A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
Pier Paolo Pandolfi and colleagues report that compound loss of Pten with Zbtb7a or Trp53 leads to de novo resistance to androgen deprivation therapy in prostate cancer. Integrative analysis of mouse and human data in a co-clinical approach identified XIAP and SRD5A1 inhibitors as potential therapie...
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| Veröffentlicht in: | Nature genetics 2013-07, Vol.45 (7), p.747-755 |
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| creator | Lunardi, Andrea Ala, Ugo Epping, Mirjam T Salmena, Leonardo Clohessy, John G Webster, Kaitlyn A Wang, Guocan Mazzucchelli, Roberta Bianconi, Maristella Stack, Edward C Lis, Rosina Patnaik, Akash Cantley, Lewis C Bubley, Glenn Cordon-Cardo, Carlos Gerald, William L Montironi, Rodolfo Signoretti, Sabina Loda, Massimo Nardella, Caterina Pandolfi, Pier Paolo |
| description | Pier Paolo Pandolfi and colleagues report that compound loss of
Pten
with
Zbtb7a
or
Trp53
leads to
de novo
resistance to androgen deprivation therapy in prostate cancer. Integrative analysis of mouse and human data in a co-clinical approach identified XIAP and SRD5A1 inhibitors as potential therapies for castration-resistant prostate cancer.
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 with deletion of either
Trp53
or
Zbtb7a
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 and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments. |
| doi_str_mv | 10.1038/ng.2650 |
| format | Article |
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Pten
with
Zbtb7a
or
Trp53
leads to
de novo
resistance to androgen deprivation therapy in prostate cancer. Integrative analysis of mouse and human data in a co-clinical approach identified XIAP and SRD5A1 inhibitors as potential therapies for castration-resistant prostate cancer.
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 with deletion of either
Trp53
or
Zbtb7a
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 and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/ng.2650</identifier><identifier>PMID: 23727860</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/208/2489 ; Agriculture ; Androgen Antagonists - therapeutic use ; Androgen suppression therapy ; Androgens ; Androgens - metabolism ; Animal Genetics and Genomics ; Animals ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Biomarkers ; Biomedicine ; Cancer Research ; Cancer therapies ; Cancer treatment ; Care and treatment ; Cell Line, Tumor ; Development and progression ; Drug Evaluation, Preclinical ; Gene Function ; Genetic aspects ; Health aspects ; Human Genetics ; Humans ; Hypotheses ; Integrated approach ; Male ; Medical research ; Medical schools ; Mice ; Mice, Transgenic ; Models, Biological ; NMR ; Nuclear magnetic resonance ; Orchiectomy ; Pathology ; Phenylthiohydantoin - analogs & derivatives ; Phenylthiohydantoin - therapeutic use ; Prostate cancer ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - therapy ; PTEN Phosphohydrolase - genetics ; Rodents ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Therapies, Investigational ; Translational Medical Research - methods ; Treatment Failure ; Tumors</subject><ispartof>Nature genetics, 2013-07, Vol.45 (7), p.747-755</ispartof><rights>Springer Nature America, Inc. 2013</rights><rights>COPYRIGHT 2013 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c732t-a588b96320bf18e4033bcd4d83b92effbb2b2c72cc2d34e2b1305d1fb2d3b8d03</citedby><cites>FETCH-LOGICAL-c732t-a588b96320bf18e4033bcd4d83b92effbb2b2c72cc2d34e2b1305d1fb2d3b8d03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ng.2650$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/ng.2650$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23727860$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lunardi, Andrea</creatorcontrib><creatorcontrib>Ala, Ugo</creatorcontrib><creatorcontrib>Epping, Mirjam T</creatorcontrib><creatorcontrib>Salmena, Leonardo</creatorcontrib><creatorcontrib>Clohessy, John G</creatorcontrib><creatorcontrib>Webster, Kaitlyn A</creatorcontrib><creatorcontrib>Wang, Guocan</creatorcontrib><creatorcontrib>Mazzucchelli, Roberta</creatorcontrib><creatorcontrib>Bianconi, Maristella</creatorcontrib><creatorcontrib>Stack, Edward C</creatorcontrib><creatorcontrib>Lis, Rosina</creatorcontrib><creatorcontrib>Patnaik, Akash</creatorcontrib><creatorcontrib>Cantley, Lewis C</creatorcontrib><creatorcontrib>Bubley, Glenn</creatorcontrib><creatorcontrib>Cordon-Cardo, Carlos</creatorcontrib><creatorcontrib>Gerald, William L</creatorcontrib><creatorcontrib>Montironi, Rodolfo</creatorcontrib><creatorcontrib>Signoretti, Sabina</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><creatorcontrib>Nardella, Caterina</creatorcontrib><creatorcontrib>Pandolfi, Pier Paolo</creatorcontrib><title>A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>Pier Paolo Pandolfi and colleagues report that compound loss of
Pten
with
Zbtb7a
or
Trp53
leads to
de novo
resistance to androgen deprivation therapy in prostate cancer. Integrative analysis of mouse and human data in a co-clinical approach identified XIAP and SRD5A1 inhibitors as potential therapies for castration-resistant prostate cancer.
