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HER2-Targeted Antibody-Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget's Disease Models : In Vivo and Immunohistochemical Analyses
| Title: | HER2-Targeted Antibody-Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget's Disease Models : In Vivo and Immunohistochemical Analyses |
| Authors: | Tokuchi, Keiko Browse this author | | Maeda, Takuya Browse this author | | Kitamura, Shinya Browse this author | | Yanagi, Teruki Browse this author →KAKEN DB | | Ujiie, Hideyuki Browse this author →KAKEN DB |
| Keywords: | antibody-drug conjugate | | HER2 | | ERBB2 | | extramammary Paget's disease | | patient-derived xenograft |
| Issue Date: | 20-Jul-2022 |
| Publisher: | MDPI |
| Journal Title: | Cancers |
| Volume: | 14 |
| Issue: | 14 |
| Start Page: | 3519 |
| Publisher DOI: | 10.3390/cancers14143519 |
| Abstract: | Simple Summary The prognosis for advanced Extramammary Paget's disease (EMPD) is almost always poor. HER2-targeted antibody-drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven to be effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in cases with the ERBB2-mutation or ERBB2-overexpression. Extramammary Paget's disease (EMPD) is an adenocarcinoma that develops mainly in the genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel therapeutic strategies need to be developed. HER2-targeted antibody-drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors. EMPD patients' clinical samples revealed a significant correlation between HER2 positivity and invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in ERBB2-mutant or ERBB2-overexpressed cases. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/86936 |
| Appears in Collections: | 北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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