Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study.

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.

journal_name

Sci Transl Med

authors

Schweizer MT,Antonarakis ES,Wang H,Ajiboye AS,Spitz A,Cao H,Luo J,Haffner MC,Yegnasubramanian S,Carducci MA,Eisenberger MA,Isaacs JT,Denmeade SR

doi

10.1126/scitranslmed.3010563

subject

Has Abstract

pub_date

2015-01-07 00:00:00

pages

269ra2

issue

269

eissn

1946-6234

issn

1946-6242

pii

7/269/269ra2

journal_volume

7

pub_type

临床试验,杂志文章
  • William Heberden and reverse translation.

    abstract::Beginning with the 18th-century physician-scientist William Heberden, the elder, Science Translational Medicine introduces a new article series about historical figures whose transformational contributions to science, medicine, and society remain relevant today. ...

    journal_title:Science translational medicine

    pub_type: 历史文章,杂志文章

    doi:10.1126/scitranslmed.aaa2250

    authors: Edelman ER,LaMarco K

    更新日期:2015-05-13 00:00:00

  • Splicing-directed therapy in a new mouse model of human accelerated aging.

    abstract::Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent dev...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3002847

    authors: Osorio FG,Navarro CL,Cadiñanos J,López-Mejía IC,Quirós PM,Bartoli C,Rivera J,Tazi J,Guzmán G,Varela I,Depetris D,de Carlos F,Cobo J,Andrés V,De Sandre-Giovannoli A,Freije JM,Lévy N,López-Otín C

    更新日期:2011-10-26 00:00:00

  • Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response.

    abstract::Venetoclax is a specific B cell lymphoma 2 (BCL-2) inhibitor with promising activity against acute myeloid leukemia (AML), but its clinical efficacy as a single agent or in combination with hypomethylating agents (HMAs), such as azacitidine, is hampered by intrinsic and acquired resistance. Here, we performed a genome...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aax2863

    authors: Sharon D,Cathelin S,Mirali S,Di Trani JM,Yanofsky DJ,Keon KA,Rubinstein JL,Schimmer AD,Ketela T,Chan SM

    更新日期:2019-10-30 00:00:00

  • Quality versus quantity: assessing individual research performance.

    abstract::Evaluating individual research performance is a complex task that ideally examines productivity, scientific impact, and research quality--a task that metrics alone have been unable to achieve. In January 2011, the French Academy of Sciences published a report on current bibliometric (citation metric) methods for evalu...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3002249

    authors: Sahel JA

    更新日期:2011-05-25 00:00:00

  • High-throughput sequencing of the T cell receptor β gene identifies aggressive early-stage mycosis fungoides.

    abstract::Mycosis fungoides (MF), the most common cutaneous T cell lymphoma (CTCL) is a malignancy of skin-tropic memory T cells. Most MF cases present as early stage (stage I A/B, limited to the skin), and these patients typically have a chronic, indolent clinical course. However, a small subset of early-stage cases develop pr...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aar5894

    authors: de Masson A,O'Malley JT,Elco CP,Garcia SS,Divito SJ,Lowry EL,Tawa M,Fisher DC,Devlin PM,Teague JE,Leboeuf NR,Kirsch IR,Robins H,Clark RA,Kupper TS

    更新日期:2018-05-09 00:00:00

  • Temporal dynamics of the human vaginal microbiota.

    abstract::Elucidating the factors that impinge on the stability of bacterial communities in the vagina may help in predicting the risk of diseases that affect women's health. Here, we describe the temporal dynamics of the composition of vaginal bacterial communities in 32 reproductive-age women over a 16-week period. The analys...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3003605

    authors: Gajer P,Brotman RM,Bai G,Sakamoto J,Schütte UM,Zhong X,Koenig SS,Fu L,Ma ZS,Zhou X,Abdo Z,Forney LJ,Ravel J

    更新日期:2012-05-02 00:00:00

  • fMRI in analgesic drug discovery.

