Epigenetically upregulating TROP2 and SLFN11 enhances therapeutic efficacy of TROP2 antibody drug conjugate sacitizumab govitecan

Zhao, Ming; DiPeri, Timothy P.; Raso, Maria Gabriela; Zheng, Xiaofeng; Rizvi, Yasmeen Q.; Evans, Kurt W.; Yang, Fei; Akçakanat, Argun; Estécio, Marcos R.H.; Tripathy, Debu; Dumbrava, Ecaterina Elena; Damodaran, Senthil; Meric‐Bernstam, Funda

doi:10.1038/s41523-023-00573-8

Cited by 3 publications

(1 citation statement)

References 64 publications

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“…Most of the currently approved Trop-2-targeted ADCs are inhibitors of topoisomerase 1 (TOP1), making high TOP1 expression a potential indicator of sensitivity to camptothecin analogues. Furthermore, the presence of the SN-38-sensitivity predictor SLFN11, HRR-related protein Rad51, and ERCC1 has shown promise in predicting clinical benefits [73,103]. Additionally, CTSL, which hydrolyzes T-DXd peptide ligators, is elevated in advanced breast cancer.…”

Section: Personalized Treatmentmentioning

confidence: 99%

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs

Jiang,

Zhou,

Liu

et al. 2024

Pharmaceuticals

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Precise targeting has become the main direction of anti-cancer drug development. Trophoblast cell surface antigen 2 (Trop-2) is highly expressed in different solid tumors but rarely in normal tissues, rendering it an attractive target. Trop-2-targeted antibody-drug conjugates (ADCs) have displayed promising efficacy in treating diverse solid tumors, especially breast cancer and urothelial carcinoma. However, their clinical application is still limited by insufficient efficacy, excessive toxicity, and the lack of biological markers related to effectiveness. This review summarizes the clinical trials and combination therapy strategies for Trop-2-targeted ADCs, discusses the current challenges, and provides new insights for future advancements.

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Section: Personalized Treatmentmentioning

confidence: 99%

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs

Jiang,

Zhou,

Liu

et al. 2024

Pharmaceuticals

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DNA demethylation and tri-methylation of H3K4 at the TACSTD2 promoter are complementary players for TROP2 regulation in colorectal cancer cells

Gehring,

Huebner,

Rani

et al. 2024

Sci Rep

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TROP2 is a powerful cancer driver in colorectal cancer cells. Divergent epigenetic regulation mechanisms for the corresponding TACSTD2 gene exist such as miRNAs or DNA methylation. However, the role of TACSTD2 promoter hypermethylation in colorectal cancer has not been investigated yet. In this study, TROP2 expression strongly correlated with promoter methylation in different colorectal tumor cell lines. Treatment with 5-Azacytidine, a DNMT1 inhibitor, led to demethylation of the TACSTD2 promoter accompanied by an increase in TROP2 protein expression. TROP2 expression correlated with promoter methylation in vivo in human colon tumor tissue, thereby verifying promoter methylation as an important factor in the regulation of TROP2 expression in colorectal cancer. When performing a ChIP-Seq analysis in HCT116 and HT29 cells, we found that TACSTD2 promoter demethylation was accompanied by tri-methylation of H3K4. In silico analysis of GSE156613 data set confirmed that a higher binding of histone mark H3K4me3 around the TACSTD2 promoter was found in TACSTD2 high expressing tumors of colon cancer patients compared to the corresponding adjacent tumor tissue. Moreover, the link between TROP2 and the H3K4me3 code was even evident in tumors showing high intratumoral heterogeneity for TROP2 staining. 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.

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ImmunoPET imaging of Trop2 in patients with solid tumours

Huang,

Zhang,

Cao

et al. 2024

EMBO Mol Med

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Accurately predicting and selecting patients who can benefit from targeted or immunotherapy is crucial for precision therapy. Trophoblast cell surface antigen 2 (Trop2) has been extensively investigated as a pan-cancer biomarker expressed in various tumours and plays a crucial role in tumorigenesis through multiple signalling pathways. Our laboratory successfully developed two 68Ga-labelled nanobody tracers that can rapidly and specifically target Trop2. Of the two tracers, [68Ga]Ga-NOTA-T4, demonstrated excellent pharmacokinetics in preclinical mouse models and a beagle dog. Moreover, [68Ga]Ga-NOTA-T4 immuno-positron emission tomography (immunoPET) allowed noninvasive visualisation of Trop2 heterogeneous and differential expression in preclinical solid tumour models and ten patients with solid tumours. [68Ga]Ga-NOTA-T4 immunoPET could facilitate clinical decision-making through patient stratification and response monitoring during Trop2-targeted therapies.

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Epigenetically upregulating TROP2 and SLFN11 enhances therapeutic efficacy of TROP2 antibody drug conjugate sacitizumab govitecan

Cited by 3 publications

References 64 publications

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs

DNA demethylation and tri-methylation of H3K4 at the TACSTD2 promoter are complementary players for TROP2 regulation in colorectal cancer cells

ImmunoPET imaging of Trop2 in patients with solid tumours

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