Brain metastases as preventive and therapeutic targets
Key Points Brain metastases are most common in patients with lung cancers, breast cancers or melanoma. Treatment includes surgery and radiation therapy. Whole-brain radiation therapy (WBRT) has been shown to prevent lung cancer brain metastases, but causes cognitive decline. In animal models of brai...
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| Veröffentlicht in: | Nature reviews. Cancer 2011-05, Vol.11 (5), p.352-363 |
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| creator | Steeg, Patricia S Camphausen, Kevin A Smith, Quentin R |
| description | Key Points
Brain metastases are most common in patients with lung cancers, breast cancers or melanoma.
Treatment includes surgery and radiation therapy. Whole-brain radiation therapy (WBRT) has been shown to prevent lung cancer brain metastases, but causes cognitive decline.
In animal models of brain metastasis, tumour cells crawl outside the blood vessels and interact with an inflamed neural microenvironment to colonize the brain.
Alterations in the expression of several genes, including
ERBB2
,
ST6GALNAC5
,
TCF
, transforming growth factor-β (
TGFB
), vascular endothelial growth factor (
VEGF
),
Serpine1
and
Timp1
, have modulated brain metastasis.
Chemotherapeutic efficacy for brain metastases remains disappointing.
In experimental models, brain metastases opened the blood–brain barrier (BBB) several-fold over the normal brain, but only 10% of lesions exhibited sufficient drug permeability to mount an apoptotic response to chemotherapy.
BBB-permeable drugs are needed to improve chemotherapeutic efficacy.
Prevention of brain metastasis formation in mice has been observed in response to lapatinib, vorinostat, pazopanib, signal transducer and activator of transcription 3 (STAT3) inhibitors and VEGF receptor (VEGFR) inhibitors.
New trial designs could test drugs for the prevention of brain metastases. Secondary prevention trials would determine the time to the development of a new brain metastasis in patients with either one or several existing lesions.
Radiosensitizers may improve the efficacy of radiation therapy while sparing normal tissue.
Inhibition of the neuroinflammatory response is hypothesized to protect the brain from WBRT-induced cognitive decline.
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. As discussed in this Review, translational research that aims to improve the outcome for patients with brain metastases needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology.
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood–tumour barrier limits the ability of drugs to enter and kill tumour cells. Translational research examining metastasis to the brain needs to be |
| doi_str_mv | 10.1038/nrc3053 |
| format | Article |
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Brain metastases are most common in patients with lung cancers, breast cancers or melanoma.
Treatment includes surgery and radiation therapy. Whole-brain radiation therapy (WBRT) has been shown to prevent lung cancer brain metastases, but causes cognitive decline.
In animal models of brain metastasis, tumour cells crawl outside the blood vessels and interact with an inflamed neural microenvironment to colonize the brain.
Alterations in the expression of several genes, including
ERBB2
,
ST6GALNAC5
,
TCF
, transforming growth factor-β (
TGFB
), vascular endothelial growth factor (
VEGF
),
Serpine1
and
Timp1
, have modulated brain metastasis.
Chemotherapeutic efficacy for brain metastases remains disappointing.
In experimental models, brain metastases opened the blood–brain barrier (BBB) several-fold over the normal brain, but only 10% of lesions exhibited sufficient drug permeability to mount an apoptotic response to chemotherapy.
BBB-permeable drugs are needed to improve chemotherapeutic efficacy.
Prevention of brain metastasis formation in mice has been observed in response to lapatinib, vorinostat, pazopanib, signal transducer and activator of transcription 3 (STAT3) inhibitors and VEGF receptor (VEGFR) inhibitors.
New trial designs could test drugs for the prevention of brain metastases. Secondary prevention trials would determine the time to the development of a new brain metastasis in patients with either one or several existing lesions.
Radiosensitizers may improve the efficacy of radiation therapy while sparing normal tissue.
Inhibition of the neuroinflammatory response is hypothesized to protect the brain from WBRT-induced cognitive decline.
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. As discussed in this Review, translational research that aims to improve the outcome for patients with brain metastases needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology.