    abstract::Functional magnetic resonance imaging offers an unprecedented opportunity to evaluate and compare drug effects on human brain activity and to provide systems-level predictions for how new drugs for chronic pain will affect the brain, thus accelerating drug discovery and repurposing (Duff et al., this issue). ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.3010342

    authors: Wager TD,Woo CW

    更新日期:2015-02-11 00:00:00

  • Complexity in common diseases: big biology for all.

    abstract::The Commentary of Mills and Sykes in Science Translational Medicine presented their thesis on the advent of high-throughput technologies and the dangers they may represent for the future of biomedical research. In response, we argue that true progress on the diagnosis and treatment of common human diseases will requir...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.3000882

    authors: Lamb JR,Gibson NW

    更新日期:2010-03-31 00:00:00

  • Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.

    abstract::KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaw7999

    authors: Molina-Arcas M,Moore C,Rana S,van Maldegem F,Mugarza E,Romero-Clavijo P,Herbert E,Horswell S,Li LS,Janes MR,Hancock DC,Downward J

    更新日期:2019-09-18 00:00:00

  • ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.

    abstract::The aim of treatment in congenital adrenal hyperplasia is to suppress excess adrenal androgens while achieving physiological glucocorticoid replacement. However, current glucocorticoid replacement regimes are inadequate because doses sufficient to suppress excess androgens almost invariably induce adverse metabolic ef...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaf9074

    authors: Nixon M,Mackenzie SD,Taylor AI,Homer NZ,Livingstone DE,Mouras R,Morgan RA,Mole DJ,Stimson RH,Reynolds RM,Elfick AP,Andrew R,Walker BR

    更新日期:2016-08-17 00:00:00

  • Wireless sensors for continuous, multimodal measurements at the skin interface with lower limb prostheses.

    abstract::Precise form-fitting of prosthetic sockets is important for the comfort and well-being of persons with limb amputations. Capabilities for continuous monitoring of pressure and temperature at the skin-prosthesis interface can be valuable in the fitting process and in monitoring for the development of dangerous regions ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.abc4327

    authors: Kwak JW,Han M,Xie Z,Chung HU,Lee JY,Avila R,Yohay J,Chen X,Liang C,Patel M,Jung I,Kim J,Namkoong M,Kwon K,Guo X,Ogle C,Grande D,Ryu D,Kim DH,Madhvapathy S,Liu C,Yang DS,Park Y,Caldwell R,Banks A,Xu S,H

    更新日期:2020-12-16 00:00:00

  • Beyond disease, how biomedical engineering can improve global health.

    abstract::Biomedical engineering tools can be harnessed to address some of the world's most challenging nondisease-focused problems. ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3009067

    authors: LeDuc P,Agaba M,Cheng CM,Gracio J,Guzman A,Middelberg A

    更新日期:2014-12-10 00:00:00

  • IVIG-mediated protection against necrotizing pneumonia caused by MRSA.

    abstract::New therapeutic approaches are urgently needed to improve survival outcomes for patients with necrotizing pneumonia caused by Staphylococcus aureus One such approach is adjunctive treatment with intravenous immunoglobulin (IVIG), but clinical practice guidelines offer conflicting recommendations. In a preclinical rabb...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aag1153

    authors: Diep BA,Le VT,Badiou C,Le HN,Pinheiro MG,Duong AH,Wang X,Dip EC,Aguiar-Alves F,Basuino L,Marbach H,Mai TT,Sarda MN,Kajikawa O,Matute-Bello G,Tkaczyk C,Rasigade JP,Sellman BR,Chambers HF,Lina G

    更新日期:2016-09-21 00:00:00

  • Grease fires turn up the heat in autoimmune disease.

    abstract::Restoring reverse cholesterol transport ameliorates the B cell hyperexpansion and autoimmune disease found to be associated with accumulation of cholesterol in CD11c+ antigen-presenting cells. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aal4997

    authors: Bhakta NR

    更新日期:2017-01-25 00:00:00

  • Endomicroscope sheds light on cervical tissue.

    abstract::A pilot study of a handheld fluorescence endomicroscope demonstrates both in vivo imaging and differentiation of normal from precancerous cervical tissue. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aal4989

    authors: Evans CL

    更新日期:2017-01-11 00:00:00

  • Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients.

