A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer
Background: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulat...
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| Veröffentlicht in: | Prostate cancer and prostatic diseases 2014-09, Vol.17 (3), p.252-258 |
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| creator | Joshua, A M Zannella, V E Downes, M R Bowes, B Hersey, K Koritzinsky, M Schwab, M Hofmann, U Evans, A van der Kwast, T Trachtenberg, J Finelli, A Fleshner, N Sweet, J Pollak, M |
| description | Background:
Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies
Methods:
Men were treated in a single-arm ‘window of opportunity’ study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students
t
-tests and/or Wilcoxon matched pairs signed rank test.
Results:
Baseline characteristics included median PSA 6 ng ml
−1
(3.22–36.11 ng ml
−1
). Median duration of drug treatment was 41 days (18–81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (
P
=0.0064 and
P
=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (
P |
| doi_str_mv | 10.1038/pcan.2014.20 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_journals_2645322478</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A381948982</galeid><sourcerecordid>A381948982</sourcerecordid><originalsourceid>FETCH-LOGICAL-c591t-ddb363b066d41abd2e4b7813a308e85f622941107d0ba873b71d14fabb20ff633</originalsourceid><addsrcrecordid>eNp9kc9vFSEQx4mxsbV682xITHpyn_xalj2-NFZNmvSiZwILtLzswgqszbv1z7D_Xv-S8vKqtkljIDMEPjPDzBeAdxitMKLi0zyosCIIs2pegCPMOt60HImX9Ux523SiJYfgdc4bhFCPe_QKHBImOG7b_gjINZz9GAu8u_l97YOJ1zA6GOc5prIEX7Z3N7cw2KjMZvmlQoG5LGa7YyZbXEyTD7DuMQ5q9NkaOKeYiyoW1m8NNr0BB06N2b598Mfgx9nn76dfm_OLL99O1-fN0Pa4NMZoyqlGnBuGlTbEMt0JTBVFworWcUJ6hjHqDNJKdFR32GDmlNYEOccpPQYf9nlr_Z-LzUVu4pJCLSkJZy0lhHXif1QdB8WMccr-UZdqtNIHF0tSw-TzINdU4J6JXpBKrZ6h6jJ28kMM1vl6_yTg5FHAlVVjucpxXIqPIT8FP-7Boc4yJ-vknPyk0lZiJHeay53mcqd5NRV__9DUoidr_sJ_RK5AswdyfQqXNj3q-rmE9za7thc</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1553144634</pqid></control><display><type>article</type><title>A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer</title><source>MEDLINE</source><source>SpringerLink Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Joshua, A M ; Zannella, V E ; Downes, M R ; Bowes, B ; Hersey, K ; Koritzinsky, M ; Schwab, M ; Hofmann, U ; Evans, A ; van der Kwast, T ; Trachtenberg, J ; Finelli, A ; Fleshner, N ; Sweet, J ; Pollak, M</creator><creatorcontrib>Joshua, A M ; Zannella, V E ; Downes, M R ; Bowes, B ; Hersey, K ; Koritzinsky, M ; Schwab, M ; Hofmann, U ; Evans, A ; van der Kwast, T ; Trachtenberg, J ; Finelli, A ; Fleshner, N ; Sweet, J ; Pollak, M</creatorcontrib><description>Background:
Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies
Methods:
Men were treated in a single-arm ‘window of opportunity’ study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students
t
-tests and/or Wilcoxon matched pairs signed rank test.
Results:
Baseline characteristics included median PSA 6 ng ml
−1
(3.22–36.11 ng ml
−1
). Median duration of drug treatment was 41 days (18–81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (
P
=0.0064 and
P
=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (
P
<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (
P
=0.08). The study is limited by small patient numbers and tumour heterogeneity.
