mTOR Is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary
Purpose: Mammalian target of rapamycin (mTOR) plays a central role in cell proliferation and is regarded as a promising target in cancer therapy, including for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic target in clear cell carcinoma of the ovary, which is regarded...
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| Veröffentlicht in: | Clinical cancer research 2009-09, Vol.15 (17), p.5404-5413 |
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| creator | MABUCHI, Seiji KAWASE, Chiaki OHMICHI, Masahide TESTA, Joseph R KIMURA, Tadashi ALTOMARE, Deborah A MORISHIGE, Kenichirou SAWADA, Kenjiro HAYASHI, Masami TSUJIMOTO, Masahiko YAMOTO, Mareo KLEIN-SZANTO, Andres J SCHILDER, Russell J |
| description | Purpose: Mammalian target of rapamycin (mTOR) plays a central role in cell proliferation and is regarded as a promising target in
cancer therapy, including for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic target in clear
cell carcinoma of the ovary, which is regarded as an aggressive, chemoresistant histologic subtype.
Experimental Design: Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression
of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus)
was examined using two pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human clear cell carcinoma
cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo .
Results: Immunohistochemical analysis showed that mTOR was more frequently activated in clear cell carcinomas than in serous adenocarcinomas
(86.6% versus 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo . Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C-CR cells, compared with the respective
parental cells. This increased expression of phospho-mTOR in cisplatin-resistant cells was associated with increased activation
of AKT. RMG1-CR and KOC7C-CR cells showed greater sensitivity to RAD001 than did parental RMG1 and KOC7C cells, respectively,
in vitro and in vivo .
Conclusion: mTOR is frequently activated in clear cell carcinoma and can be a promising therapeutic target in the management of clear
cell carcinoma. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in
patients previously treated with cisplatin. (Clin Cancer Res 2009;15(17):5404â13) |
| doi_str_mv | 10.1158/1078-0432.CCR-09-0365 |
| format | Article |
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cancer therapy, including for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic target in clear
cell carcinoma of the ovary, which is regarded as an aggressive, chemoresistant histologic subtype.
Experimental Design: Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression
of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus)
was examined using two pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human clear cell carcinoma
cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo .
Results: Immunohistochemical analysis showed that mTOR was more frequently activated in clear cell carcinomas than in serous adenocarcinomas
(86.6% versus 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo . Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C-CR cells, compared with the respective
parental cells. This increased expression of phospho-mTOR in cisplatin-resistant cells was associated with increased activation
of AKT. RMG1-CR and KOC7C-CR cells showed greater sensitivity to RAD001 than did parental RMG1 and KOC7C cells, respectively,
in vitro and in vivo .
Conclusion: mTOR is frequently activated in clear cell carcinoma and can be a promising therapeutic target in the management of clear
cell carcinoma. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in
patients previously treated with cisplatin. (Clin Cancer Res 2009;15(17):5404â13)</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-09-0365</identifier><identifier>PMID: 19690197</identifier><identifier>CODEN: CCREF4</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adenocarcinoma, Clear Cell - drug therapy ; Adenocarcinoma, Clear Cell - pathology ; AKT ; Animals ; Antineoplastic agents ; Antineoplastic Agents - therapeutic use ; Biological and medical sciences ; Cell Line, Tumor ; cisplatin ; Cisplatin - therapeutic use ; clear cell carcinoma ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - physiology ; Everolimus ; Female ; Female genital diseases ; Gynecology. Andrology. Obstetrics ; Humans ; Immunosuppressive Agents - pharmacology ; Immunosuppressive Agents - therapeutic use ; Medical sciences ; Mice ; Mice, Nude ; mTOR ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - pathology ; Pharmacology. Drug treatments ; Protein Kinases - drug effects ; Protein Kinases - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; RAD001 ; Sirolimus - analogs & derivatives ; Sirolimus - pharmacology ; Sirolimus - therapeutic use ; Tissue Array Analysis ; TOR Serine-Threonine Kinases ; Tumors ; Xenograft Model Antitumor Assays</subject><ispartof>Clinical cancer research, 2009-09, Vol.15 (17), p.5404-5413</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-6d7f76340ab1a279918ac42af9d900c46225b6519f3075e91c4ef413caae40773</citedby><cites>FETCH-LOGICAL-c540t-6d7f76340ab1a279918ac42af9d900c46225b6519f3075e91c4ef413caae40773</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3342,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22140140$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19690197$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MABUCHI, Seiji</creatorcontrib><creatorcontrib>KAWASE, Chiaki</creatorcontrib><creatorcontrib>OHMICHI, Masahide</creatorcontrib><creatorcontrib>TESTA, Joseph R</creatorcontrib><creatorcontrib>KIMURA, Tadashi</creatorcontrib><creatorcontrib>ALTOMARE, Deborah A</creatorcontrib><creatorcontrib>MORISHIGE, Kenichirou</creatorcontrib><creatorcontrib>SAWADA, Kenjiro</creatorcontrib><creatorcontrib>HAYASHI, Masami</creatorcontrib><creatorcontrib>TSUJIMOTO, Masahiko</creatorcontrib><creatorcontrib>YAMOTO, Mareo</creatorcontrib><creatorcontrib>KLEIN-SZANTO, Andres J</creatorcontrib><creatorcontrib>SCHILDER, Russell J</creatorcontrib><title>mTOR Is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: Mammalian target of rapamycin (mTOR) plays a central role in cell proliferation and is regarded as a promising target in
cancer therapy, including for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic target in clear
cell carcinoma of the ovary, which is regarded as an aggressive, chemoresistant histologic subtype.
