Head-to-Head Comparison of the Expression Differences of NECTIN-4, TROP-2, and HER2 in Urothelial Carcinoma and Its Histologic Variants

Fan, Yu; Li, Qinhan; Shen, Qi; Liu, Zhifu; Zhang, Zhenan; Zhou, Tianjun; Yu, Wei; He, Zhisong; He, Qun; Zhang, Qian

doi:10.3389/fonc.2022.858865

Cited by 18 publications

(14 citation statements)

References 40 publications

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“…119 Thus, the selection principle of ADCs is based on whether the antigens corresponding to the antibodies that make up ADCs are highly expressed in BC. 129 Currently, ADCs is a novel therapeutic strategy for BC. For instance, the EMA and US FDA have granted EV accelerated approval for mUC treatment following the failure of ICI and platinum chemotherapy.…”

Section: Clinical and Preclinical Applications Of Adcs In Bcmentioning

confidence: 99%

“…Especially in urothelial carcinoma, the proportion of Trop-2 overexpression patients was as high as 90.3%. 129,135 138 Given these positive results, approval was accelerated for the application of SG in patients with metastatic or locally advanced UC who had previously received PD-1 or PD-L1 inhibitors and platinum-containing chemotherapy. 139…”

Section: Adcs That Target Trop-2: Sgmentioning

confidence: 99%

“…ADCs can selectively deliver diverse cytotoxic drugs to cancer cells with overexpressed targets, consequently reducing toxicity, increasing efficacy, and enhancing therapeutic activity 119 . Thus, the selection principle of ADCs is based on whether the antigens corresponding to the antibodies that make up ADCs are highly expressed in BC 129 . Currently, ADCs is a novel therapeutic strategy for BC.…”

Section: Characteristics Of Adcsmentioning

confidence: 99%

“…Trop‐2 is a transmembrane glycoprotein overexpressed in various cancers. Especially in urothelial carcinoma, the proportion of Trop‐2 overexpression patients was as high as 90.3% 129,135 . SG (IMMU‐132) was designed to contain an anti‐Trop‐2 mAb linked to an active metabolite of irinotecan, SN‐38, through a hydrolyzable linker 136 .…”

Section: Characteristics Of Adcsmentioning

confidence: 99%

“…ADCs that target Nectin-4: EV Nectin-4 is a cell adhesion molecule expressed on the surface of numerous solid tumors, which is highly expressed in 79.2% of patients with UC. 129,132 in patients with metastatic or locally advanced disease who progressed to anti-PD-1/L1 therapy and platinumbased chemotherapy. After a median follow-up of 11.1 months, a 30% reduction in the probability of death was observed using EV compared with that with chemotherapy.…”

Section: 31mentioning

confidence: 99%

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Targeted therapies in bladder cancer: signaling pathways, applications, and challenges

Peng,

Chu,

Peng

et al. 2023

MedComm

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Bladder cancer (BC) is one of the most prevalent malignancies in men. Understanding molecular characteristics via studying signaling pathways has made tremendous breakthroughs in BC therapies. Thus, targeted therapies including immune checkpoint inhibitors (ICIs), antibody–drug conjugates (ADCs), and tyrosine kinase inhibitor (TKI) have markedly improved advanced BC outcomes over the last few years. However, the considerable patients still progress after a period of treatment with current therapeutic regimens. Therefore, it is crucial to guide future drug development to improve BC survival, based on the molecular characteristics of BC and clinical outcomes of existing drugs. In this perspective, we summarize the applications and benefits of these targeted drugs and highlight our understanding of mechanisms of low response rates and immune escape of ICIs, ADCs toxicity, and TKI resistance. We also discuss potential solutions to these problems. In addition, we underscore the future drug development of targeting metabolic reprogramming and cancer stem cells (CSCs) with a deep understanding of their signaling pathways features. We expect that finding biomarkers, developing novo drugs and designing clinical trials with precisely selected patients and rationalized drugs will dramatically improve the quality of life and survival of patients with advanced BC.

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Section: Clinical and Preclinical Applications Of Adcs In Bcmentioning

confidence: 99%

Section: Adcs That Target Trop-2: Sgmentioning

confidence: 99%

Section: Characteristics Of Adcsmentioning

confidence: 99%

Section: Characteristics Of Adcsmentioning

confidence: 99%

Section: 31mentioning

confidence: 99%

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Targeted therapies in bladder cancer: signaling pathways, applications, and challenges

Peng,

Chu,

Peng

et al. 2023

MedComm

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A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer

Hong,

Chen,

Wang

et al. 2023

Advanced Science

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More than half of non‐muscle‐invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder‐preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2‐targeted antibody‐drug conjugate, RC48‐ADC, intravesical instillation for NMIBC treatment. In this preclinical study, it is revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48‐ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48‐ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase‐dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48‐ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate‐buffered saline control. The potential toxicity of intravesical RC48‐ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48‐ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48‐ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48‐ADC in NMIBC patients.

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PD‐L1 and nectin‐4 expression and genomic characterization of bladder cancer with divergent differentiation

Martini,

Case,

Gratz

et al. 2024

Cancer

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BackgroundBladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin‐4 and programmed death ligand‐1 (PD‐L1) has been reported in BCDD. Importantly, nectin‐4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD‐L1 expression is associated with responses to immune checkpoint inhibitors (ICIs).MethodsThe authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin‐4 and PD‐L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole‐exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs.ResultsThe results indicated that nectin‐4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD‐L1–positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs.ConclusionsIn this study, the authors identified clinically relevant data on nectin‐4 and PD‐L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis‐generating data.

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Head-to-Head Comparison of the Expression Differences of NECTIN-4, TROP-2, and HER2 in Urothelial Carcinoma and Its Histologic Variants

Cited by 18 publications

References 40 publications

Targeted therapies in bladder cancer: signaling pathways, applications, and challenges

Targeted therapies in bladder cancer: signaling pathways, applications, and challenges

A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer

PD‐L1 and nectin‐4 expression and genomic characterization of bladder cancer with divergent differentiation

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