Conclusions:
Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.</description><identifier>ISSN: 1365-7852</identifier><identifier>EISSN: 1476-5608</identifier><identifier>DOI: 10.1038/pcan.2014.20</identifier><identifier>PMID: 24861559</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/51 ; 692/308/575 ; Aged ; Algorithms ; Antidiabetics ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - therapeutic use ; Biomarkers, Tumor - blood ; Biomedical and Life Sciences ; Biomedicine ; Biopsy ; Cancer Research ; Cell proliferation ; Dosage and administration ; Drug therapy ; Electron transport ; Epidemiology ; Health aspects ; Health services ; Heterogeneity ; Humans ; Insulin ; Insulin resistance ; Kinases ; Male ; Median (statistics) ; Metabolism ; Metformin ; Metformin - administration & dosage ; Metformin - adverse effects ; Metformin - therapeutic use ; Middle Aged ; Neoadjuvant Therapy ; Neoplasm Grading ; Neoplasm Staging ; original-article ; Patient outcomes ; Patients ; Physiological aspects ; Pilot Projects ; Prostate cancer ; Prostatectomy ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - surgery ; Rank tests ; Signaling ; Statistical analysis ; Statistical tests ; TOR protein ; Toxicity ; Tumors</subject><ispartof>Prostate cancer and prostatic diseases, 2014-09, Vol.17 (3), p.252-258</ispartof><rights>Macmillan Publishers Limited 2014</rights><rights>COPYRIGHT 2014 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 2014</rights><rights>Macmillan Publishers Limited 2014.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c591t-ddb363b066d41abd2e4b7813a308e85f622941107d0ba873b71d14fabb20ff633</citedby><cites>FETCH-LOGICAL-c591t-ddb363b066d41abd2e4b7813a308e85f622941107d0ba873b71d14fabb20ff633</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/pcan.2014.20$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/pcan.2014.20$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24861559$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Joshua, A M</creatorcontrib><creatorcontrib>Zannella, V E</creatorcontrib><creatorcontrib>Downes, M R</creatorcontrib><creatorcontrib>Bowes, B</creatorcontrib><creatorcontrib>Hersey, K</creatorcontrib><creatorcontrib>Koritzinsky, M</creatorcontrib><creatorcontrib>Schwab, M</creatorcontrib><creatorcontrib>Hofmann, U</creatorcontrib><creatorcontrib>Evans, A</creatorcontrib><creatorcontrib>van der Kwast, T</creatorcontrib><creatorcontrib>Trachtenberg, J</creatorcontrib><creatorcontrib>Finelli, A</creatorcontrib><creatorcontrib>Fleshner, N</creatorcontrib><creatorcontrib>Sweet, J</creatorcontrib><creatorcontrib>Pollak, M</creatorcontrib><title>A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer</title><title>Prostate cancer and prostatic diseases</title><addtitle>Prostate Cancer Prostatic Dis</addtitle><addtitle>Prostate Cancer Prostatic Dis</addtitle><description>Background:
Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies
Methods:
Men were treated in a single-arm ‘window of opportunity’ study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students
t
-tests and/or Wilcoxon matched pairs signed rank test.
Results:
Baseline characteristics included median PSA 6 ng ml
−1
(3.22–36.11 ng ml
−1
). Median duration of drug treatment was 41 days (18–81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (
P
=0.0064 and
P
=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (
P
<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (
P
=0.08). The study is limited by small patient numbers and tumour heterogeneity.