Experimental Design: Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression
of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus)
was examined using two pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human clear cell carcinoma
cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo .
Results: Immunohistochemical analysis showed that mTOR was more frequently activated in clear cell carcinomas than in serous adenocarcinomas
(86.6% versus 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo . Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C-CR cells, compared with the respective
parental cells. This increased expression of phospho-mTOR in cisplatin-resistant cells was associated with increased activation
of AKT. RMG1-CR and KOC7C-CR cells showed greater sensitivity to RAD001 than did parental RMG1 and KOC7C cells, respectively,
in vitro and in vivo .
Conclusion: mTOR is frequently activated in clear cell carcinoma and can be a promising therapeutic target in the management of clear
cell carcinoma. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in
patients previously treated with cisplatin. (Clin Cancer Res 2009;15(17):5404â13)</description><subject>Adenocarcinoma, Clear Cell - drug therapy</subject><subject>Adenocarcinoma, Clear Cell - pathology</subject><subject>AKT</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>cisplatin</subject><subject>Cisplatin - therapeutic use</subject><subject>clear cell carcinoma</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - physiology</subject><subject>Everolimus</subject><subject>Female</subject><subject>Female genital diseases</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>mTOR</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Kinases - drug effects</subject><subject>Protein Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>RAD001</subject><subject>Sirolimus - analogs & derivatives</subject><subject>Sirolimus - pharmacology</subject><subject>Sirolimus - therapeutic use</subject><subject>Tissue Array Analysis</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkV2LEzEUhgdxcdfVn6DkRsSL2c3npLkRdPBjYaFS63U4Tc90IjOZmqQVwR9vSut-XCUkzzl5c56qesXoFWNqds2ontVUCn7VtouampqKRj2pLphSuha8UU_L_j9zXj1P6SelTDIqn1XnzDSGMqMvqr_jcr4gN4kA-Ran0ScfNmTZY4Qt7rJ3ZAlxg5l8nHJPfCCtT9sBsg_1dwzJZ79HAmH94HyByacMIZN2QIikxWEgLUTnwzQCmTqSeyTzPcQ_L6qzDoaEL0_rZfXj86dl-7W-nX-5aT_c1k5JmutmrTvdCElhxYBrY9gMnOTQmbWh1MmGc7VqFDOdoFqhYU5iJ5lwACip1uKyen_su92tRlw7DDnCYLfRjyWFncDbxzfB93Yz7S3XUsxUUxq8PTWI068dpmzLpFz5GAScdsnqEk4oylUh1ZF0cUopYnf3CqP2IM4epNiDFFvEWWrsQVype_0w4n3VyVQB3pwASA6GLkJwPt1xnDNZ9NLCvTtyvd_0v31E6wqJMWIqNlxvmbJM2zJYKf4BbsWwcg</recordid><startdate>20090901</startdate><enddate>20090901</enddate><creator>MABUCHI, Seiji</creator><creator>KAWASE, Chiaki</creator><creator>OHMICHI, Masahide</creator><creator>TESTA, Joseph R</creator><creator>KIMURA, Tadashi</creator><creator>ALTOMARE, Deborah A</creator><creator>MORISHIGE, Kenichirou</creator><creator>SAWADA, Kenjiro</creator><creator>HAYASHI, Masami</creator><creator>TSUJIMOTO, Masahiko</creator><creator>YAMOTO, Mareo</creator><creator>KLEIN-SZANTO, Andres J</creator><creator>SCHILDER, Russell J</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090901</creationdate><title>mTOR Is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary</title><author>MABUCHI, Seiji ; KAWASE, Chiaki ; OHMICHI, Masahide ; TESTA, Joseph R ; KIMURA, Tadashi ; ALTOMARE, Deborah A ; MORISHIGE, Kenichirou ; SAWADA, Kenjiro ; HAYASHI, Masami ; TSUJIMOTO, Masahiko ; YAMOTO, Mareo ; KLEIN-SZANTO, Andres J ; SCHILDER, Russell J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-6d7f76340ab1a279918ac42af9d900c46225b6519f3075e91c4ef413caae40773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adenocarcinoma, Clear Cell - drug therapy</topic><topic>Adenocarcinoma, Clear Cell - pathology</topic><topic>AKT</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>cisplatin</topic><topic>Cisplatin - therapeutic use</topic><topic>clear cell carcinoma</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - physiology</topic><topic>Everolimus</topic><topic>Female</topic><topic>Female genital diseases</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Immunosuppressive Agents - pharmacology</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>mTOR</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Kinases - drug