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Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc
Jason Williams,
Adam T. Higgins,
Katie J. Stott,
Carly Thomas,
Lydia Farrell 
,
Cleo Bonnet ,
Sev Peneva,
Anna Powell ,
Trevor Hay,
Tianqi Wang,
Claire Morgan ,
Sarah Dwyer,
Joshua D’Ambrogio,
Catherine Hogan,
Matthew J. Smalley,
Lee Parry ,
Paul Dyson
,
Cleo Bonnet ,
Sev Peneva,
Anna Powell ,
Trevor Hay,
Tianqi Wang,
Claire Morgan ,
Sarah Dwyer,
Joshua D’Ambrogio,
Catherine Hogan,
Matthew J. Smalley,
Lee Parry ,
Paul Dyson
Cell and Bioscience, Volume: 14, Issue: 1
Swansea University Authors:
Jason Williams, Lydia Farrell , Cleo Bonnet , Sev Peneva, Anna Powell , Claire Morgan , Paul Dyson
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DOI (Published version): 10.1186/s13578-024-01206-8
Abstract
BackgroundBacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of thi...
| Published in: | Cell and Bioscience |
|---|---|
| ISSN: | 2045-3701 |
| Published: |
Springer Science and Business Media LLC
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa65889 |
| first_indexed |
2024-03-25T13:21:00Z |
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| last_indexed |
2024-11-25T14:17:05Z |
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<?xml version="1.0"?><rfc1807><datestamp>2024-07-15T11:48:16.9547753</datestamp><bib-version>v2</bib-version><id>65889</id><entry>2024-03-25</entry><title>Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc</title><swanseaauthors><author><sid>d90c652981ecd2052b4feb54e9dc069f</sid><firstname>Jason</firstname><surname>Williams</surname><name>Jason Williams</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>13cc2d4d6ef6f4094c4f8df0b217dd58</sid><ORCID>0000-0002-7643-6009</ORCID><firstname>Lydia</firstname><surname>Farrell</surname><name>Lydia Farrell</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>3494ef2ef460035abd3f3867c51600f7</sid><ORCID>0000-0002-9264-8044</ORCID><firstname>Cleo</firstname><surname>Bonnet</surname><name>Cleo Bonnet</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>de5fddba66c43de0d92f52f30a5c98de</sid><firstname>Sev</firstname><surname>Peneva</surname><name>Sev Peneva</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>b232c310a6c9458e8669feae92e558a0</sid><ORCID>0000-0002-8581-5262</ORCID><firstname>Anna</firstname><surname>Powell</surname><name>Anna Powell</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>52c886f26c1b4d9d817000ac6e58a486</sid><ORCID>0000-0002-3969-0710</ORCID><firstname>Claire</firstname><surname>Morgan</surname><name>Claire Morgan</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>300e3f46b70ae83f563b24f41d00cd17</sid><ORCID>0000-0002-0558-2666</ORCID><firstname>Paul</firstname><surname>Dyson</surname><name>Paul Dyson</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2024-03-25</date><deptcode>MEDS</deptcode><abstract>BackgroundBacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of this is the short-term nature of RNA interference in vivo due to plasmid instability. To overcome this, we sought to develop tumour-targeting attenuated bacteria that stably express shRNA by virtue of integration of an expression cassette within the bacterial chromosome and demonstrate therapeutic efficacy in vitro and in vivo.ResultsThe attenuated tumour targeting Salmonella typhimurium SL7207 strain was modified to carry chromosomally integrated shRNA expression cassettes at the xylA locus. The colorectal cancer cell lines SW480, HCT116 and breast cancer cell line MCF7 were used to demonstrate the ability of these modified strains to perform intracellular infection and deliver effective RNA and protein knockdown of the target gene c-Myc. In vivo therapeutic efficacy was demonstrated using the Lgr5creERT2Apcflx/flx and BlgCreBrca2flx/flp53flx/flx orthotopic immunocompetent mouse models of colorectal and breast cancer, respectively. In vitro co-cultures of breast and colorectal cancer cell lines with modified SL7207 demonstrated a significant 50–95% (P < 0.01) reduction in RNA and protein expression with SL7207/c-Myc