Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target
Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHL-HBs or those...
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| creator | Sizdahkhani, Saman Feldman, Michael J. Piazza, Martin G. Ksendzovsky, Alexander Edwards, Nancy A. Ray-Chaudhury, Abhik Maric, Dragan Merrill, Marsha J. Pacak, Karel Zhuang, Zhengping Chittiboina, Prashant |
| description | Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHL-HBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX – caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat
68
Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy. |
| doi_str_mv | 10.1038/srep40822 |
| format | Article |
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68
Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep40822</identifier><identifier>PMID: 28094316</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/106 ; 13/2 ; 13/31 ; 13/51 ; 14 ; 38 ; 38/77 ; 59 ; 59/78 ; 692/4028/546 ; 692/4028/67/1244 ; 692/699/375/1922 ; Apoptosis ; Apoptosis - drug effects ; Avidity ; Brain Neoplasms - drug therapy ; Brain Neoplasms - pathology ; Caspase ; Caspase-3 ; Cells, Cultured ; Central nervous system ; Female ; Hemangioblastoma - drug therapy ; Hemangioblastoma - pathology ; Humanities and Social Sciences ; Humans ; Infarction ; Middle Aged ; Morbidity ; multidisciplinary ; Neoplasia ; Nervous system ; Neurological disorders ; Octreotide ; Octreotide - analogs & derivatives ; Octreotide - pharmacology ; Octreotide - therapeutic use ; Organometallic Compounds - therapeutic use ; Patients ; Positron emission tomography ; Radiopharmaceuticals - therapeutic use ; Receptors, Somatostatin - agonists ; Receptors, Somatostatin - genetics ; Receptors, Somatostatin - metabolism ; Science ; Science (multidisciplinary) ; Somatostatin ; Somatostatin receptors ; Stromal cells ; Tumors ; Vascular endothelial growth factor ; VHL protein ; von Hippel-Lindau Disease - drug therapy ; von Hippel-Lindau Disease - pathology</subject><ispartof>Scientific reports, 2017-01, Vol.7 (1), p.40822-40822, Article 40822</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Jan 2017</rights><rights>Copyright © 2017, The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-e598c90cd2fa614fb68858ee53b049f22fdcaf89be3d25649994e3a704befce23</citedby><cites>FETCH-LOGICAL-c504t-e598c90cd2fa614fb68858ee53b049f22fdcaf89be3d25649994e3a704befce23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240113/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240113/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28094316$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sizdahkhani, Saman</creatorcontrib><creatorcontrib>Feldman, Michael J.</creatorcontrib><creatorcontrib>Piazza, Martin G.</creatorcontrib><creatorcontrib>Ksendzovsky, Alexander</creatorcontrib><creatorcontrib>Edwards, Nancy A.</creatorcontrib><creatorcontrib>Ray-Chaudhury, Abhik</creatorcontrib><creatorcontrib>Maric, Dragan</creatorcontrib><creatorcontrib>Merrill, Marsha J.</creatorcontrib><creatorcontrib>Pacak, Karel</creatorcontrib><creatorcontrib>Zhuang, Zhengping</creatorcontrib><creatorcontrib>Chittiboina, Prashant</creatorcontrib><title>Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHL-HBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX – caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat
68
Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy.</description><subject>13</subject><subject>13/1</subject><subject>13/106</subject><subject>13/2</subject><subject>13/31</subject><subject>13/51</subject><subject>14</subject><subject>38</subject><subject>38/77</subject><subject>59</subject><subject>59/78</subject><subject>692/4028/546</subject><subject>692/4028/67/1244</subject><subject>692/699/375/1922</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Avidity</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - pathology</subject><subject>Caspase</subject><subject>Caspase-3</subject><subject>Cells, Cultured</subject><subject>Central nervous system</subject><subject>Female</subject><subject>Hemangioblastoma - drug therapy</subject><subject>Hemangioblastoma - pathology</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Infarction</subject><subject>Middle Aged</subject><subject>Morbidity</subject><subject>multidisciplinary</subject><subject>Neoplasia</subject><subject>Nervous system</subject><subject>Neurological disorders</subject><subject>Octreotide</subject><subject>Octreotide - analogs & derivatives</subject><subject>Octreotide - pharmacology</subject><subject>Octreotide - therapeutic use</subject><subject>Organometallic Compounds - therapeutic use</subject><subject>Patients</subject><subject>Positron emission tomography</subject><subject>Radiopharmaceuticals - therapeutic use</subject><subject>Receptors, Somatostatin - agonists</subject><subject>Receptors, Somatostatin - genetics</subject><subject>Receptors, Somatostatin - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Somatostatin</subject><subject>Somatostatin receptors</subject><subject>Stromal cells</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>VHL protein</subject><subject>von Hippel-Lindau Disease - drug therapy</subject><subject>von Hippel-Lindau Disease - pathology</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNplkV1rFDEUhoMottRe-AfKQG9UGJvP2eRGKEWtsOCF9TpkMie7KTPJNMks9t8b2bpsNSQkcB6ec8KL0FuCPxLM5FVOMHMsKX2BTinmoqWM0pdH7xN0nvM9rktQxYl6jU6oxIoz0p2i9CNOpsRcTPGhSWBhLjE18GtOkLOPoal7V8-tn2cY27UPg1lak3O03hQYmi1MJmx87EeTS5XlJjoHKTch7mBsyhaSmWEp3jbFpA2UN-iVM2OG86f7DP388vnu5rZdf__67eZ63VqBeWlBKGkVtgN1piPc9Z2UQgII1mOuHKVusMZJ1QMbqOi4UooDMyvMe3AWKDtDn_beeeknGCyEksyo5-Qnkx51NF4_rwS_1Zu404JyTAirgndPghQfFshFTz5bGEcTIC5ZE9kRIVYrtqro5T_ofVxSqN-rlFKCSIJFpd7vKZtirrm5wzAE6z9h6kOYlb04nv5A_o2uAh_2QK6lsIF01PI_22_-36yv</recordid><startdate>20170117</startdate><enddate>20170117</enddate><creator>Sizdahkhani, Saman</creator><creator>Feldman, Michael J.</creator><creator>Piazza, Martin G.</creator><creator>Ksendzovsky, Alexander</creator><creator>Edwards, Nancy A.</creator><creator>Ray-Chaudhury, Abhik</creator><creator>Maric, Dragan</creator><creator>Merrill, Marsha J.</creator><creator>Pacak, Karel</creator><creator>Zhuang, Zhengping</creator><creator>Chittiboina, Prashant</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170117</creationdate><title>Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target</title><author>Sizdahkhani, Saman ; Feldman, Michael J. ; Piazza, Martin G. ; Ksendzovsky, Alexander ; Edwards, Nancy A. ; Ray-Chaudhury, Abhik ; Maric, Dragan ; Merrill, Marsha J. ; Pacak, Karel ; Zhuang, Zhengping ; Chittiboina, Prashant</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-e598c90cd2fa614fb68858ee53b049f22fdcaf89be3d25649994e3a704befce23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13</topic><topic>13/1</topic><topic>13/106</topic><topic>13/2</topic><topic>13/31</topic><topic>13/51</topic><topic>14</topic><topic>38</topic><topic>38/77</topic><topic>59</topic><topic>59/78</topic><topic>692/4028/546</topic><topic>692/4028/67/1244</topic><topic>692/699/375/1922</topic><topic>Apoptosis</topic><topic>Apoptosis - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sizdahkhani, Saman</au><au>Feldman, Michael J.</au><au>Piazza, Martin G.</au><au>Ksendzovsky, Alexander</au><au>Edwards, Nancy A.</au><au>Ray-Chaudhury, Abhik</au><au>Maric, Dragan</au><au>Merrill, Marsha J.</au><au>Pacak, Karel</au><au>Zhuang, Zhengping</au><au>Chittiboina, Prashant</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-01-17</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>40822</spage><epage>40822</epage><pages>40822-40822</pages><artnum>40822</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHL-HBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX – caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat
68
Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28094316</pmid><doi>10.1038/srep40822</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/1 13/106 13/2 13/31 13/51 14 38 38/77 59 59/78 692/4028/546 692/4028/67/1244 692/699/375/1922 Apoptosis Apoptosis - drug effects Avidity Brain Neoplasms - drug therapy Brain Neoplasms - pathology Caspase Caspase-3 Cells, Cultured Central nervous system Female Hemangioblastoma - drug therapy Hemangioblastoma - pathology Humanities and Social Sciences Humans Infarction Middle Aged Morbidity multidisciplinary Neoplasia Nervous system Neurological disorders Octreotide Octreotide - analogs & derivatives Octreotide - pharmacology Octreotide - therapeutic use Organometallic Compounds - therapeutic use Patients Positron emission tomography Radiopharmaceuticals - therapeutic use Receptors, Somatostatin - agonists Receptors, Somatostatin - genetics Receptors, Somatostatin - metabolism Science Science (multidisciplinary) Somatostatin Somatostatin receptors Stromal cells Tumors Vascular endothelial growth factor VHL protein von Hippel-Lindau Disease - drug therapy von Hippel-Lindau Disease - pathology |
| title | Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target |
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