Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer

Melissa R. Junttila, Weiguang Mao, Xi Wang, Bu Er Wang, Thinh S Pham, John A Flygare, Shang Fan Yu, Sharon Yee, David M Goldenberg, Carter Fields, Jeffrey Eastham-Anderson, Mallika Singh, Rajesh Vij, Jo Anne Hongo, Ron Firestein, Melissa Schutten, Kelly Flagella, Paul Polakis, Andrew G. Polson

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Abstract

Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an antibody conjugated to distinct cytotoxic drugs. One antibody-drug conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.

Original languageEnglish
Article number314ra186
Number of pages11
JournalScience Translational Medicine
Volume7
Issue number314
DOIs
Publication statusPublished - 18 Nov 2015

Cite this

Junttila, M. R., Mao, W., Wang, X., Wang, B. E., Pham, T. S., Flygare, J. A., ... Polson, A. G. (2015). Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. Science Translational Medicine, 7(314), [314ra186]. https://doi.org/10.1126/scitranslmed.aac7433
Junttila, Melissa R. ; Mao, Weiguang ; Wang, Xi ; Wang, Bu Er ; Pham, Thinh S ; Flygare, John A ; Yu, Shang Fan ; Yee, Sharon ; Goldenberg, David M ; Fields, Carter ; Eastham-Anderson, Jeffrey ; Singh, Mallika ; Vij, Rajesh ; Hongo, Jo Anne ; Firestein, Ron ; Schutten, Melissa ; Flagella, Kelly ; Polakis, Paul ; Polson, Andrew G. / Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. In: Science Translational Medicine. 2015 ; Vol. 7, No. 314.
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abstract = "Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an antibody conjugated to distinct cytotoxic drugs. One antibody-drug conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.",
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Junttila, MR, Mao, W, Wang, X, Wang, BE, Pham, TS, Flygare, JA, Yu, SF, Yee, S, Goldenberg, DM, Fields, C, Eastham-Anderson, J, Singh, M, Vij, R, Hongo, JA, Firestein, R, Schutten, M, Flagella, K, Polakis, P & Polson, AG 2015, 'Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer', Science Translational Medicine, vol. 7, no. 314, 314ra186. https://doi.org/10.1126/scitranslmed.aac7433

Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. / Junttila, Melissa R.; Mao, Weiguang; Wang, Xi; Wang, Bu Er; Pham, Thinh S; Flygare, John A; Yu, Shang Fan; Yee, Sharon; Goldenberg, David M; Fields, Carter; Eastham-Anderson, Jeffrey; Singh, Mallika; Vij, Rajesh; Hongo, Jo Anne; Firestein, Ron; Schutten, Melissa; Flagella, Kelly; Polakis, Paul; Polson, Andrew G.

In: Science Translational Medicine, Vol. 7, No. 314, 314ra186, 18.11.2015.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer

AU - Junttila, Melissa R.

AU - Mao, Weiguang

AU - Wang, Xi

AU - Wang, Bu Er

AU - Pham, Thinh S

AU - Flygare, John A

AU - Yu, Shang Fan

AU - Yee, Sharon

AU - Goldenberg, David M

AU - Fields, Carter

AU - Eastham-Anderson, Jeffrey

AU - Singh, Mallika

AU - Vij, Rajesh

AU - Hongo, Jo Anne

AU - Firestein, Ron

AU - Schutten, Melissa

AU - Flagella, Kelly

AU - Polakis, Paul

AU - Polson, Andrew G.

PY - 2015/11/18

Y1 - 2015/11/18

N2 - Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an antibody conjugated to distinct cytotoxic drugs. One antibody-drug conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.

AB - Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an antibody conjugated to distinct cytotoxic drugs. One antibody-drug conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.

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