Targeting Trop-2 in cancer: Recent research progress and clinical application

Qiu, Shuying; Zhang, Jianping; Wang, Zhuo; Liang, Hui; Hou, Jili; Zhang, Nan; Wang, Xian; Lu, Haiqi

doi:10.1016/j.bbcan.2023.188902

Cited by 27 publications

(15 citation statements)

References 131 publications

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“…A second drug Datopotamab Deruxtecan is being explored in several clinical trials and has shown reduced side effects. Kidney effects were not reported (27). To the best of our knowledge Tacstd2 expression has not previously been explored in relation to ADPKD.…”

Section: Discussionmentioning

confidence: 99%

The Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) oncogene is upregulated in pre-cystic epithelial cells revealing a new target for polycystic kidney disease

Smith,

Frantz,

Preval

et al. 2023

Preprint

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Polycystic kidney disease (PKD) is an important cause of end stage renal disease, but treatment options are limited. While later stages of the disease have been extensively studied, mechanisms driving the initial conversion of renal tubules into cysts are not understood. To identify factors that promote the initiation of cysts we deleted polycystin-2 (Pkd2) in mice and surveyed transcriptional changes before and immediately after cysts developed. We identified 74 genes which we term cyst initiation candidates (CICs). To identify conserved changes with relevance to human disease we compared these murine CICs to single cell transcriptomic data derived from patients with PKD and from healthy controls. Tumor-associated calcium signal transducer 2 (Tacstd2) stood out as an epithelial-expressed gene whose levels were elevated prior to cystic transformation and further increased with disease progression. Human tissue biopsies and organoids show that TACSTD2 protein is low in normal kidney cells but is elevated in cyst lining cells. While TACSTD2 has not been studied in PKD, it has been studied in cancer where it is highly expressed in solid tumors while showing minimal expression in normal tissue. This property is being exploited by antibody drug conjugates that target TACSTD2 for the delivery of cytotoxic drugs. Our finding that Tacstd2 is highly expressed in cysts, but not normal tissue, suggests that it should be explored as a candidate for drug development in PKD. More immediately, our work suggests that PKD patients undergoing TACSTD2 treatment for cancer should be monitored for kidney effects.One Sentence SummaryThe oncogene, tumor-associated calcium signal transducer 2 (Tacstd2) mRNA increased in abundance shortly after Pkd2 loss and may be a driver of cyst initiation in polycystic kidney disease.

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Section: Discussionmentioning

confidence: 99%

The Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) oncogene is upregulated in pre-cystic epithelial cells revealing a new target for polycystic kidney disease

Smith,

Frantz,

Preval

et al. 2023

Preprint

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“…TROP2 is comprised of an ectodomain, a single transmembrane region and an intracellular tail [ 7 , 8 ]. Among them, the thyroglobulin type-1 domain in the extracellular region is able to hinder the activity of cysteine proteases and potentially contributes to the metastasis of tumor cells [ 9 ]. The intracellular region of TROP2 has a serine residue at position 303 (S303) and a phosphatidyl-inositol 4,5-biphosphate (PIP2) binding site.…”

Section: Introductionmentioning

confidence: 99%

“…IP3 mediates the release of Ca 2+ stored in the endoplasmic reticulum, leading to the activation of the mitogen-activated protein kinase (MAPK) pathway, which promotes cell cycle progression [ 10 ]. Furthermore, TROP2 has been reported to promote tumor cell growth, proliferation and migration and to inhibit cell adhesion and apoptosis through complex signaling networks [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…These findings provide theoretical support for the development of pancreatic cancer drugs targeting TROP2 including antibody–drug conjugates (ADCs). Extensive studies have demonstrated the superior antitumor ability of TROP2-targeted ADCs in the treatment of cancers such as breast cancer, lung cancer, and urothelial cancer, and sacituzumab govitecan has received U.S. Food and Drug Administration approval for the treatment of breast cancer and urothelial cancer [ 8 , 9 , 11 , 12 ]. However, few systematic studies on TROP2-targeted ADC development for pancreatic cancer have been reported.…”

Section: Introductionmentioning

confidence: 99%

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TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer

Xu,

Zhu,

Wang

et al. 2023

J Nanobiotechnol

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Background Pancreatic cancer is a highly aggressive malignancy with limited treatment options and a poor prognosis. Trophoblast cell surface antigen 2 (TROP2), a cell surface antigen overexpressed in the tumors of more than half of pancreatic cancer patients, has been identified as a potential target for antibody–drug conjugates (ADCs). Almost all reported TROP2-targeted ADCs are of the IgG type and have been poorly studied in pancreatic cancer. Here, we aimed to develop a novel nanobody-drug conjugate (NDC) targeting TROP2 for the treatment of pancreatic cancer. Results In this study, we developed a novel TROP2-targeted NDC, HuNbTROP2-HSA-MMAE, for the treatment of TROP2-positive pancreatic cancer. HuNbTROP2-HSA-MMAE is characterized by the use of nanobodies against TROP2 and human serum albumin (HSA) and has a drug-antibody ratio of 1. HuNbTROP2-HSA-MMAE exhibited specific binding to TROP2 and was internalized into tumor cells with high endocytosis efficiency within 5 h, followed by intracellular translocation to lysosomes and release of MMAE to induce cell apoptosis in TROP2-positive pancreatic cancer cells through the caspase-3/9 pathway. In a xenograft model of pancreatic cancer, doses of 0.2 mg/kg and 1 mg/kg HuNbTROP2-HSA-MMAE demonstrated significant antitumor effects, and a dose of 5 mg/kg even eradicated the tumor. Conclusion HuNbTROP2-HSA-MMAE has desirable affinity, internalization efficiency and antitumor activity. It holds significant promise as a potential therapeutic option for the treatment of TROP2-positive pancreatic cancer. Graphical Abstract

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“…HER2 low expressing breast cancers did not show signi cant survival improvement after anti-HER2 therapy and were therefore collectively classi ed as HER2 negative breast cancers. However, the development of new treatments, such as DS-8201 and Trop2, has improved prognostic of the HER2-low subtype [1,[7][8][9]. This suggests the potential of HER2 low expressing breast cancer as a new subtype and expands treatment opportunities of novel ADC targeted drugs to wider population with breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Clinical characteristics and survival analysis of HER2 negative breast cancer: AR and negative PD-L1 predict worse pathological complete response rate

Zhang,

Yang,

Chen

et al. 2023

Preprint

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Background: HER2-low breast cancer has the potential to emerge as a distinct subtype. Several studies have compared differences between HER2-low and HER2-0 breast cancers, but consensus conclusions have not been reached. Furthermore, a biomarker for predicting pathological complete response (pCR) rates in patients with HER2-low breast cancer remains to be discovered. Method: We collected data of 777 patients from three centers (the Cancer Center of Guangdong Provincial People's Hospital, the Oncology Center of the First Affiliated Hospital of Sun Yat-Sen University and the Sun Yat-Sen University Cancer Center), stratifying them into HER2-low and HER2-0 groups. We compared differences in survival and pCR rates between the two groups and investigated potential biomarkers that could serve as reliable predictors of pCR. Results: The study found higher pCR rates in HER2-0 breast cancers compared to HER2-low tumors (289 patients [30.1%] vs 475 patients [18.1%], p<0.0001). Survival analysis did not show significant advantage for HER2-low tumors over HER2-0 breast cancers. Binary logistic analysis revealed that androgen receptor (AR) expression predicts worse pCR rates in both the overall patient cohort and the HER2-0 breast cancer patient cohort (overall patients: OR: 0.479, 95%CI: (0.250, 0.917), p=0.026; HER2-0 patients: OR: 0.267, 95%CI: (0.080, 0.892), p=0.032). In contrast, programmed death ligand 1 (PD-L1) predicts favorable pCR rates in the overall patient cohort (OR: 3.199, 95%CI: (1.020, 10.037), p=0.046). Conclusion: There is insufficient evidence to classify HER2-low breast cancer as a new subtype. Our study revealed that AR expression, along with negative PD-L1 expression, contributes to poorer pCR outcomes.

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Targeting Trop-2 in cancer: Recent research progress and clinical application

Cited by 27 publications

References 131 publications

The Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) oncogene is upregulated in pre-cystic epithelial cells revealing a new target for polycystic kidney disease

The Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) oncogene is upregulated in pre-cystic epithelial cells revealing a new target for polycystic kidney disease

TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer

Clinical characteristics and survival analysis of HER2 negative breast cancer: AR and negative PD-L1 predict worse pathological complete response rate

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