TROP2 overexpression

Dato-DXd is active in breast cancer models. Dato-DXd has TROP2 dependent and independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.

Our data indicate that targeted therapy using e.g., trastuzumab deruxtecan, bicalutamide, pembrolizumab, cetuximab, entrectinib or sacituzumab govitecan might be a promising option especially for a relevant subset of patients with RM-SGC not suitable for salvage surgery. However, evidence from clinical studies regarding response rates to these therapies remains sparse, which underlines the need of multicenter clinical trials.

MAP3K1, NOTCH2, PTEN and MAGI2 mutations were significantly different between Trop2 medium expression and Trop2 high expression BC patients. The effects of Trop2 mutation on the expression, variation, methylation, and phosphorylation of other genes were comprehensively revealed. High expression level of Trop2 and Trop2 mutation were predictive biomarker for poor prognosis and targeted therapy in BC.

AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Enrollment began in December 2023 and is currently ongoing.

AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Enrollment began in December 2023 and is currently ongoing.

Our results showed overexpression of FOLR1 and TROP2 in a significant proportion of high-grade EC, suggesting that targeted therapy against these markers may be a novel option for patients with EC. FOLR1 and HER2 positivity appeared mutually exclusive, while co-expression of FOLR1-TROP2 and HER2-TROP2 was also infrequent, observed in <5% of all tumors.

Treatment with 5-Azacytidine, a DNMT1 inhibitor, led to demethylation of the TACSTD2 promoter accompanied by an increase in TROP2 protein expression...Our data provide novel evidence for promoter demethylation and simultaneous gains of the active histone mark H3K4me3 across CpG-rich sequences, both being complementary mechanisms in the transcriptional regulation of TACSTD2 in colon cancer. The functional consequences of TROP2 loss in colorectal cancer needs to be further investigated.

Additionally, we detect shed Trop2 in urine from men with clinically significant prostate cancer. Our study identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer.

Gene expression analysis revealed that TROP2, VWCE, and BMP7 were involved in early metastatic seeding. The high expression of these genes may warrant careful surveillance or adjuvant therapy, even in stages I-II CRC cases.

Our results suggest an important contribution of TROP2 expression to the primary resistance to PD-L1 blockade in NSCLC. TROP2-biomarker-based strategy may be relevant in selecting NSCLC patients who are more likely to benefit from a combination of immunotherapy and an anti-TROP2 agent.

High expression of TROP2 and nectin-4 in pSCC support evaluation of these markers as therapeutic targets pending validation of our findings.

It displayed significant tumor-targeting ability and excellent tumor-suppressive effects in vivo, resulting in 5/8 tumor elimination at 12 mg/kg in the T3M4 xenograft model or complete tumor disappearance at 10 mg/kg in BxPc-3 xenografts in nude mice. Its half-life in mice was about 87 h. These data suggested that hIMB1636-MMAE was a promising candidate for the treatment of pancreatic cancer with TROP2 overexpression.

In the work, we reported two nanobody tracers targeting human Trop2 which may facilitate better use of Trop2-targeted therapeutics by noninvasively displaying expression dynamics of the target.

In metaplastic breast cancers (MpBC), there is limited expression of TROP2, and downregulating transcription factor ZEB1 upregulates E-cad and TROP2, thus sensitizing cancers to TROP2 ADC sacituzumab govitecan (SG). Decitabine also increases SLFN11, a biomarker of topoisomerase 1 inhibitor (TOP1) sensitivity and is synergistic with SG which has a TOP1 payload, in TROP2-expressing SLFN11-low BC cells. In conclusion, TROP2 and SLFN11 expression can be epigenetically modulated and the combination of demethylating agent decitabine with TROP2 ADCs may represent a novel therapeutic approach for tumors with low TROP2 or SLFN11 expression.

Consistent high expression of TROP2 protein in thymoma and thymic carcinoma suggest a potential therapeutic role for anti-TROP2 antibody-drug conjugates in metastatic tumors

Furthermore, TROP2 expression was significantly positively correlated with the expression levels of METTL3 and METTL1 in BCa patients. Overall, our results revealed that METTL3/METTL1-mediated dual mA/mG RNA modifications enhanced TROP2 translation and promoted BCa development, indicating a novel RNA epigenetic mechanism in BCa.

We analyzed the largest NSCLC gene expression data set worldwide including the whole-transcriptome profile of 891 pre-treatment tumors from POPLAR and OAK trials, two randomized studies assessing the efficacy of atezolizumab versus docetaxel in NSCLC. Our study revealed that TROP2 expression by tumor cells in NSCLC is associated with worse outcome in patients with NSCLC independently of PDL1 expression. Targeting TROP2 in combination with ICI may represent a promising strategy to improve ICI efficacy in pts with TROP2-high NSCLC.

This mRNA-based biomarker analysis demonstrated that SG improves PFS and OS outcomes in patients with pretreated, endocrine-resistant HR+/HER2– mBC regardless of Trop-2 mRNA expression. There was no correlation between Trop-2 mRNA expression and HER2 status. Trop-2 mRNA expression was not predictive of benefit with SG.

Anti-TROP-2 ADCs represent an innovative upcoming weapon against both non-small cell lung cancer and small cell lung cancer subtypes, pending the results of several ongoing trials. The proper combination and placement of this agent throughout the lung cancer treatment pathway, the identification of potentially predictive biomarkers of benefit, as well as the optimal management and impact of peculiar toxicity (i.e. interstitial lung disease) are the next questions to be answered.