targeted strains. In vivo, following establishment of tumour tissue, a single intra-peritoneal administration of 1 × 106 CFU of SL7207/c-Myc was sufficient to permit tumour colonisation and significantly extend survival with no overt toxicity in control animals.ConclusionsIn summary we have demonstrated that tumour tropic bacteria can be modified to safely deliver therapeutic levels of gene knockdown. This technology has the potential to specifically target primary and secondary solid tumours with personalised therapeutic payloads, providing new multi-cancer detection and treatment options with minimal off-target effects. Further understanding of the tropism mechanisms and impact on host immunity and microbiome is required to progress to clinical translation.</abstract><type>Journal Article</type><journal>Cell and Bioscience</journal><volume>14</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2045-3701</issnElectronic><keywords>Bacterial therapy; RNAi; Colorectal cancer &amp; breast cancer</keywords><publishedDay>23</publishedDay><publishedMonth>3</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-03-23</publishedDate><doi>10.1186/s13578-024-01206-8</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>The research was supported by grants to P.D. from the Welsh Government Life Sciences Research Network, the Welsh Government Bridging Fund, Agor-IP, and a Cancer Research UK Pioneer Award (reference C51116/A21905). And an Early Detection Project grant awarded to L.P and P.D(C23498/A27517).</funders><projectreference/><lastEdited>2024-07-15T11:48:16.9547753</lastEdited><Created>2024-03-25T13:17:36.6547219</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Jason</firstname><surname>Williams</surname><order>1</order></author><author><firstname>Adam T.</firstname><surname>Higgins</surname><order>2</order></author><author><firstname>Katie J.</firstname><surname>Stott</surname><order>3</order></author><author><firstname>Carly</firstname><surname>Thomas</surname><order>4</order></author><author><firstname>Lydia</firstname><surname>Farrell</surname><orcid>0000-0002-7643-6009</orcid><order>5</order></author><author><firstname>Cleo</firstname><surname>Bonnet</surname><orcid>0000-0002-9264-8044</orcid><order>6</order></author><author><firstname>Sev</firstname><surname>Peneva</surname><order>7</order></author><author><firstname>Anna</firstname><surname>Powell</surname><orcid>0000-0002-8581-5262</orcid><order>8</order></author><author><firstname>Trevor</firstname><surname>Hay</surname><order>9</order></author><author><firstname>Tianqi</firstname><surname>Wang</surname><order>10</order></author><author><firstname>Claire</firstname><surname>Morgan</surname><orcid>0000-0002-3969-0710</orcid><order>11</order></author><author><firstname>Sarah</firstname><surname>Dwyer</surname><order>12</order></author><author><firstname>Joshua</firstname><surname>D’Ambrogio</surname><order>13</order></author><author><firstname>Catherine</firstname><surname>Hogan</surname><order>14</order></author><author><firstname>Matthew J.</firstname><surname>Smalley</surname><order>15</order></author><author><firstname>Lee</firstname><surname>Parry</surname><orcid>0000-0002-4467-9196</orcid><order>16</order></author><author><firstname>Paul</firstname><surname>Dyson</surname><orcid>0000-0002-0558-2666</orcid><order>17</order></author></authors><documents><document><filename>65889__29859__ed74052f3dfd4d999d05e62c170b33aa.pdf</filename><originalFilename>65889.pdf</originalFilename><uploaded>2024-03-27T08:31:37.5273287</uploaded><type>Output</type><contentLength>2757148</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>This article is licensed under a Creative Commons Attribution 4.0 International License.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>http://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807> |
| spelling |