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 with deletion of either
Trp53
or
Zbtb7a
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 and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.</description><subject>631/208/2489</subject><subject>Agriculture</subject><subject>Androgen Antagonists - therapeutic use</subject><subject>Androgen suppression therapy</subject><subject>Androgens</subject><subject>Androgens - metabolism</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis</subject><subject>Biomarkers</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>Care and treatment</subject><subject>Cell Line, Tumor</subject><subject>Development and progression</subject><subject>Drug Evaluation, Preclinical</subject><subject>Gene Function</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Integrated approach</subject><subject>Male</subject><subject>Medical research</subject><subject>Medical schools</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Models, Biological</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Orchiectomy</subject><subject>Pathology</subject><subject>Phenylthiohydantoin - analogs & derivatives</subject><subject>Phenylthiohydantoin - therapeutic use</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Prostatic Neoplasms - therapy</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>Rodents</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><subject>Therapies, Investigational</subject><subject>Translational Medical Research - methods</subject><subject>Treatment Failure</subject><subject>Tumors</subject><issn>1061-4036</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNk0tr3DAQgE1padK09B8UQw9tD97qZdm-FJbQRyAQ6OsqJHnsVbAlV_KGlv75jkma7IZCFx1saT59Hs9IWfackhUlvH7r-xWTJXmQHdNSyIJWtH6I70TSQhAuj7InKV0SQoUg9ePsiPGKVbUkx9nvdW5DYQfnndVDrqcpBm03uWvBz65zkPIR7EZ7l8aUa9_mU5iXEMLzBqKeFqQLcYnF0IPPW5iiu9KzCz6PkFyatbeQO5-jGycz5HZZiU-zR50eEjy7eZ5k3z68_3r6qTi_-Hh2uj4vbMXZXOiyrk0jOSOmozXg_3BjW9HW3DQMus4YZpitmLWs5QKYoZyULe0MTk3dEn6Svbv2TlszQmsx_agHhVmOOv5SQTu1H_Fuo_pwpXhV45AoeH0jiOHHFtKsRpcsDIP2ELZJ0bIUTSnwu_9HsfKkaqQUiL68h16GbfRYCaSapqnKqmnuqF4PoJzvAqZoF6lac15x2UjCkFr9g8LRwuhs8NA5XN_b8GZvAzIz_Jx7vU1JnX35rNaSCyqQLw9gD_VefD_cu7C73lfXrMUzlCJ0t-2jRC1XQPleLVcAyRe73b7l_p75uxYlDPke4k7d77n-APjgDEg</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Lunardi, 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co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer</title><author>Lunardi, Andrea ; Ala, Ugo ; Epping, Mirjam T ; Salmena, Leonardo ; Clohessy, John G ; Webster, Kaitlyn A ; Wang, Guocan ; Mazzucchelli, Roberta ; Bianconi, Maristella ; Stack, Edward C ; Lis, Rosina ; Patnaik, Akash ; Cantley, Lewis C ; Bubley, Glenn ; Cordon-Cardo, Carlos ; Gerald, William L ; Montironi, Rodolfo ; Signoretti, Sabina ; Loda, Massimo ; Nardella, Caterina ; Pandolfi, Pier Paolo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c732t-a588b96320bf18e4033bcd4d83b92effbb2b2c72cc2d34e2b1305d1fb2d3b8d03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/208/2489</topic><topic>Agriculture</topic><topic>Androgen Antagonists - therapeutic use</topic><topic>Androgen suppression therapy</topic><topic>Androgens</topic><topic>Androgens - metabolism</topic><topic>Animal Genetics and Genomics</topic><topic>Animals</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis</topic><topic>Biomarkers</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Cancer therapies</topic><topic>Cancer treatment</topic><topic>Care and treatment</topic><topic>Cell Line, Tumor</topic><topic>Development and progression</topic><topic>Drug Evaluation, Preclinical</topic><topic>Gene Function</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>Integrated approach</topic><topic>Male</topic><topic>Medical