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Review
. 2024 Aug 15:15:1447280.
doi: 10.3389/fimmu.2024.1447280. eCollection 2024.

Sacituzumab govitecan in triple-negative breast cancer: from bench to bedside, and back

Valentina Rossi #  1 , Alessandra Turati #  1 , Antonio Rosato  1   2 , Debora Carpanese  1
Affiliations
Review

Sacituzumab govitecan in triple-negative breast cancer: from bench to bedside, and back

Valentina Rossi et al. Front Immunol. .

Abstract

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.

Keywords: Trop-2; antibody-drug conjugate (ADC); immunotherapy; metastatic TNBC; sacituzumab govitecan (IMMU-132); target therapeutics; triple negative breast cancer (TNBC).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) Trop-2 mRNA profile. Boxplots summarizing the mRNA quantification of Trop-2 in pathological malignancies (left). Values represent the median number Fragments Per Kilobase of exon per Million reads (FPKM), generated by The Cancer Genome Atlas (TCGA). Values from brain, testis and liver ranging up to 10 median FPKM result not visible. All described tissues are indicated in the correspondent body district (right). (B) Trop-2 downstream pathways. Schematic resume of Trop-2 molecular downstream mechanisms triggered in cancerous setting: ERK1/2MAPK pathway emerges in all main tumorigenic, proliferative and metastatic processes, alongside with the other PIP2/PKC-induced calcium-regulated downstream pathways (RAF/Nf-kB/Cyclin D/E) (24). JAK/STAT and PI3K/AKT were described to be implicated in survival, proliferation and metastatic processes (25), as for the Src mediated intervention on the integrin-fibronectin axis (26). In addition, regulated proteolysis of Trop-2 was found to drive proliferative and self-renewal signaling via β-catenin (27). Possible ambiguous interplays occurring between Trop-2 and other plausible receptor already cited in the text are also illustrated.
Figure 2
Figure 2
(A) Structure of SG. Schematic representation of the chemical structure of the linkage of SN-38 (shown in orange) to the hRS7 antibody (pink) via the CL2A-linker (blue). Specifically, the CL2A linker binds to the 20th position of SN-38, stabilizing the lactone ring and forming a pH-sensitive carbonate bond. The presence of a short polyethylene glycol (PEG) segment enhances the water solubility of such SN-38 conjugate. Moreover, the maleimide inserted at the end of the linker enables a stable thioether bond with sulfhydryl moieties formed after mild reduction of the hRS7 mAb. The average DAR is 7.6 (61). (B) Mechanism of action of SG. i) The ADC recognizes and binds to Trop-2 on the tumor cell, being then be internalized; ii) the payload undergoes intracellular trafficking and enters the lysosomes following antibody catabolism and hydrolysis of the linker, the payload is released and induces apoptotic cell death. Neighboring cancer cells are affected by the bystander effect (64, 65), due to the release of SN-38 from the target cell or within the extracellular space, thus contributing to an amplified anti-tumor effect (61, 66). The unconjugated hRS7 mAb showed some effector function in vitro (i.e. antibody-dependent cellular cytoxicity), which resulted mitigated in the ADC due to mAb reduction for conjugation purposes (67, 68).
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References

    1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. (2023) 73:17–48. doi: 10.3322/caac.21763 - DOI - PubMed
    1. Meng X, Cai Y, Chang X, Guo Y. A novel conditional survival nomogram for monitoring real-time prognosis of non-metastatic triple-negative breast cancer. Front Endocrinol (Lausanne). (2023) 14. doi: 10.3389/fendo.2023.1119105 - DOI - PMC - PubMed
    1. Boyle P. Triple-negative breast cancer: Epidemiological considerations and recommendations. Ann Oncol. (2012) 23(Suppl 6):vi7–12. doi: 10.1093/annonc/mds187 - DOI - PubMed
    1. Bou Zerdan M, Ghorayeb T, Saliba F, Allam S, Bou Zerdan M, Yaghi M, et al. . Triple negative breast cancer: updates on classification and treatment in 2021. Cancers. (2022) 14(5):1253. doi: 10.3390/cancers14051253 - DOI - PMC - PubMed
    1. Qiu S, Zhang J, Wang Z, Lan H, Hou J, Zhang N, et al. . Targeting Trop-2 in cancer: Recent research progress and clinical application. Biochim Biophys Acta Rev Cancer. (2023) 1878:188902. doi: 10.1016/j.bbcan.2023.188902 - DOI - PubMed

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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors are grateful to the 5 per mille reference year 2019 - BRIDGE for the financial support of the project FREEDA to DC. They also thank the funding of the Associazione Italiana per la Ricerca sul Cancro AIRC-MFAG 2023 ID 28866 to DC; AIRC-IG 2018 ID 21354 to AR.

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