2024-07-15T11:48:16.9547753 v2 65889 2024-03-25 Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc d90c652981ecd2052b4feb54e9dc069f Jason Williams Jason Williams true false 13cc2d4d6ef6f4094c4f8df0b217dd58 0000-0002-7643-6009 Lydia Farrell Lydia Farrell true false 3494ef2ef460035abd3f3867c51600f7 0000-0002-9264-8044 Cleo Bonnet Cleo Bonnet true false de5fddba66c43de0d92f52f30a5c98de Sev Peneva Sev Peneva true false b232c310a6c9458e8669feae92e558a0 0000-0002-8581-5262 Anna Powell Anna Powell true false 52c886f26c1b4d9d817000ac6e58a486 0000-0002-3969-0710 Claire Morgan Claire Morgan true false 300e3f46b70ae83f563b24f41d00cd17 0000-0002-0558-2666 Paul Dyson Paul Dyson true false 2024-03-25 MEDS BackgroundBacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of this is the short-term nature of RNA interference in vivo due to plasmid instability. To overcome this, we sought to develop tumour-targeting attenuated bacteria that stably express shRNA by virtue of integration of an expression cassette within the bacterial chromosome and demonstrate therapeutic efficacy in vitro and in vivo.ResultsThe attenuated tumour targeting Salmonella typhimurium SL7207 strain was modified to carry chromosomally integrated shRNA expression cassettes at the xylA locus. The colorectal cancer cell lines SW480, HCT116 and breast cancer cell line MCF7 were used to demonstrate the ability of these modified strains to perform intracellular infection and deliver effective RNA and protein knockdown of the target gene c-Myc. In vivo therapeutic efficacy was demonstrated using the Lgr5creERT2Apcflx/flx and BlgCreBrca2flx/flp53flx/flx orthotopic immunocompetent mouse models of colorectal and breast cancer, respectively. In vitro co-cultures of breast and colorectal cancer cell lines with modified SL7207 demonstrated a significant 50–95% (P < 0.01) reduction in RNA and protein expression with SL7207/c-Myc targeted strains. In vivo, following establishment of tumour tissue, a single intra-peritoneal administration of 1 × 106 CFU of SL7207/c-Myc was sufficient to permit tumour colonisation and significantly extend survival with no overt toxicity in control animals.ConclusionsIn summary we have demonstrated that tumour tropic bacteria can be modified to safely deliver therapeutic levels of gene knockdown. This technology has the potential to specifically target primary and secondary solid tumours with personalised therapeutic payloads, providing new multi-cancer detection and treatment options with minimal off-target effects. Further understanding of the tropism mechanisms and impact on host immunity and microbiome is required to progress to clinical translation. Journal Article Cell and Bioscience 14 1 Springer Science and Business Media LLC 2045-3701 Bacterial therapy; RNAi; Colorectal cancer & breast cancer 23 3 2024 2024-03-23 10.1186/s13578-024-01206-8 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee The research was supported by grants to P.D. from the Welsh Government Life Sciences Research Network, the Welsh Government Bridging Fund, Agor-IP, and a Cancer Research UK Pioneer Award (reference C51116/A21905). And an Early Detection Project grant awarded to L.P and P.D(C23498/A27517). 2024-07-15T11:48:16.9547753 2024-03-25T13:17:36.6547219 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Jason Williams 1 Adam T. Higgins 2 Katie J. Stott 3 Carly Thomas 4 Lydia Farrell 0000-0002-7643-6009 5 Cleo Bonnet 0000-0002-9264-8044 6 Sev Peneva 7 Anna Powell 0000-0002-8581-5262 8 Trevor Hay 9 Tianqi Wang 10 Claire Morgan 0000-0002-3969-0710 11 Sarah Dwyer 12 Joshua D’Ambrogio 13 Catherine Hogan 14 Matthew J. Smalley 15 Lee Parry 0000-0002-4467-9196 16 Paul Dyson 0000-0002-0558-2666 17 65889__29859__ed74052f3dfd4d999d05e62c170b33aa.pdf 65889.pdf 2024-03-27T08:31:37.5273287 Output 2757148 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/ |
| title |
Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc |
| spellingShingle |
Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc Jason Williams Lydia Farrell Cleo Bonnet Sev Peneva Anna Powell Claire Morgan Paul Dyson |
| title_short |
Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc |
| title_full |
Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc |
| title_fullStr |
Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc |