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood–tumour barrier limits the ability of drugs to enter and kill tumour cells. Translational research examining metastasis to the brain needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology, to develop and implement new clinical trial designs. Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.</description><identifier>ISSN: 1474-175X</identifier><identifier>EISSN: 1474-1768</identifier><identifier>DOI: 10.1038/nrc3053</identifier><identifier>PMID: 21472002</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1059/2326 ; 631/67/1059/602 ; 692/698/1688/64 ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Biomedical and Life Sciences ; Biomedicine ; Blood-brain barrier ; Blood-Brain Barrier - metabolism ; Brain ; Brain cancer ; Brain Neoplasms - pathology ; Brain Neoplasms - secondary ; Brain Neoplasms - therapy ; Cancer ; Cancer Research ; Care and treatment ; Chemotherapy ; Clinical trials ; Cognition ; Cognitive ability ; Drug development ; Health aspects ; Humans ; Metastases ; Pharmacokinetics ; Radiation ; Radiotherapy ; review-article ; Reviews ; Translation</subject><ispartof>Nature reviews. Cancer, 2011-05, Vol.11 (5), p.352-363</ispartof><rights>Springer Nature Limited 2011</rights><rights>COPYRIGHT 2011 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c580t-6b7acb4c64e20954cddf3a4d3add218f434a340c28f8a035c1bfb7b1643a6bdd3</citedby><cites>FETCH-LOGICAL-c580t-6b7acb4c64e20954cddf3a4d3add218f434a340c28f8a035c1bfb7b1643a6bdd3</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/nrc3053$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nrc3053$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,2725,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21472002$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Steeg, Patricia S</creatorcontrib><creatorcontrib>Camphausen, Kevin A</creatorcontrib><creatorcontrib>Smith, Quentin R</creatorcontrib><title>Brain metastases as preventive and therapeutic targets</title><title>Nature reviews. Cancer</title><addtitle>Nat Rev Cancer</addtitle><addtitle>Nat Rev Cancer</addtitle><description>Key Points
Brain metastases are most common in patients with lung cancers, breast cancers or melanoma.
Treatment includes surgery and radiation therapy. Whole-brain radiation therapy (WBRT) has been shown to prevent lung cancer brain metastases, but causes cognitive decline.
In animal models of brain metastasis, tumour cells crawl outside the blood vessels and interact with an inflamed neural microenvironment to colonize the brain.
Alterations in the expression of several genes, including
ERBB2
,
ST6GALNAC5
,
TCF
, transforming growth factor-β (
TGFB
), vascular endothelial growth factor (
VEGF
),
Serpine1
and
Timp1
, have modulated brain metastasis.
Chemotherapeutic efficacy for brain metastases remains disappointing.
In experimental models, brain metastases opened the blood–brain barrier (BBB) several-fold over the normal brain, but only 10% of lesions exhibited sufficient drug permeability to mount an apoptotic response to chemotherapy.
BBB-permeable drugs are needed to improve chemotherapeutic efficacy.
Prevention of brain metastasis formation in mice has been observed in response to lapatinib, vorinostat, pazopanib, signal transducer and activator of transcription 3 (STAT3) inhibitors and VEGF receptor (VEGFR) inhibitors.
New trial designs could test drugs for the prevention of brain metastases. Secondary prevention trials would determine the time to the development of a new brain metastasis in patients with either one or several existing lesions.
Radiosensitizers may improve the efficacy of radiation therapy while sparing normal tissue.
Inhibition of the neuroinflammatory response is hypothesized to protect the brain from WBRT-induced cognitive decline.
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. As discussed in this Review, translational research that aims to improve the outcome for patients with brain metastases needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology.
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood–tumour barrier limits the ability of drugs to enter and kill tumour cells. Translational research examining metastasis to the brain needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology, to develop and implement new clinical trial designs. Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.</description><subject>631/67/1059/2326</subject><subject>631/67/1059/602</subject><subject>692/698/1688/64</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Blood-brain barrier</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Brain</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain Neoplasms - secondary</subject><subject>Brain Neoplasms - therapy</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Cognition</subject><subject>Cognitive ability</subject><subject>Drug development</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Metastases</subject><subject>Pharmacokinetics</subject><subject>Radiation</subject><subject>Radiotherapy</subject><subject>review-article</subject><subject>Reviews</subject><subject>Translation</subject><issn>1474-175X</issn><issn>1474-1768</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptklFrFDEQxxex2FrFT6AsFqwvV5NNssm9CLVYFQq-KPgWZpPZu5Td5EyyB3775rjrtaeSQEL-v_lPZpKqekXJBSVMffDRMCLYk-qEcslnVLbq6X4vfh1Xz1O6JYS2VNJn1XFTlIaQ5qRqP0Vwvh4xQyoTUw2pXkVco89ujTV4W-clRljhlJ2pM8QF5vSiOuphSPhyt55WP68__7j6Orv5_uXb1eXNzAhF8qztJJiOm5ZjQ-aCG2t7BtwysLahqueMA-PENKpXQJgwtOs72dGWM2g7a9lp9XHru5q6Ea0pt4ow6FV0I8Q_OoDTh4p3S70Iay2ZoA1hxeB8ZxDD7wlT1qNLBocBPIYpaSU5VVQoVci3f5G3YYq-VKdV2ygi5lIW6GwLLWBA7XwfSlazsdSXjRBUzuftJunFf6gyLI7OBI-9K-cHAe8eBSwRhrxMYSgdDz4dgrtyTAwpRez3raBEb36C3v2EQr553Lk9d__0BXi_BVKR_ALjQ73_er3eoh7yFHHvda_fAb0SxLo</recordid><startdate>20110501</startdate><enddate>20110501</enddate><creator>Steeg, Patricia