Engineering Growth Factor Ligands and Receptors for Therapeutic Innovation

Overview

Journal Trends Cancer

Publisher Cell Press

Specialty Oncology

Date 2024 Oct 10

PMID 39389907

Authors

Xinran An

Justin Paoloni

Yuseong Oh

Jamie B Spangler

Affiliations

Soon will be listed here.

Abstract

Growth factors signal through engagement and activation of their respective cell surface receptors to choreograph an array of cellular functions, including proliferation, growth, repair, migration, differentiation, and survival. Because of their vital role in determining cell fate and maintaining homeostasis, dysregulation of growth factor pathways leads to the development and/or progression of disease, particularly in the context of cancer. Exciting advances in protein engineering technologies have enabled innovative strategies to redesign naturally occurring growth factor ligands and receptors as targeted therapeutics. We review growth factor protein engineering efforts, including affinity modulation, molecular fusion, the design of decoy receptors, dual specificity constructs, and vaccines. Collectively, these approaches are catapulting next-generation drugs to treat cancer and a host of other conditions.

References

Youssoufian H, Hicklin D, Rowinsky E . Review: monoclonal antibodies to the vascular endothelial growth factor receptor-2 in cancer therapy. Clin Cancer Res. 2007; 13(18 Pt 2):5544s-5548s. DOI: 10.1158/1078-0432.CCR-07-1107. View

Guan N, Liu Z, Zhao Y, Li Q, Wang Y . Engineered biomaterial strategies for controlling growth factors in tissue engineering. Drug Deliv. 2020; 27(1):1438-1451. PMC: 7594870. DOI: 10.1080/10717544.2020.1831104. View

Senger D, Galli S, Dvorak A, Perruzzi C, Harvey V, Dvorak H . Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983; 219(4587):983-5. DOI: 10.1126/science.6823562. View

Chen Y, Qi S, Perrino S, Hashimoto M, Brodt P . Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug. Cells. 2020; 9(5). PMC: 7290707. DOI: 10.3390/cells9051098. View

Steed D . The role of growth factors in wound healing. Surg Clin North Am. 1997; 77(3):575-86. DOI: 10.1016/s0039-6109(05)70569-7. View

Pai L, Gallo M, Fitzgerald D, Pastan I . Antitumor activity of a transforming growth factor alpha-Pseudomonas exotoxin fusion protein (TGF-alpha-PE40). Cancer Res. 1991; 51(11):2808-12. View

Apte R, Chen D, Ferrara N . VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019; 176(6):1248-1264. PMC: 6410740. DOI: 10.1016/j.cell.2019.01.021. View

Holmes D, Zachary I . The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol. 2005; 6(2):209. PMC: 551528. DOI: 10.1186/gb-2005-6-2-209. View

Janku F . Tumor heterogeneity in the clinic: is it a real problem?. Ther Adv Med Oncol. 2014; 6(2):43-51. PMC: 3932055. DOI: 10.1177/1758834013517414. View

10.

Boesen T, Soni B, Schwartz T, Halkier T . Single-chain vascular endothelial growth factor variant with antagonist activity. J Biol Chem. 2002; 277(43):40335-41. DOI: 10.1074/jbc.M204107200. View

11.

Cao L, Coventry B, Goreshnik I, Huang B, Sheffler W, Park J . Design of protein-binding proteins from the target structure alone. Nature. 2022; 605(7910):551-560. PMC: 9117152. DOI: 10.1038/s41586-022-04654-9. View

12.

Barker P, Mantyh P, Arendt-Nielsen L, Viktrup L, Tive L . Nerve Growth Factor Signaling and Its Contribution to Pain. J Pain Res. 2020; 13:1223-1241. PMC: 7266393. DOI: 10.2147/JPR.S247472. View

13.

Goetz R, Mohammadi M . Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol. 2013; 14(3):166-80. PMC: 3695728. DOI: 10.1038/nrm3528. View

14.

Roberts R . The extracellular signal-regulated kinase (ERK) pathway: a potential therapeutic target in hypertension. J Exp Pharmacol. 2016; 4:77-83. PMC: 4863547. DOI: 10.2147/JEP.S28907. View

15.

Goustin A, Leof E, Shipley G, Moses H . Growth factors and cancer. Cancer Res. 1986; 46(3):1015-29. View

16.

Wong R, Guillaud L . The role of epidermal growth factor and its receptors in mammalian CNS. Cytokine Growth Factor Rev. 2004; 15(2-3):147-56. DOI: 10.1016/j.cytogfr.2004.01.004. View

17.

Esparis-Ogando A, Carlos Montero J, Arribas J, Ocana A, Pandiella A . Targeting the EGF/HER Ligand-Receptor System in Cancer. Curr Pharm Des. 2016; 22(39):5887-5898. DOI: 10.2174/1381612822666160715132233. View

18.

Kieran M, Kalluri R, Cho Y . The VEGF pathway in cancer and disease: responses, resistance, and the path forward. Cold Spring Harb Perspect Med. 2012; 2(12):a006593. PMC: 3543071. DOI: 10.1101/cshperspect.a006593. View

19.

Witsch E, Sela M, Yarden Y . Roles for growth factors in cancer progression. Physiology (Bethesda). 2010; 25(2):85-101. PMC: 3062054. DOI: 10.1152/physiol.00045.2009. View

20.

Tsujioka H, Yotsumoto F, Shirota K, Horiuchi S, Yoshizato T, Kuroki M . Emerging strategies for ErbB ligand-based targeted therapy for cancer. Anticancer Res. 2010; 30(8):3107-12. View