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Open AccessArticle

Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape

1
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho–Maklaya Street 16/10, 117997 Moscow, Russia
2
Prokhorov General Physics Institute, Russian Academy of Sciences, Vavilova Street 38, 119991 Moscow, Russia
3
National Research Center “Kurchatov Institute”, Akademika Kurchatova pl. 1, 123182 Moscow, Russia
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Shubnikov Institute of Crystallography of Federal Scientific Research Centre ‘Crystallography and Photonics’ of Russian Academy of Sciences, Leninskiy Prospect, 59, 119333 Moscow, Russia
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Moscow Institute of Physics and Technology, Institutsky Lane 9, Dolgoprudny, 141701 Moscow, Russia
6
Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”, Orlova Roscha 1, 188300 Gatchina, Russia
7
Peter the Great St. Petersburg Polytechnic University, Politehnicheskaya 29, 195251 St. Petersburg, Russia
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The Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
9
Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(10), 3014; https://doi.org/10.3390/cancers12103014
Received: 10 September 2020 / Revised: 6 October 2020 / Accepted: 13 October 2020 / Published: 16 October 2020
(This article belongs to the Section Cancer Therapy)
Targeted therapy of solid tumors represents a great challenge because of heterogeneity of tumor-associated antigen expression. To overcome this obstacle we propose a dual targeting therapy based on protein preparations capable of recognizing different of tumor-associated antigens on a tumor cell producing a directed cytotoxic effect. The dual specific therapy of breast carcinoma-bearing mice using the designed preparations eliminates both the primary tumor and distant metastases. The mono-targeting therapy aimed at single tumor-associated antigen did not suppress metastases at all. The proposed approach can serve as a potential therapeutic strategy that surpasses mono-specific targeting strategies in the anti-cancer efficacy.
We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The combined therapeutic effect is achieved owing to two highly toxic proteins—a low immunogenic variant of Pseudomonas aeruginosa exotoxin A and ribonuclease Barnase from Bacillus amyloliquefaciens. The delivery of toxins to cancer cells was carried out by targeting designed ankyrin repeat proteins (DARPins). We have shown that both target agents efficiently accumulate in the tumor. Simultaneous treatment of breast carcinoma-bearing mice with anti-EpCAM fusion toxin based on LoPE and HER2-specific liposomes loaded with Barnase leads to concurrent elimination of primary tumor and metastases. Monotherapy with anti-HER2- or anti-EpCAM-toxins did not produce a comparable effect on metastases. The proposed approach can be considered as a promising strategy for significant improvement of cancer therapy. View Full-Text
Keywords: Barnase; liposomes; HER2; EpCAM; cancer therapy Barnase; liposomes; HER2; EpCAM; cancer therapy
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Shramova, E.; Proshkina, G.; Shipunova, V.; Ryabova, A.; Kamyshinsky, R.; Konevega, A.; Schulga, A.; Konovalova, E.; Telegin, G.; Deyev, S. Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape. Cancers 2020, 12, 3014.

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