Immunotoxin Therapies for the Treatment of Epidermal Growth Factor Receptor-Dependent Cancers

Simon, Nathan; FitzGerald, David J.

doi:10.3390/toxins8050137

Cited by 44 publications

(38 citation statements)

References 133 publications

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“…Important multidrug resistance mechanisms in cancer are apoptosis inhibition, DNA repair, drug efflux, altered drug metabolism and others610. Some immunotoxin-based anti-cancer drugs enter cells by receptor mediated endocytosis to kill tumour cells11. Vesicle trafficking, including the release of extracellular micro-vesicles, is critical in carcinogenesis, which involves invasion, metastasis, cell cycle regulation, angiogenesis, tumour immune privilege, neoplastic coagulopathy and multidrug resistance (MDR)12.…”

mentioning

confidence: 99%

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Kadioglu

Cao

Kosyakova

et al. 2016

Sci Rep

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We systematically characterised multifactorial multidrug resistance (MDR) in CEM/ADR5000 cells, a doxorubicin-resistant sub-line derived from drug-sensitive, parental CCRF-CEM cells developed in vitro. RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed. Chromosomal aberrations were identified by array-comparative genomic hybridisation (aCGH) and multicolour fluorescence in situ hybridisation (mFISH). Fifteen ATP-binding cassette transporters and numerous new genes were overexpressed in CEM/ADR5000 cells. The basic karyotype in CCRF-CEM cells consisted of 47, XX, der(5)t(5;14) (q35.33;q32.3), del(9) (p14.1), +20. CEM/ADR5000 cells acquired additional aberrations, including X-chromosome loss, 4q and 14q deletion, chromosome 7 inversion, balanced and unbalanced two and three way translocations: t(3;10), der(3)t(3;13), der(5)t(18;5;14), t(10;16), der(18)t(7;18), der(18)t(21;18;5), der(21;21;18;5) and der(22)t(9;22). CCRF-CEM consisted of two and CEM/ADR5000 of five major sub-clones, indicating genetic tumor heterogeneity. Loss of 3q27.1 in CEM/ADR5000 caused down-regulation of ABCC5 and ABCF3 expression, Xq28 loss down-regulated ABCD1 expression. ABCB1, the most well-known MDR gene, was 448-fold up-regulated due to 7q21.12 amplification. In addition to well-known drug resistance genes, numerous novel genes and genomic aberrations were identified. Transcriptomics and genetics in CEM/AD5000 cells unravelled a range of MDR mechanisms, which is much more complex than estimated thus far. This may have important implications for future treatment strategies.

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confidence: 99%

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Kadioglu

Cao

Kosyakova

et al. 2016

Sci Rep

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“…Immunotherapy using mabs is known as a potent and specific strategy to treat a wide variety of malignancies (Mahmuda et al, 2017). Despite the potency of mabs to fight cancer, it has been shown that most cancers can resist against naked mabs (Reslan, Dalle, & Dumontet, 2009), hence, the use of immunotoxins has been recommended as the appropriate alternative to avoid this problem (Simon & FitzGerald, 2016). In general, success in designing an immunotoxin completely depends on the use of The results of RNA fragmentation assay on 1% agarose gel.…”

Section: Discussionmentioning

confidence: 99%

Production and introduction of a novel immunotoxin based on engineered RNase A for inducing death to Her1‐positive cell lines

Forouharmehr

Nassiri

Ghovvati

et al. 2019

Journal Cellular Physiology

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The present study was performed to design an immunotoxin consisting of engineered RNase A and scFv of Cetuximab. To accomplish this study goal, at first to evade RNase A from its inhibitors in the cytoplasm, six amino acids of RNase A were substituted, then the physicochemical features of engineered RNase A were assessed. To investigate the interaction between the engineered RNase A and the ribonuclease inhibitor, protein-protein docking was performed. After engineering the RNase A, it was theoretically conjugated with scFv of Cetuximab using a cleavable linker to produce scFv-engineered RNase A. Then, wild-RNase A (14 kD), engineered RNase A (14 kD) and scFv-engineered RNase A (42 kDa) were expressed in the BL21 (DE3) strain of Escherichia coli and purified by Ni-NTA columns. To confirm the expressed proteins, western blot analysis was performed. The functioning of wild-RNase A and engineered RNase A were investigated by RNA fragmentation assay. Finally, to evaluate the cytotoxicity of scFv-engineered RNase A, a dose-response cytotoxicity assay was performed on Her1-positive and Her1-negative cell lines. The results showed that engineered RNase A could maintain its structure and disulfide bonds and evade its inhibitor. Expression and purification were successfully conducted and both enzymes could degrade yeast RNA. The result of cytotoxicity showed that the engineered immunotoxin could induce cell death to Her1-positive cell lines with an IC 50 of 50 nM.It appears that scFv-engineered RNase A can be a promising molecule for use.

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“…Following the binding to HER1, they enter into the trafficking pathways then, toxins are translocated into the cytoplasm and cause cytotoxicity followed by death of the target cell. Both PE and DT block ribosome protein translation in cells …”

Section: Anit‐her1 Mabs and Derivativesmentioning

confidence: 99%

“…Both PE and DT block ribosome protein translation in cells. [70] Anit-HER2 mAbs and derivatives Approved monoclonal antibodies…”

Section: Scfv-1171mentioning

confidence: 99%

Monoclonal antibody-based therapeutics, targeting the epidermal growth factor receptor family: from herceptin to Pan HER

Moradi‐Kalbolandi

Hosseinzade

Salehi

et al. 2018

Journal of Pharmacy and Pharmacology

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Objectives Monoclonal antibody-based of cancer therapy has been considered as one of the most successful therapeutic strategies for both haematologic malignancies and solid tumours in the last two decades. Epidermal growth factor receptor (EGFR) family signalling pathways play a key role in the regulation of cell proliferation, survival and differentiation. Hence, anti-EGFR family mAbs is one of the most promising approaches in cancer therapy. Key findings Here, recent advances in anti-EGFR mAb including approved or successfully tested in preclinical and clinical studies have been reviewed. Although we focus on monoclonal antibodies against the EGF receptor, but the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy, to some extend the resistance to existing anti-EGFR therapies and some therapeutic strategies to overcome resistance such as combination of mAbs on different pathways are briefly discussed as well. Summary The EGFR family receptors, is considered as an attractive target for mAb development to inhibit their consecutive activities in tumour growth and resistance. However, due to resistance mechanisms, the combination therapies may become a good candidate for targeting EGFR family receptors.

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Immunotoxin Therapies for the Treatment of Epidermal Growth Factor Receptor-Dependent Cancers

Cited by 44 publications

References 133 publications

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Production and introduction of a novel immunotoxin based on engineered RNase A for inducing death to Her1‐positive cell lines

Monoclonal antibody-based therapeutics, targeting the epidermal growth factor receptor family: from herceptin to Pan HER

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