Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine-Glycine-Aspartate) Strategies

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2024 Nov 27

PMID 39598465

Authors

Bojana Bogdanovic

Daniel Fagret

Catherine Ghezzi

Christopher Montemagno

Affiliations

Soon will be listed here.

Abstract

Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including variable efficacy and unmet high expectations. Nevertheless, the consistent expression of integrins on tumor and stromal cells underscores their ongoing relevance and potential. Traditional RGD-based imaging and therapeutic agents have faced limitations, such as inconsistent target expression and rapid systemic clearance, which have reduced their effectiveness. To overcome these challenges, recent research has focused on advancing RGD-based strategies and exploring innovative solutions. This review offers a thorough analysis of the latest developments in the RGD-integrin field, with a particular focus on addressing previous limitations. It delves into new dual-targeting approaches and cutting-edge RGD-based agents designed to improve both tumor diagnosis and therapeutic outcomes. By examining these advancements, this review illuminates new pathways for enhancing the specificity and efficacy of integrin-targeted therapies, paving the way for more effective cancer diagnosis and treatment strategies.

References

Hoshino A, Costa-Silva B, Shen T, Rodrigues G, Hashimoto A, Mark M . Tumour exosome integrins determine organotropic metastasis. Nature. 2015; 527(7578):329-35. PMC: 4788391. DOI: 10.1038/nature15756. View

Zang J, Lin R, Wen X, Wang C, Zhao T, Jakobsson V . A Head-to-Head Comparison of 68Ga-LNC1007 and 2-18F-FDG/68Ga-FAPI-02 PET/CT in Patients With Various Cancers. Clin Nucl Med. 2023; 48(10):861-868. DOI: 10.1097/RLU.0000000000004820. View

Pirooznia N, Abdi K, Beiki D, Emami F, Arab S, Sabzevari O . Lu-labeled cyclic RGD peptide as an imaging and targeted radionuclide therapeutic agent in non-small cell lung cancer: Biological evaluation and preclinical study. Bioorg Chem. 2020; 102:104100. DOI: 10.1016/j.bioorg.2020.104100. View

Liao J, Chen R, Lin B, Deng R, Liang Y, Zeng J . Cross-Talk between the TGF-β and Cell Adhesion Signaling Pathways in Cancer. Int J Med Sci. 2024; 21(7):1307-1320. PMC: 11134594. DOI: 10.7150/ijms.96274. View

Parihar A, Sood A, Kumar R, Bhusari P, Shukla J, Mittal B . Novel use of Lu-DOTA-RGD in treatment of Ga-DOTA-RGD-avid lesions in papillary thyroid cancer with TENIS. Eur J Nucl Med Mol Imaging. 2018; 45(10):1836-1837. DOI: 10.1007/s00259-018-4036-x. View

Carlsen E, Loft M, Loft A, Czyzewska D, Andreassen M, Langer S . Prospective Phase II Trial of [Ga]Ga-NODAGA-E[c(RGDyK)] PET/CT Imaging of Integrin αβ for Prognostication in Patients with Neuroendocrine Neoplasms. J Nucl Med. 2022; 64(2):252-259. PMC: 9902862. DOI: 10.2967/jnumed.122.264383. View

Nabors L, Fink K, Mikkelsen T, Grujicic D, Tarnawski R, Nam D . Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol. 2015; 17(5):708-17. PMC: 4482861. DOI: 10.1093/neuonc/nou356. View

Truong H, Xiong J, Ghotra V, Nirmala E, Haazen L, Le Devedec S . β1 integrin inhibition elicits a prometastatic switch through the TGFβ-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer. Sci Signal. 2014; 7(312):ra15. DOI: 10.1126/scisignal.2004751. View

Cooper J, Giancotti F . Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell. 2019; 35(3):347-367. PMC: 6684107. DOI: 10.1016/j.ccell.2019.01.007. View

10.

Liu Z, Niu G, Wang F, Chen X . (68)Ga-labeled NOTA-RGD-BBN peptide for dual integrin and GRPR-targeted tumor imaging. Eur J Nucl Med Mol Imaging. 2009; 36(9):1483-94. DOI: 10.1007/s00259-009-1123-z. View

11.

Su C, Li J, Zhang L, Wang H, Wang F, Tao Y . The Biological Functions and Clinical Applications of Integrins in Cancers. Front Pharmacol. 2020; 11:579068. PMC: 7522798. DOI: 10.3389/fphar.2020.579068. View

12.

Alday-Parejo B, Stupp R, Ruegg C . Are Integrins Still Practicable Targets for Anti-Cancer Therapy?. Cancers (Basel). 2019; 11(7). PMC: 6678560. DOI: 10.3390/cancers11070978. View

13.

Stupp R, Hegi M, Neyns B, Goldbrunner R, Schlegel U, Clement P . Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010; 28(16):2712-8. DOI: 10.1200/JCO.2009.26.6650. View

14.

Kadry Y, Calderwood D . Chapter 22: Structural and signaling functions of integrins. Biochim Biophys Acta Biomembr. 2020; 1862(5):183206. PMC: 7063833. DOI: 10.1016/j.bbamem.2020.183206. View

15.

Vogetseder A, Thies S, Ingold B, Roth P, Weller M, Schraml P . αv-Integrin isoform expression in primary human tumors and brain metastases. Int J Cancer. 2013; 133(10):2362-71. DOI: 10.1002/ijc.28267. View

16.

Aashiq M, Silverman D, Naara S, Takahashi H, Amit M . Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies. Cancers (Basel). 2019; 11(9). PMC: 6770909. DOI: 10.3390/cancers11091382. View

17.

Calderwood D . Integrin activation. J Cell Sci. 2004; 117(Pt 5):657-66. DOI: 10.1242/jcs.01014. View

18.

Wu Y, Pagel M, Muldoon L, Fu R, Neuwelt E . High αv Integrin Level of Cancer Cells Is Associated with Development of Brain Metastasis in Athymic Rats. Anticancer Res. 2017; 37(8):4029-4040. PMC: 5800856. DOI: 10.21873/anticanres.11788. View

19.

Liu F, Wu Q, Dong Z, Liu K . Integrins in cancer: Emerging mechanisms and therapeutic opportunities. Pharmacol Ther. 2023; 247:108458. DOI: 10.1016/j.pharmthera.2023.108458. View

20.

Taghipour Y, Zarebkohan A, Salehi R, Rahimi F, Torchilin V, Hamblin M . An update on dual targeting strategy for cancer treatment. J Control Release. 2022; 349:67-96. DOI: 10.1016/j.jconrel.2022.06.044. View