research</topic><topic>Medical schools</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Models, Biological</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Orchiectomy</topic><topic>Pathology</topic><topic>Phenylthiohydantoin - analogs & derivatives</topic><topic>Phenylthiohydantoin - therapeutic use</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Prostatic Neoplasms - therapy</topic><topic>PTEN Phosphohydrolase - genetics</topic><topic>Rodents</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - genetics</topic><topic>Therapies, Investigational</topic><topic>Translational Medical Research - methods</topic><topic>Treatment Failure</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lunardi, Andrea</creatorcontrib><creatorcontrib>Ala, Ugo</creatorcontrib><creatorcontrib>Epping, Mirjam T</creatorcontrib><creatorcontrib>Salmena, Leonardo</creatorcontrib><creatorcontrib>Clohessy, John G</creatorcontrib><creatorcontrib>Webster, Kaitlyn 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Sabina</au><au>Loda, Massimo</au><au>Nardella, Caterina</au><au>Pandolfi, Pier Paolo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>45</volume><issue>7</issue><spage>747</spage><epage>755</epage><pages>747-755</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><abstract>Pier Paolo Pandolfi and colleagues report that compound loss of
Pten
with
Zbtb7a
or
Trp53
leads to
de novo
resistance to androgen deprivation therapy in prostate cancer. Integrative analysis of mouse and human data in a co-clinical approach identified XIAP and SRD5A1 inhibitors as potential therapies for castration-resistant prostate cancer.
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 with deletion of either
Trp53
or
Zbtb7a
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 and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>23727860</pmid><doi>10.1038/ng.2650</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature genetics, 2013-07, Vol.45 (7), p.747-755 |
| issn | 1061-4036 1546-1718 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3787876 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 631/208/2489 Agriculture Androgen Antagonists - therapeutic use Androgen suppression therapy Androgens Androgens - metabolism Animal Genetics and Genomics Animals Antineoplastic Agents - therapeutic use Apoptosis Biomarkers Biomedicine Cancer Research Cancer therapies Cancer treatment Care and treatment Cell Line, Tumor Development and progression Drug Evaluation, Preclinical Gene Function Genetic aspects Health aspects Human Genetics Humans Hypotheses Integrated approach Male Medical research Medical schools Mice Mice, Transgenic Models, Biological NMR Nuclear magnetic resonance Orchiectomy Pathology Phenylthiohydantoin - analogs & derivatives Phenylthiohydantoin - therapeutic use Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Prostatic Neoplasms - therapy PTEN Phosphohydrolase - genetics Rodents Signal Transduction - drug effects Signal Transduction - genetics Therapies, Investigational Translational Medical Research - methods Treatment Failure Tumors |
| title | A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T07%3A27%3A29IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20co-clinical%20approach%20identifies%20mechanisms%20and%20potential%20therapies%20for%20androgen%20deprivation%20resistance%20in%20prostate%20cancer&rft.jtitle=Nature%20genetics&rft.au=Lunardi,%20Andrea&rft.date=2013-07-01&rft.volume=45&rft.issue=7&rft.spage=747&rft.epage=755&rft.pages=747-755&rft.issn=1061-4036&rft.eissn=1546-1718&rft_id=info:doi/10.1038/ng.2650&rft_dat=%3Cgale_pubme%3EA337369602%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1399975799&rft_id=info:pmid/23727860&rft_galeid=A337369602&rfr_iscdi=true |