:Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, 30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2-9.1), 4.0 (3.2-4.8), 4.1 (2.9-5.4) and 2.8 (2.5-3.2) months; median duration of enzalutamide was 9.1 (7.3-not reached), 4.7 (3.7-7.7), 5.4 (3.8-8.4) and 3.9 (3.0-4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7-16.5). 12-month OS was 78% (59-100%), 64% (45-90%), 77% (61-97%) and 51% (41-62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved 30% PSA decline with subsequent enzalutamide.Conclusions:The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.Prostate Cancer and Prostatic Disease advance online publication, 20 January 2015; doi:10.1038/pcan.2014.53.
    Prostate Cancer and Prostatic Diseases 01/2015; 18(2). DOI:10.1038/pcan.2014.53 · 2.83 Impact Factor
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    ABSTRACT: Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment. However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death. Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28). After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy. Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar androgen therapy (BAT). BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients). Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs. BAT shows promise as treatment for CRPC and should be further evaluated in larger trials. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 01/2015; 7(269):269ra2-269ra2. DOI:10.1126/scitranslmed.3010563 · 14.41 Impact Factor
  • Emmanuel S Antonarakis
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    ABSTRACT: There is an emerging interest in understanding mechanisms of response and resistance to next-generation hormonal therapies: abiraterone and enzalutamide. While many explanations for resistance to these agents have been postulated, the importance of androgen receptor splice variants is gaining momentum. Androgen receptor (AR) splice variants are constitutively active isoforms of the AR that lack the ligand-binding domain yet retain their transcriptional activity in a ligand-independent fashion. Of these, AR variant-7 may be the most important, and has been implicated in primary resistance to abiraterone and enzalutamide in men with advanced prostate cancer. In this editorial, the clinical relevance of AR splice variant-7 (AR-V7) will be reviewed within the context of AR-directed therapies, and next steps for the analytical and clinical validation of this potential biomarker will be proposed.
    Expert Review of Anticancer Therapy 12/2014; 15(2):1-3. DOI:10.1586/14737140.2015.999044 · 3.06 Impact Factor
  • Emmanuel S Antonarakis · Mary Nakazawa · Jun Luo
    New England Journal of Medicine 12/2014; 371(23):2234. DOI:10.1056/NEJMc1412594 · 54.42 Impact Factor
  • D L Suzman · X C Zhou · M L Zahurak · J Lin · E S Antonarakis
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    ABSTRACT: BACKGROUND:Multiple phase-2 trials in men with biochemically-recurrent prostate cancer (BRPC) have assessed the impact of nonhormonal agents on PSA kinetics. We have previously demonstrated that changes in PSA kinetics correlate with metastasis-free survival; however, it is unknown whether these changes also correlate with overall survival (OS).METHODS:We performed a combined retrospective analysis of 146 men with BRPC treated on phase-2 trials using one of four investigational drugs: lenalidomide (n=60), marimastat (n=39), ATN-224 (n=22) and imatinib (n=25). We examined factors influencing OS, including within-subject changes in PSA kinetics (PSA slope, PSA doubling time and PSA velocity), before and 6 months after treatment initiation.RESULTS:After a median follow-up of 83.1 months, 49 of 146 men had died. In univariate Cox regression analysis, two factors were associated with OS: baseline PSA velocity and change in PSA velocity on therapy. In a landmark multivariable model, stratified by study (which controlled for age, Gleason score, type of local therapy and use of androgen-deprivation therapy prior to metastases), baseline PSA velocity and increase in PSA velocity on therapy remained independent predictors of OS. Median OS for men with an increase in PSA velocity on treatment was 115.4 months and was not reached for men with a decrease in PSA velocity (hazard ratio=0.47, 95% confidence interval 0.25-0.88; P=0.02).CONCLUSIONS:This hypothesis-generating study suggests that within-subject changes in PSA velocity after initiation of nonhormonal therapy may correlate with OS in men with BRPC. If validated in prospective trials, change in PSA velocity may represent a reasonable intermediate end point for screening new agents in these patients.Prostate Cancer and Prostatic Disease advance online publication, 11 November 2014; doi:10.1038/pcan.2014.44.
    Prostate Cancer and Prostatic Diseases 11/2014; 18(1). DOI:10.1038/pcan.2014.44 · 2.83 Impact Factor
  • European Journal of Cancer 11/2014; 50. DOI:10.1016/S0959-8049(14)70130-3 · 4.82 Impact Factor
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    ABSTRACT: BACKGROUND Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting.METHODS We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (≥ 50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models.RESULTSOne-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P = 0.089). Median TTPP was 7.2 months (95% CI = 4.5 – 17.2) in the D-naïve group versus 2.6 mo (95% CI = 1.9 – 3.5) in the D-pretreated group (P < 0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI = 2.5 – 4.8) for D-pretreated men (P < 0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR = 2.32; 95% CI = 1.19 – 4.50; P = 0.013) and marginally significant for PFS (HR = 1.90; 95% CI = 0.94 – 3.84; P = 0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n = 34), results suggested a trend towards shorter duration of response in D-pretreated patients.CONCLUSIONS The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 11/2014; 74(15). DOI:10.1002/pros.22874 · 3.57 Impact Factor
  • European Journal of Cancer 11/2014; 50:143. DOI:10.1016/S0959-8049(14)70560-X · 4.82 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):1648-1648. DOI:10.1158/1538-7445.AM2014-1648 · 9.28 Impact Factor
  • Daniel L Suzman · Emmanuel S Antonarakis
    Oncology (Williston Park, N.Y.) 10/2014; 28(10). · 2.98 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2910-2910. DOI:10.1158/1538-7445.AM2014-2910 · 9.28 Impact Factor

Publication Stats

994 Citations
741.45 Total Impact Points

Institutions

  • 2007–2015
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, Maryland, United States
  • 2006–2015
    • Johns Hopkins Medicine
      • Department of Medicine
      Baltimore, Maryland, United States
    • University of Wales
      Cardiff, Wales, United Kingdom
  • 2014
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2013
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 2010
    • Walter Reed National Military Medical Center
      • Department of Surgery
      Washington, Washington, D.C., United States
  • 2009
    • Wayne State University
      Detroit, Michigan, United States