Conclusions:
Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.</description><subject>13/51</subject><subject>692/308/575</subject><subject>Aged</subject><subject>Algorithms</subject><subject>Antidiabetics</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomarkers, Tumor - blood</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biopsy</subject><subject>Cancer Research</subject><subject>Cell proliferation</subject><subject>Dosage and administration</subject><subject>Drug therapy</subject><subject>Electron transport</subject><subject>Epidemiology</subject><subject>Health aspects</subject><subject>Health services</subject><subject>Heterogeneity</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin resistance</subject><subject>Kinases</subject><subject>Male</subject><subject>Median (statistics)</subject><subject>Metabolism</subject><subject>Metformin</subject><subject>Metformin - administration & dosage</subject><subject>Metformin - adverse effects</subject><subject>Metformin - therapeutic use</subject><subject>Middle Aged</subject><subject>Neoadjuvant Therapy</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Staging</subject><subject>original-article</subject><subject>Patient outcomes</subject><subject>Patients</subject><subject>Physiological aspects</subject><subject>Pilot Projects</subject><subject>Prostate cancer</subject><subject>Prostatectomy</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Prostatic Neoplasms - surgery</subject><subject>Rank tests</subject><subject>Signaling</subject><subject>Statistical analysis</subject><subject>Statistical tests</subject><subject>TOR protein</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>1365-7852</issn><issn>1476-5608</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kc9vFSEQx4mxsbV682xITHpyn_xalj2-NFZNmvSiZwILtLzswgqszbv1z7D_Xv-S8vKqtkljIDMEPjPDzBeAdxitMKLi0zyosCIIs2pegCPMOt60HImX9Ux523SiJYfgdc4bhFCPe_QKHBImOG7b_gjINZz9GAu8u_l97YOJ1zA6GOc5prIEX7Z3N7cw2KjMZvmlQoG5LGa7YyZbXEyTD7DuMQ5q9NkaOKeYiyoW1m8NNr0BB06N2b598Mfgx9nn76dfm_OLL99O1-fN0Pa4NMZoyqlGnBuGlTbEMt0JTBVFworWcUJ6hjHqDNJKdFR32GDmlNYEOccpPQYf9nlr_Z-LzUVu4pJCLSkJZy0lhHXif1QdB8WMccr-UZdqtNIHF0tSw-TzINdU4J6JXpBKrZ6h6jJ28kMM1vl6_yTg5FHAlVVjucpxXIqPIT8FP-7Boc4yJ-vknPyk0lZiJHeay53mcqd5NRV__9DUoidr_sJ_RK5AswdyfQqXNj3q-rmE9za7thc</recordid><startdate>201409</startdate><enddate>201409</enddate><creator>Joshua, A M</creator><creator>Zannella, V E</creator><creator>Downes, M R</creator><creator>Bowes, B</creator><creator>Hersey, K</creator><creator>Koritzinsky, M</creator><creator>Schwab, M</creator><creator>Hofmann, U</creator><creator>Evans, A</creator><creator>van der Kwast, T</creator><creator>Trachtenberg, J</creator><creator>Finelli, A</creator><creator>Fleshner, N</creator><creator>Sweet, J</creator><creator>Pollak, M</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><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>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>M7Z</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>201409</creationdate><title>A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer</title><author>Joshua, A M ; Zannella, V E ; Downes, M R ; Bowes, B ; Hersey, K ; Koritzinsky, M ; Schwab, M ; Hofmann, U ; Evans, A ; van der Kwast, T ; Trachtenberg, J ; Finelli, A ; Fleshner, N ; Sweet, J ; Pollak, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c591t-ddb363b066d41abd2e4b7813a308e85f622941107d0ba873b71d14fabb20ff633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>13/51</topic><topic>692/308/575</topic><topic>Aged</topic><topic>Algorithms</topic><topic>Antidiabetics</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomarkers, Tumor - blood</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biopsy</topic><topic>Cancer Research</topic><topic>Cell proliferation</topic><topic>Dosage and administration</topic><topic>Drug therapy</topic><topic>Electron transport</topic><topic>Epidemiology</topic><topic>Health aspects</topic><topic>Health services</topic><topic>Heterogeneity</topic><topic>Humans</topic><topic>Insulin</topic><topic>Insulin resistance</topic><topic>Kinases</topic><topic>Male</topic><topic>Median (statistics)</topic><topic>Metabolism</topic><topic>Metformin</topic><topic>Metformin - administration & dosage</topic><topic>Metformin - adverse effects</topic><topic>Metformin - therapeutic use</topic><topic>Middle Aged</topic><topic>Neoadjuvant Therapy</topic><topic>Neoplasm Grading</topic><topic>Neoplasm Staging</topic><topic>original-article</topic><topic>Patient