    abstract::The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local express...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3007240

    authors: Mlecnik B,Bindea G,Angell HK,Sasso MS,Obenauf AC,Fredriksen T,Lafontaine L,Bilocq AM,Kirilovsky A,Tosolini M,Waldner M,Berger A,Fridman WH,Rafii A,Valge-Archer V,Pagès F,Speicher MR,Galon J

    更新日期:2014-03-19 00:00:00

  • Researching genetic versus nongenetic determinants of disease: a comparison and proposed unification.

    abstract::Research standards deviate in genetic versus nongenetic epidemiology. Besides some immutable differences, such as the correlation pattern between variables, these divergent research standards can converge considerably. Current research designs that dissociate genetic and nongenetic measurements are reaching their limi...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000247

    authors: Ioannidis JP,Loy EY,Poulton R,Chia KS

    更新日期:2009-11-18 00:00:00

  • An extracorporeal bioartificial liver embedded with 3D-layered human liver progenitor-like cells relieves acute liver failure in pigs.

    abstract::Clinical advancement of the bioartificial liver is hampered by the lack of expandable human hepatocytes and appropriate bioreactors and carriers to encourage hepatic cells to function during extracorporeal circulation. We have recently developed an efficient approach for derivation of expandable liver progenitor-like ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aba5146

    authors: Li WJ,Zhu XJ,Yuan TJ,Wang ZY,Bian ZQ,Jing HS,Shi X,Chen CY,Fu GB,Huang WJ,Shi YP,Liu Q,Zeng M,Zhang HD,Wu HP,Yu WF,Zhai B,Yan HX

    更新日期:2020-07-08 00:00:00

  • Rapid emergence of protease inhibitor resistance in hepatitis C virus.

    abstract::About 170 million people worldwide are infected with hepatitis C virus (HCV). The current standard therapy leads to sustained viral elimination in only approximately 50% of the treated patients. Telaprevir, an HCV protease inhibitor, has substantial antiviral activity in patients with chronic HCV infection. However, i...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000544

    authors: Rong L,Dahari H,Ribeiro RM,Perelson AS

    更新日期:2010-05-05 00:00:00

  • Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner.

    abstract::Variants in the leucine-rich repeat kinase-2 (LRRK2) gene are associated with Parkinson's disease, leprosy, and Crohn's disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested t...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aas9292

    authors: Shutinoski B,Hakimi M,Harmsen IE,Lunn M,Rocha J,Lengacher N,Zhou YY,Khan J,Nguyen A,Hake-Volling Q,El-Kodsi D,Li J,Alikashani A,Beauchamp C,Majithia J,Coombs K,Shimshek D,Marcogliese PC,Park DS,Rioux JD,Philpott D

    更新日期:2019-09-25 00:00:00

  • Sex matters for mechanism.

    abstract::Some funding agencies now require consideration of sex and gender in preclinical research, a policy that heralds opportunities and challenges for researchers. ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3009859

    authors: Danska JS

    更新日期:2014-10-15 00:00:00

  • Achieving a nationwide learning health system.

    abstract::We outline the fundamental properties of a highly participatory rapid learning system that can be developed in part from meaningful use of electronic health records (EHRs). Future widespread adoption of EHRs will make increasing amounts of medical information available in computable form. Secured and trusted use of th...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3001456

    authors: Friedman CP,Wong AK,Blumenthal D

    更新日期:2010-11-10 00:00:00

  • Long noncoding RNA Chast promotes cardiac remodeling.

    abstract::Recent studies highlighted long noncoding RNAs (lncRNAs) to play an important role in cardiac development. However, understanding of lncRNAs in cardiac diseases is still limited. Global lncRNA expression profiling indicated that several lncRNA transcripts are deregulated during pressure overload-induced cardiac hypert...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaf1475

    authors: Viereck J,Kumarswamy R,Foinquinos A,Xiao K,Avramopoulos P,Kunz M,Dittrich M,Maetzig T,Zimmer K,Remke J,Just A,Fendrich J,Scherf K,Bolesani E,Schambach A,Weidemann F,Zweigerdt R,de Windt LJ,Engelhardt S,Dandekar T,

