Inhibition of Hypoxia and EGFR Sensitizes TNBC to Cisplatin and Suppresses Bulk and Cancer Stem Cells
Despite progress being made in our understanding of triple negative breast cancer (TNBC), the overall survival and disease-free survival for TNBC patients continues to be considerably poorer than their ER/PR/HER2+ counterparts. Metastasis and chemoresistance are the pivotal issues holding back the l...
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Université d'Ottawa / University of Ottawa
2020
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Online Access: | http://hdl.handle.net/10393/41506 http://dx.doi.org/10.20381/ruor-25730 |
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ndltd-uottawa.ca-oai-ruor.uottawa.ca-10393-415062020-11-28T05:28:30Z Inhibition of Hypoxia and EGFR Sensitizes TNBC to Cisplatin and Suppresses Bulk and Cancer Stem Cells McGarry, Sarah Wang, Lisheng breast cancer cancer stem cells cisplatin TNBC EGFR Metformin Gefitinib Hypoxia CD44+/CD24- ALDH+ Chemoresistance PDX Despite progress being made in our understanding of triple negative breast cancer (TNBC), the overall survival and disease-free survival for TNBC patients continues to be considerably poorer than their ER/PR/HER2+ counterparts. Metastasis and chemoresistance are the pivotal issues holding back the long-term success of TNBC treatments. In addition to the bulk tumor cells, cancer stem cells (CSCs) have emerged as important targets for alleviating TNBC progression and relapse. Cisplatin, a platinum based chemotherapeutic agent, has shown promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with tumor hypoxia that in turn promotes CSC enrichment and drug resistance. My work is to develop a combinational treatment to improve the long-term therapeutic potential of cisplatin that not only targeted the bulk TNBC population but also ALDHhigh and CD44+/CD24- CSC populations. Through clinical dataset analysis, I found that patient TNBC tumors expressed high levels of epidermal growth factor receptor (EGFR) and hypoxia genes. A similar expression pattern was demonstrated in cisplatin-resistant ovarian cancer. I therefore developed a combinational therapeutic to co-inhibit EGFR and hypoxia using metformin (an AMPK activator) and gefitinib (an EGFR inhibitor), which sensitized bulk TNBC cells to cisplatin and also led to the effective inhibition of both CD44+/CD24- and ALDHhigh CSCs. I obtained similar results by using clinically relevant TNBC patient samples ex vivo. Since these drugs are already frequently used in the clinic, this study illustrates a novel, clinically translatable therapeutic approach to improve the long-term therapeutic outcome of cisplatin for TNBC treatment. 2020-11-26T17:59:34Z 2020-11-26T17:59:34Z 2020-11-26 Thesis http://hdl.handle.net/10393/41506 http://dx.doi.org/10.20381/ruor-25730 en application/pdf Université d'Ottawa / University of Ottawa |
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breast cancer cancer stem cells cisplatin TNBC EGFR Metformin Gefitinib Hypoxia CD44+/CD24- ALDH+ Chemoresistance PDX |
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breast cancer cancer stem cells cisplatin TNBC EGFR Metformin Gefitinib Hypoxia CD44+/CD24- ALDH+ Chemoresistance PDX McGarry, Sarah Inhibition of Hypoxia and EGFR Sensitizes TNBC to Cisplatin and Suppresses Bulk and Cancer Stem Cells |
description |
Despite progress being made in our understanding of triple negative breast cancer (TNBC), the overall survival and disease-free survival for TNBC patients continues to be considerably poorer than their ER/PR/HER2+ counterparts. Metastasis and chemoresistance are the pivotal issues holding back the long-term success of TNBC treatments. In addition to the bulk tumor cells, cancer stem cells (CSCs) have emerged as important targets for alleviating TNBC progression and relapse.
Cisplatin, a platinum based chemotherapeutic agent, has shown promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with tumor hypoxia that in turn promotes CSC enrichment and drug resistance. My work is to develop a combinational treatment to improve the long-term therapeutic potential of cisplatin that not only targeted the bulk TNBC population but also ALDHhigh and CD44+/CD24- CSC populations.
Through clinical dataset analysis, I found that patient TNBC tumors expressed high levels of epidermal growth factor receptor (EGFR) and hypoxia genes. A similar expression pattern was demonstrated in cisplatin-resistant ovarian cancer. I therefore developed a combinational therapeutic to co-inhibit EGFR and hypoxia using metformin (an AMPK activator) and gefitinib (an EGFR inhibitor), which sensitized bulk TNBC cells to cisplatin and also led to the effective inhibition of both CD44+/CD24- and ALDHhigh CSCs. I obtained similar results by using clinically relevant TNBC patient samples ex vivo. Since these drugs are already frequently used in the clinic, this study illustrates a novel, clinically translatable therapeutic approach to improve the long-term therapeutic outcome of cisplatin for TNBC treatment. |
author2 |
Wang, Lisheng |
author_facet |
Wang, Lisheng McGarry, Sarah |
author |
McGarry, Sarah |
author_sort |
McGarry, Sarah |
title |
Inhibition of Hypoxia and EGFR Sensitizes TNBC to Cisplatin and Suppresses Bulk and Cancer Stem Cells |
title_short |
Inhibition of Hypoxia and EGFR Sensitizes TNBC to Cisplatin and Suppresses Bulk and Cancer Stem Cells |
title_full |
Inhibition of Hypoxia and EGFR Sensitizes TNBC to Cisplatin and Suppresses Bulk and Cancer Stem Cells |
title_fullStr |
Inhibition of Hypoxia and EGFR Sensitizes TNBC to Cisplatin and Suppresses Bulk and Cancer Stem Cells |
title_full_unstemmed |
Inhibition of Hypoxia and EGFR Sensitizes TNBC to Cisplatin and Suppresses Bulk and Cancer Stem Cells |
title_sort |
inhibition of hypoxia and egfr sensitizes tnbc to cisplatin and suppresses bulk and cancer stem cells |
publisher |
Université d'Ottawa / University of Ottawa |
publishDate |
2020 |
url |
http://hdl.handle.net/10393/41506 http://dx.doi.org/10.20381/ruor-25730 |
work_keys_str_mv |
AT mcgarrysarah inhibitionofhypoxiaandegfrsensitizestnbctocisplatinandsuppressesbulkandcancerstemcells |
_version_ |
1719362865982341120 |