effects</topic><topic>Protein Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>RAD001</topic><topic>Sirolimus - analogs & derivatives</topic><topic>Sirolimus - pharmacology</topic><topic>Sirolimus - therapeutic use</topic><topic>Tissue Array Analysis</topic><topic>TOR Serine-Threonine Kinases</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MABUCHI, Seiji</creatorcontrib><creatorcontrib>KAWASE, Chiaki</creatorcontrib><creatorcontrib>OHMICHI, Masahide</creatorcontrib><creatorcontrib>TESTA, Joseph R</creatorcontrib><creatorcontrib>KIMURA, Tadashi</creatorcontrib><creatorcontrib>ALTOMARE, Deborah A</creatorcontrib><creatorcontrib>MORISHIGE, Kenichirou</creatorcontrib><creatorcontrib>SAWADA, Kenjiro</creatorcontrib><creatorcontrib>HAYASHI, Masami</creatorcontrib><creatorcontrib>TSUJIMOTO, Masahiko</creatorcontrib><creatorcontrib>YAMOTO, Mareo</creatorcontrib><creatorcontrib>KLEIN-SZANTO, Andres J</creatorcontrib><creatorcontrib>SCHILDER, Russell J</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MABUCHI, Seiji</au><au>KAWASE, Chiaki</au><au>OHMICHI, Masahide</au><au>TESTA, Joseph R</au><au>KIMURA, Tadashi</au><au>ALTOMARE, Deborah A</au><au>MORISHIGE, Kenichirou</au><au>SAWADA, Kenjiro</au><au>HAYASHI, Masami</au><au>TSUJIMOTO, Masahiko</au><au>YAMOTO, Mareo</au><au>KLEIN-SZANTO, Andres J</au><au>SCHILDER, Russell J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>mTOR Is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2009-09-01</date><risdate>2009</risdate><volume>15</volume><issue>17</issue><spage>5404</spage><epage>5413</epage><pages>5404-5413</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><coden>CCREF4</coden><abstract>Purpose: Mammalian target of rapamycin (mTOR) plays a central role in cell proliferation and is regarded as a promising target in
cancer therapy, including for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic target in clear
cell carcinoma of the ovary, which is regarded as an aggressive, chemoresistant histologic subtype.
Experimental Design: Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression
of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus)
was examined using two pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human clear cell carcinoma
cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo .
Results: Immunohistochemical analysis showed that mTOR was more frequently activated in clear cell carcinomas than in serous adenocarcinomas
(86.6% versus 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo . Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C-CR cells, compared with the respective
parental cells. This increased expression of phospho-mTOR in cisplatin-resistant cells was associated with increased activation
of AKT. RMG1-CR and KOC7C-CR cells showed greater sensitivity to RAD001 than did parental RMG1 and KOC7C cells, respectively,
in vitro and in vivo .
Conclusion: mTOR is frequently activated in clear cell carcinoma and can be a promising therapeutic target in the management of clear
cell carcinoma. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in
patients previously treated with cisplatin. (Clin Cancer Res 2009;15(17):5404â13)</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>19690197</pmid><doi>10.1158/1078-0432.CCR-09-0365</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2009-09, Vol.15 (17), p.5404-5413 |
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| subjects | Adenocarcinoma, Clear Cell - drug therapy Adenocarcinoma, Clear Cell - pathology AKT Animals Antineoplastic agents Antineoplastic Agents - therapeutic use Biological and medical sciences Cell Line, Tumor cisplatin Cisplatin - therapeutic use clear cell carcinoma Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - physiology Everolimus Female Female genital diseases Gynecology. Andrology. Obstetrics Humans Immunosuppressive Agents - pharmacology Immunosuppressive Agents - therapeutic use Medical sciences Mice Mice, Nude mTOR Ovarian Neoplasms - drug therapy Ovarian Neoplasms - pathology Pharmacology. Drug treatments Protein Kinases - drug effects Protein Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism RAD001 Sirolimus - analogs & derivatives Sirolimus - pharmacology Sirolimus - therapeutic use Tissue Array Analysis TOR Serine-Threonine Kinases Tumors Xenograft Model Antitumor Assays |
| title | mTOR Is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary |
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