Trop2: Jack of All Trades, Master of None

Lenárt, Sára; Lenárt, Peter; Šmarda, Jan; Remšík, Ján; Souček, Karel; Beneš, Petr

doi:10.3390/cancers12113328

Cited by 74 publications

(66 citation statements)

References 179 publications

(248 reference statements)

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“…Trophoblast cell surface antigen 2 (TROP2) is a 36 kDa transmembrane glycoprotein, highly expressed on several types of solid cancer ( Cubas et al, 2009 ; Zeng et al, 2016 ). It is also considered a stem cell marker ( Lenárt et al, 2020 ). Hou J. et al (2019) demonstrated high TROP2 expression on GBM cells from surgically removed patient tumors compared to low levels on normal brain cells.…”

Section: Targets Of Car T Cell Therapy In Preclinical Studiesmentioning

confidence: 99%

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

et al. 2021

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.

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Section: Targets Of Car T Cell Therapy In Preclinical Studiesmentioning

confidence: 99%

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

et al. 2021

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“…Trop2 is a 46-kDa monomeric glycoprotein that has properties such as preferential overexpression, constitutive endocytosis, and routing to lysosomes that make it a highly attractive target for ADCs. A review of Trop2 and its function in normal and diseased cells can be found in [ 119 ]. Trop2 overexpression on the cell surface is well documented, and it has been identified in approximately 30 different tumor types [ 119 ].…”

Section: Target Antigens For Approved Adcs and Their Endocytosis Characteristicsmentioning

confidence: 99%

“…A review of Trop2 and its function in normal and diseased cells can be found in [ 119 ]. Trop2 overexpression on the cell surface is well documented, and it has been identified in approximately 30 different tumor types [ 119 ]. However, Trop2 is interesting due to the amount of protein detected in the cytoplasm of tumor cells and the association with patient prognosis.…”

Section: Target Antigens For Approved Adcs and Their Endocytosis Characteristicsmentioning

confidence: 99%

Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development

2021

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Biologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in cancer. Antibody-drug conjugates (ADCs) have revitalized the concept of targeted chemotherapy by coupling inhibitory antibodies to cytotoxic payloads. Significant advances in ADC technology and format, and target biology have hastened the FDA approval of nine ADCs (four since 2019). Although the links between aberrant endocytic machinery and cancer are emerging, the impact of dysregulated internalization processes of ADC targets and response rates or resistance have not been well studied. This is despite the reliance on ADC uptake and trafficking to lysosomes for linker cleavage and payload release. In this review, we describe what is known about all the target antigens for the currently approved ADCs. Specifically, internalization efficiency and relevant intracellular sorting activities are described for each receptor under normal processes, and when complexed to an ADC. In addition, we discuss aberrant endocytic processes that have been directly linked to preclinical ADC resistance mechanisms. The implications of endocytosis in regard to therapeutic effectiveness in the clinic are also described. Unexpectedly, information on endocytosis is scarce (absent for two receptors). Moreover, much of what is known about endocytosis is not in the context of receptor-ADC/antibody complexes. This review provides a deeper understanding of the pertinent principles of receptor endocytosis for the currently approved ADCs.

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“… 12 It consists of 323 amino acids 13 and has extracellular domain, short transmembrane domain and a cytoplasmic tail. 14 …”

Section: Introductionmentioning

confidence: 99%

The Role of TROP2 in BCC and Cutaneous SCC: A Clinical and Immunohistochemical Study

Farag

El-Rebey

Shoeib

et al. 2021

CCID

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Background Nonmelanoma skin cancer (NMSC) mainly includes basal (BCC) and squamous (SCC) cell carcinoma. Trophoblast cell-surface antigen2 (TROP2), a cell–signal transduction, is one of the tumor-related calcium signal transducer gene family. TROP2 was highly expressed in many cancers, however, its role in BCC and SCC has not yet been studied. Objective To investigate TROP2 immunohistochemical expression in BCC and SCC (lesional and peri-lesional) skin compared to controls and correlates its expression with the clinicopathologic parameters of the studied cases. Methods This case–control study included 17 BCC and 15 SCC patients as well as 12 age and sex matched controls. History and clinical examination were completed. Histological examination of skin biopsies was done together with TROP2 immune-staining. Results In the studied BCC and SCC cases, there was a significant stepwise up-regulation of TROP2 H score from control to peri-lesional, ended by lesional epidermis in one hand (p=0.003 for BCC and p<0.001 for SCC) and tumor island in another hand (p=0.001 for BCC and p=0.003 for SCC). TROP2 expression in both BCC and SCC tumor tissues was not affected by any of the studied clinicopathological parameters of the investigated cases. Conclusion TROP2 could have an important role in BCC and SCC pathogenesis. TROP2 targeting may have appraising effect in clinical application in BCC and SCC management.

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Trop2: Jack of All Trades, Master of None

Cited by 74 publications

References 179 publications

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development

The Role of TROP2 in BCC and Cutaneous SCC: A Clinical and Immunohistochemical Study

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