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Development of PET Imaging Probes fo...

Al-saden, Noor.

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Development of PET Imaging Probes for Predicting Response of Breast Cancer to Trastuzumab Emtansine (T-DM1).

Record Type:	Electronic resources : Monograph/item
Title/Author:	Development of PET Imaging Probes for Predicting Response of Breast Cancer to Trastuzumab Emtansine (T-DM1)./
Author:	Al-saden, Noor.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	173 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-06, Section: B.
Contained By:	Dissertations Abstracts International81-06B.
Subject:	Pharmaceutical sciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13860265
ISBN:	9781392512340

Development of PET Imaging Probes for Predicting Response of Breast Cancer to Trastuzumab Emtansine (T-DM1).
Al-saden, Noor.

Development of PET Imaging Probes for Predicting Response of Breast Cancer to Trastuzumab Emtansine (T-DM1). - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 173 p.

Source: Dissertations Abstracts International, Volume: 81-06, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

This item must not be sold to any third party vendors.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-20% of breast cancers (BC) and represents an aggressive tumour phenotype conferring a poor prognosis in patients. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for treatment of advanced and metastatic HER2-positive BC. Despite the efficacy of T-DM1 and lower side effects compared to conventional chemotherapy, many eligible patients do not respond. The thesis hypothesis is PET imaging that probes T-DM1 delivery to tumours and its ability to mediate HER2 downregulation would be useful in predicting the response to T-DM1 treatment. An in vivo comparison revealed that 89Zr-DFO-T-DM1 exhibited significantly higher uptake than 89Zr-DFO-trastuzumab in mice with HER2-positive BC xenografts suggesting that 89Zr-DFO-T-DM1 may be more effective to study the delivery of T-DM1 to tumours. The correlation between tumour HER2 density, uptake of 89Zr-DFO-T-DM1, response to T-DM1, and in vitro cytotoxicity to T-DM1 was studied. There was a non-linear but direct correlation between the tumour to blood (T/B) ratios for 89Zr-DFO-T-DM1 and HER2 expression (r2=1.00). There was a direct linear correlation between the T/B ratio for 89Zr-DFO-T-DM1 and tumour doubling ratio (r2=0.97). In addition, in vitro cytotoxicity of T-DM1 demonstrated an inverse correlation with tumour doubling ratio and T/B ratio in mice treated with T-DM1 (r2=1.00). The ability of microPET/CT using 64Cu-NOTA-pertuzumab Fab fragments to detect decreased HER2 expression on tumours in vivo in NOD/SCID mice after T-DM1 treatment was also studied. However, instead of reduced tumour uptake of the imaging probe after T-DM1 treatment, an increase was observed. Further ex vivo analysis of the tumour vasculature showed reduced blood vessel density suggesting that T-DM1 caused normalization of vessels in the tumour microenvironment which increased the uptake of the imaging probe. I conclude that PET is a promising tool for imaging response of HER2-positive BC to treatment with T-DM1.

ISBN: 9781392512340Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

Breast Cancer

Development of PET Imaging Probes for Predicting Response of Breast Cancer to Trastuzumab Emtansine (T-DM1).
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300 $a 173 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-06, Section: B.
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506 $a This item must not be sold to any third party vendors.
520 $a The human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-20% of breast cancers (BC) and represents an aggressive tumour phenotype conferring a poor prognosis in patients. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for treatment of advanced and metastatic HER2-positive BC. Despite the efficacy of T-DM1 and lower side effects compared to conventional chemotherapy, many eligible patients do not respond. The thesis hypothesis is PET imaging that probes T-DM1 delivery to tumours and its ability to mediate HER2 downregulation would be useful in predicting the response to T-DM1 treatment. An in vivo comparison revealed that 89Zr-DFO-T-DM1 exhibited significantly higher uptake than 89Zr-DFO-trastuzumab in mice with HER2-positive BC xenografts suggesting that 89Zr-DFO-T-DM1 may be more effective to study the delivery of T-DM1 to tumours. The correlation between tumour HER2 density, uptake of 89Zr-DFO-T-DM1, response to T-DM1, and in vitro cytotoxicity to T-DM1 was studied. There was a non-linear but direct correlation between the tumour to blood (T/B) ratios for 89Zr-DFO-T-DM1 and HER2 expression (r2=1.00). There was a direct linear correlation between the T/B ratio for 89Zr-DFO-T-DM1 and tumour doubling ratio (r2=0.97). In addition, in vitro cytotoxicity of T-DM1 demonstrated an inverse correlation with tumour doubling ratio and T/B ratio in mice treated with T-DM1 (r2=1.00). The ability of microPET/CT using 64Cu-NOTA-pertuzumab Fab fragments to detect decreased HER2 expression on tumours in vivo in NOD/SCID mice after T-DM1 treatment was also studied. However, instead of reduced tumour uptake of the imaging probe after T-DM1 treatment, an increase was observed. Further ex vivo analysis of the tumour vasculature showed reduced blood vessel density suggesting that T-DM1 caused normalization of vessels in the tumour microenvironment which increased the uptake of the imaging probe. I conclude that PET is a promising tool for imaging response of HER2-positive BC to treatment with T-DM1.
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