Here, we demonstrated antigen specific killing of Trop2 overexpressing tumor cells in vitro. Targeted deployment of recombinant immunotoxin to specifically engage and kill Trop2 positive cells is a potential approach for cancer therapeutics. As such, the ability of the rIT to specifically target and kill Trop2 expressing tumors is an important initial finding towards the possibility of antigen-dependent elimination of Trop2 expressing cancer cells.

Recently, the TROP2-targeting ADC sacituzumab govitecan has received an accelerated approval from the FDA for adult patients with metastatic TNBC, as more than 85% of TNBC is marked by TROP2 overexpression. Patient-derived TNBC xenografts with co-expression of PTK7 and TROP2 have been screened for future in vivo drug efficacy screening. In summary, BCG033 has the potential to exert anti-tumor efficacy in TNBC and other solid tumors co-expressing PTK7 and TROP2.

Culture supernatant of Veillonella parvula NCTC11810 promoted the apoptosis and inhibited the proliferation and invasion ability of HN6 cells, while sodium propionate (SP), the main metabolite of Veillonella parvula NCTC11810, played a similar role through the inhibition of TROP2/PI3K/Akt pathway. Studies above supported the proliferation-inhibiting, invasion-inhibiting, and apoptosis-promoting function of Veillonella parvula NCTC11810 in OSCC cells which provided new insights into oral microbiota and their metabolite as a therapeutic method for OSCC patients with TROP2 high expressing.

Given that the excessive production of Th1 cytokines induced by CD3-mediated T-cell overactivation may lead to toxicity in the clinic, we devised a strategy to modify this CD3-induced T cell activation by a two-step reduction in the bispecific antibody binding affinity for CD3 to a level that retained the ability of the bispecific antibody to effectively inhibit tumor growth while greatly reducing the amount of Th1 cytokines secreted by T cells. Thus, we provide insight into the design of T cell engagers that exhibit a promising toxicity profile while retaining inhibitory effects on tumor growth.

Higher TROP2 expression related to longer survival in the patients with AGC treated with NIVO monotherapy.

The levels of TROP2 expression were determined to be significantly correlated with the potencies of DS001 treatment, but not with the overall survival rates of the patients. Our results demonstrated that TROP2 could serve as a patient-tailoring and predictive biomarker for ADC therapeutics but not as a general prognostic biomarker to predicate patient survival.

TROP2 promotes gastric cancer cell invasion and migration by decreasing DSG2 expression through EGFR/AKT and DSG2/PG/β-catenin pathways.

Sacituzumab govitecan (SG), a humanized anti-TROP2 antibody conjugated with SN-38, was approved for treatment of metastatic triple negative breast cancer, with the greatest efficacy in patients with medium or high TROP2 levels. TROP2 is expressed in most breast cancers, but is expressed less frequently in MpBC, an aggressive subtype unresponsive to traditional therapies. Epigenetic modulator decitabine upregulates TROP2 and SLFN11 expression and enhances antitumor efficacy of SG. Combinatorial treatment of TROP2 ADCs with epigenetic modulators of TROP2 represent a novel therapeutic strategy for tumors with low TROP2 or SLFN11 expression.

Furthermore, exosomal release of Trop2 was also decreased in NA and NA mutants. This data suggests that site-specific N-glycan addition determines Trop2 surface density, claudin-7 interaction and exosomal release.

TROP2 promotes the development of PTC. TROP2 expression was correlated with ISG15 and tumor-infiltrating immune cells in thyroid cancer.

Furthermore, in vivo experiments on CHO/TROP2 and MCF7 xenografts revealed that TrMab‑6 significantly reduced tumor growth, whereas it did not show antitumor activities against parental CHO‑K1 and MCF7/TROP2‑knockout xenografts. The findings suggest that TrMab‑6 is a promising treatment option for TROP2‑expressing breast cancers.

Trop2 expression is related to ovarian cancer stage and postoperative survival. Trop2 can promote ovarian cancer cell proliferation and metastasis by activating the AKT/β-catenin signaling pathway and knockdown of Trop2 inhibits the progression of ovarian cancer.

Overexpression of Trop2 rescues TCO-induced inhibition of cell proliferation and EMT. Our findings demonstrate that TCO markedly inhibits cell proliferation and EMT in lung cancer cells and provides guidance for its drug development.

In summary, our results point to a favorable prognostic significance of TROP2 overexpression in a large cohort of oral cancer patients, suggesting it as an attractive clinical marker.

Western blot analysis showed a 40 kDa band in lysates prepared from both CHO/TROP2-PA and MCF7 cells. Furthermore, TROP2 was strongly detected by immunohistochemical analysis using TrMab-29, indicating that TrMab-29 may be a valuable tool for the detection of TROP2 in cancer.

TROP2 is overexpressed in various human cancers and TROP2 overexpression appears to correlate with poor prognosis leading to the suggestion that TROP2 could be a therapeutic target for various carcinomas. Our results suggest that TROP2 expression is higher in advanced tumors and these results need to be supported by larger studies.

Furthermore, TROP2 in 57/61 (93.4%) of the breast cancer specimens was strongly detected using immunohistochemical analysis with TrMab‑6. In conclusion, the current study demonstrated that TrMab‑6 may be a valuable tool for the detection of TROP2 in a wide variety of breast cancer types.

One of these agents, sacituzumab govitecan, has been recently granted an accelerated approval for therapy of metastatic triple-negative breast cancer. In this article, we review the current knowledge about the yet controversial function of Trop2 in homeostasis and pathology.