| title_full_unstemmed |
Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc |
| title_sort |
Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc |
| author_id_str_mv |
d90c652981ecd2052b4feb54e9dc069f 13cc2d4d6ef6f4094c4f8df0b217dd58 3494ef2ef460035abd3f3867c51600f7 de5fddba66c43de0d92f52f30a5c98de b232c310a6c9458e8669feae92e558a0 52c886f26c1b4d9d817000ac6e58a486 300e3f46b70ae83f563b24f41d00cd17 |
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d90c652981ecd2052b4feb54e9dc069f_***_Jason Williams 13cc2d4d6ef6f4094c4f8df0b217dd58_***_Lydia Farrell 3494ef2ef460035abd3f3867c51600f7_***_Cleo Bonnet de5fddba66c43de0d92f52f30a5c98de_***_Sev Peneva b232c310a6c9458e8669feae92e558a0_***_Anna Powell 52c886f26c1b4d9d817000ac6e58a486_***_Claire Morgan 300e3f46b70ae83f563b24f41d00cd17_***_Paul Dyson |
| author |
Jason Williams Lydia Farrell Cleo Bonnet Sev Peneva Anna Powell Claire Morgan Paul Dyson |
| author2 |
Jason Williams Adam T. Higgins Katie J. Stott Carly Thomas Lydia Farrell Cleo Bonnet Sev Peneva Anna Powell Trevor Hay Tianqi Wang Claire Morgan Sarah Dwyer Joshua D’Ambrogio Catherine Hogan Matthew J. Smalley Lee Parry Paul Dyson |
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Cell and Bioscience |
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14 |
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2024 |
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Swansea University |
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2045-3701 |
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10.1186/s13578-024-01206-8 |
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Springer Science and Business Media LLC |
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Faculty of Medicine, Health and Life Sciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science |
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BackgroundBacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of this is the short-term nature of RNA interference in vivo due to plasmid instability. To overcome this, we sought to develop tumour-targeting attenuated bacteria that stably express shRNA by virtue of integration of an expression cassette within the bacterial chromosome and demonstrate therapeutic efficacy in vitro and in vivo.ResultsThe attenuated tumour targeting Salmonella typhimurium SL7207 strain was modified to carry chromosomally integrated shRNA expression cassettes at the xylA locus. The colorectal cancer cell lines SW480, HCT116 and breast cancer cell line MCF7 were used to demonstrate the ability of these modified strains to perform intracellular infection and deliver effective RNA and protein knockdown of the target gene c-Myc. In vivo therapeutic efficacy was demonstrated using the Lgr5creERT2Apcflx/flx and BlgCreBrca2flx/flp53flx/flx orthotopic immunocompetent mouse models of colorectal and breast cancer, respectively. In vitro co-cultures of breast and colorectal cancer cell lines with modified SL7207 demonstrated a significant 50–95% (P < 0.01) reduction in RNA and protein expression with SL7207/c-Myc targeted strains. In vivo, following establishment of tumour tissue, a single intra-peritoneal administration of 1 × 106 CFU of SL7207/c-Myc was sufficient to permit tumour colonisation and significantly extend survival with no overt toxicity in control animals.ConclusionsIn summary we have demonstrated that tumour tropic bacteria can be modified to safely deliver therapeutic levels of gene knockdown. This technology has the potential to specifically target primary and secondary solid tumours with personalised therapeutic payloads, providing new multi-cancer detection and treatment options with minimal off-target effects. Further understanding of the tropism mechanisms and impact on host immunity and microbiome is required to progress to clinical translation. |
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2024-03-23T08:28:59Z |
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1821393435599306752 |
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11.04748 |