outcomes</topic><topic>Patients</topic><topic>Physiological aspects</topic><topic>Pilot Projects</topic><topic>Prostate cancer</topic><topic>Prostatectomy</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Prostatic Neoplasms - surgery</topic><topic>Rank tests</topic><topic>Signaling</topic><topic>Statistical analysis</topic><topic>Statistical tests</topic><topic>TOR protein</topic><topic>Toxicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Joshua, A M</creatorcontrib><creatorcontrib>Zannella, V E</creatorcontrib><creatorcontrib>Downes, M R</creatorcontrib><creatorcontrib>Bowes, B</creatorcontrib><creatorcontrib>Hersey, K</creatorcontrib><creatorcontrib>Koritzinsky, M</creatorcontrib><creatorcontrib>Schwab, M</creatorcontrib><creatorcontrib>Hofmann, U</creatorcontrib><creatorcontrib>Evans, A</creatorcontrib><creatorcontrib>van der Kwast, T</creatorcontrib><creatorcontrib>Trachtenberg, J</creatorcontrib><creatorcontrib>Finelli, A</creatorcontrib><creatorcontrib>Fleshner, N</creatorcontrib><creatorcontrib>Sweet, J</creatorcontrib><creatorcontrib>Pollak, M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Prostate cancer and prostatic diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Joshua, A M</au><au>Zannella, V E</au><au>Downes, M R</au><au>Bowes, B</au><au>Hersey, K</au><au>Koritzinsky, M</au><au>Schwab, M</au><au>Hofmann, U</au><au>Evans, A</au><au>van der Kwast, T</au><au>Trachtenberg, J</au><au>Finelli, A</au><au>Fleshner, N</au><au>Sweet, J</au><au>Pollak, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer</atitle><jtitle>Prostate cancer and prostatic diseases</jtitle><stitle>Prostate Cancer Prostatic Dis</stitle><addtitle>Prostate Cancer Prostatic Dis</addtitle><date>2014-09</date><risdate>2014</risdate><volume>17</volume><issue>3</issue><spage>252</spage><epage>258</epage><pages>252-258</pages><issn>1365-7852</issn><eissn>1476-5608</eissn><abstract>Background:
Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies
Methods:
Men were treated in a single-arm ‘window of opportunity’ study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students
t
-tests and/or Wilcoxon matched pairs signed rank test.
Results:
Baseline characteristics included median PSA 6 ng ml
−1
(3.22–36.11 ng ml
−1
). Median duration of drug treatment was 41 days (18–81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (
P
=0.0064 and
P
=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (
P
<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (
P
=0.08). The study is limited by small patient numbers and tumour heterogeneity.
Conclusions:
Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24861559</pmid><doi>10.1038/pcan.2014.20</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1365-7852 |
| ispartof | Prostate cancer and prostatic diseases, 2014-09, Vol.17 (3), p.252-258 |
| issn | 1365-7852 1476-5608 |
| language | eng |
| recordid | cdi_proquest_journals_2645322478 |
| source | MEDLINE; SpringerLink Journals; EZB-FREE-00999 freely available EZB journals |
| subjects | 13/51 692/308/575 Aged Algorithms Antidiabetics Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Biomarkers, Tumor - blood Biomedical and Life Sciences Biomedicine Biopsy Cancer Research Cell proliferation Dosage and administration Drug therapy Electron transport Epidemiology Health aspects Health services Heterogeneity Humans Insulin Insulin resistance Kinases Male Median (statistics) Metabolism Metformin Metformin - administration & dosage Metformin - adverse effects Metformin - therapeutic use Middle Aged Neoadjuvant Therapy Neoplasm Grading Neoplasm Staging original-article Patient outcomes Patients Physiological aspects Pilot Projects Prostate cancer Prostatectomy Prostatic Neoplasms - drug therapy Prostatic Neoplasms - pathology Prostatic Neoplasms - surgery Rank tests Signaling Statistical analysis Statistical tests TOR protein Toxicity Tumors |
| title | A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T14%3A58%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20pilot%20%E2%80%98window%20of%20opportunity%E2%80%99%20neoadjuvant%20study%20of%20metformin%20in%20localised%20prostate%20cancer&rft.jtitle=Prostate%20cancer%20and%20prostatic%20diseases&rft.au=Joshua,%20A%20M&rft.date=2014-09&rft.volume=17&rft.issue=3&rft.spage=252&rft.epage=258&rft.pages=252-258&rft.issn=1365-7852&rft.eissn=1476-5608&rft_id=info:doi/10.1038/pcan.2014.20&rft_dat=%3Cgale_proqu%3EA381948982%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1553144634&rft_id=info:pmid/24861559&rft_galeid=A381948982&rfr_iscdi=true |