S</creator><creator>Camphausen, Kevin A</creator><creator>Smith, Quentin R</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>7RV</scope><scope>7TK</scope><scope>7TM</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>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20110501</creationdate><title>Brain metastases as preventive and therapeutic targets</title><author>Steeg, Patricia S ; Camphausen, Kevin A ; Smith, Quentin R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c580t-6b7acb4c64e20954cddf3a4d3add218f434a340c28f8a035c1bfb7b1643a6bdd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>631/67/1059/2326</topic><topic>631/67/1059/602</topic><topic>692/698/1688/64</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Blood-brain barrier</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Brain</topic><topic>Brain cancer</topic><topic>Brain Neoplasms - pathology</topic><topic>Brain Neoplasms - secondary</topic><topic>Brain Neoplasms - therapy</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Cognition</topic><topic>Cognitive ability</topic><topic>Drug development</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Metastases</topic><topic>Pharmacokinetics</topic><topic>Radiation</topic><topic>Radiotherapy</topic><topic>review-article</topic><topic>Reviews</topic><topic>Translation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Steeg, Patricia S</creatorcontrib><creatorcontrib>Camphausen, Kevin A</creatorcontrib><creatorcontrib>Smith, Quentin R</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>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</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>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</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><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature reviews. Cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Steeg, Patricia S</au><au>Camphausen, Kevin A</au><au>Smith, Quentin R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Brain metastases as preventive and therapeutic targets</atitle><jtitle>Nature reviews. Cancer</jtitle><stitle>Nat Rev Cancer</stitle><addtitle>Nat Rev Cancer</addtitle><date>2011-05-01</date><risdate>2011</risdate><volume>11</volume><issue>5</issue><spage>352</spage><epage>363</epage><pages>352-363</pages><issn>1474-175X</issn><eissn>1474-1768</eissn><abstract>Key Points
Brain metastases are most common in patients with lung cancers, breast cancers or melanoma.
Treatment includes surgery and radiation therapy. Whole-brain radiation therapy (WBRT) has been shown to prevent lung cancer brain metastases, but causes cognitive decline.
In animal models of brain metastasis, tumour cells crawl outside the blood vessels and interact with an inflamed neural microenvironment to colonize the brain.
Alterations in the expression of several genes, including
ERBB2
,
ST6GALNAC5
,
TCF
, transforming growth factor-β (
TGFB
), vascular endothelial growth factor (
VEGF
),
Serpine1
and
Timp1
, have modulated brain metastasis.
Chemotherapeutic efficacy for brain metastases remains disappointing.
In experimental models, brain metastases opened the blood–brain barrier (BBB) several-fold over the normal brain, but only 10% of lesions exhibited sufficient drug permeability to mount an apoptotic response to chemotherapy.
BBB-permeable drugs are needed to improve chemotherapeutic efficacy.
Prevention of brain metastasis formation in mice has been observed in response to lapatinib, vorinostat, pazopanib, signal transducer and activator of transcription 3 (STAT3) inhibitors and VEGF receptor (VEGFR) inhibitors.
New trial designs could test drugs for the prevention of brain metastases. Secondary prevention trials would determine the time to the development of a new brain metastasis in patients with either one or several existing lesions.
Radiosensitizers may improve the efficacy of radiation therapy while sparing normal tissue.
Inhibition of the neuroinflammatory response is hypothesized to protect the brain from WBRT-induced cognitive decline.
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. As discussed in this Review, translational research that aims to improve the outcome for patients with brain metastases needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology.
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood–tumour barrier limits the ability of drugs to enter and kill tumour cells. Translational research examining metastasis to the brain needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology, to develop and implement new clinical trial designs. Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>21472002</pmid><doi>10.1038/nrc3053</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/67/1059/2326 631/67/1059/602 692/698/1688/64 Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Biomedical and Life Sciences Biomedicine Blood-brain barrier Blood-Brain Barrier - metabolism Brain Brain cancer Brain Neoplasms - pathology Brain Neoplasms - secondary Brain Neoplasms - therapy Cancer Cancer Research Care and treatment Chemotherapy Clinical trials Cognition Cognitive ability Drug development Health aspects Humans Metastases Pharmacokinetics Radiation Radiotherapy review-article Reviews Translation |
| title | Brain metastases as preventive and therapeutic targets |
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