    更新日期:2016-02-17 00:00:00

  • PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors.

    abstract::PTEN (phosphatase and tensin homolog) loss of function is the most common genetic aberration in endometrioid endometrial carcinomas. In addition to its well-described role in cell signaling, PTEN is involved in the maintenance of genomic stability. Loss of PTEN function causes defects in repair of DNA double-strand br...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3001538

    authors: Dedes KJ,Wetterskog D,Mendes-Pereira AM,Natrajan R,Lambros MB,Geyer FC,Vatcheva R,Savage K,Mackay A,Lord CJ,Ashworth A,Reis-Filho JS

    更新日期:2010-10-13 00:00:00

  • Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation.

    abstract::SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer's disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggestin...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3007747

    authors: Caglayan S,Takagi-Niidome S,Liao F,Carlo AS,Schmidt V,Burgert T,Kitago Y,Füchtbauer EM,Füchtbauer A,Holtzman DM,Takagi J,Willnow TE

    更新日期:2014-02-12 00:00:00

  • Clinical trial design: The nobility of randomization.

    abstract::A clinical trial evaluating HIV vaccine therapy teaches us much about optimal design (Sneller et al, this issue). ...

    journal_title:Science translational medicine

    pub_type: 杂志文章,评审

    doi:10.1126/scitranslmed.aaq0810

    authors: Michael NL

    更新日期:2017-12-06 00:00:00

  • Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel.

    abstract::The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients wit...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aah4985

    authors: Umanah GKE,Pignatelli M,Yin X,Chen R,Crawford J,Neifert S,Scarffe L,Behensky AA,Guiberson N,Chang M,Ma E,Kim JW,Castro CC,Mao X,Chen L,Andrabi SA,Pletnikov MV,Pulver AE,Avramopoulos D,Bonci A,Valle D,Dawson TM,

    更新日期:2017-12-13 00:00:00

  • Exosomes derived from Vδ2-T cells control Epstein-Barr virus-associated tumors and induce T cell antitumor immunity.

    abstract::Treatment of life-threatening Epstein-Barr virus (EBV)-associated tumors remains a great challenge, especially for patients with relapsed or refractory disease. Here, we found that exosomes derived from phosphoantigen-expanded Vδ2-T cells (Vδ2-T-Exos) contained death-inducing ligands (FasL and TRAIL), an activating re...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaz3426

    authors: Wang X,Xiang Z,Liu Y,Huang C,Pei Y,Wang X,Zhi H,Wong WH,Wei H,Ng IO,Lee PP,Chan GC,Lau YL,Tu W

    更新日期:2020-09-30 00:00:00

  • Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

    abstract::Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10 Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kin...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaw3521

    authors: Tang AT,Sullivan KR,Hong CC,Goddard LM,Mahadevan A,Ren A,Pardo H,Peiper A,Griffin E,Tanes C,Mattei LM,Yang J,Li L,Mericko-Ishizuka P,Shen L,Hobson N,Girard R,Lightle R,Moore T,Shenkar R,Polster SP,Roedel CJ,Li

    更新日期:2019-11-27 00:00:00

  • Recommendations for biomarker identification and qualification in clinical proteomics.

    abstract::Clinical proteomics has yielded some early positive results-the identification of potential disease biomarkers-indicating the promise for this analytical approach to improve the current state of the art in clinical practice. However, the inability to verify some candidate molecules in subsequent studies has led to ske...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3001249

    authors: Mischak H,Allmaier G,Apweiler R,Attwood T,Baumann M,Benigni A,Bennett SE,Bischoff R,Bongcam-Rudloff E,Capasso G,Coon JJ,D'Haese P,Dominiczak AF,Dakna M,Dihazi H,Ehrich JH,Fernandez-Llama P,Fliser D,Frokiaer J,Garin

    更新日期:2010-08-25 00:00:00