4.2 Oncology treatment: Targeted therapy
Targeted cancer therapy is medicine that blocks, destroys or interferes with a specific signalling pathway/property/target in cancer cells that is needed for cancer cells to grow and spread. There are two main types:
- Small molecules that diffuse through the cell membrane and inhibit intracellular targets ā end in ā-ibā
- Monoclonal antibodies that bind to the extracellular part of a receptor or to a ligand ā end in ā-mabā
Principles of targeted therapy in mRCC
Mutation or methylation of VHL imitates a hypoxic (oxygen deficiency) state in the nucleus such that the protein complex pVHL is not formed and/or cannot break down hypoxia-inducible factors (HIF-1Ī±, HIF-2Ī± and HIF-3Ī±), resulting in HIF accumulation in the cell. This results in increased Ā°transcription Ā°of several genes which are important for:
- Angiogenesis, i.e. formation of blood vessels (vascular endothelial growth factor, VEGF; platelet-derived growth factor, PDGF)
- Tumour proliferation, i.e. tumour growth (transforming growth factor-alpha, TGF-Ī±)
- Metabolism, i.e. increased energy metabolism (glucose transporter, Glut 1; carbonic anhydrase IX, CAIX; erythropoietin, EPO)
- Immune suppression, i.e. inactivation of the immune system (interleukin-6, IL-6)
Kidney cancer is characterized by abnormally high formation of new blood vessels (angiogenesis).
Types of targeted therapy in mRCC
Source:Ā 6
Tyrosine kinase receptors
Tyrosine kinase receptors (TKR) are located in the cell membrane and are important regulators of cell growth and differentiation. They have an extracellular part where the ligand/signal molecule binds and a cytoplasmic part that acts as an enzyme that can activate other enzymes in the cell. Kinases are enzymes that phosphorylate, i.e., transfer a phosphate group. Examples of TKR: VEGFR, EGFR, PDGFR, insulin receptor etc.
By binding a ligand (signal molecule) to the tyrosine kinase receptor (TKR) on the outside of the cell ā> two TKRs join together to form a dimer ā> the two TKR tails phosphorylate each otherās tyrosine ā> TKR active ā> activation of intracellular signalling pathways ā> cell response.
The efficacy of tyrosine kinase inhibitors in mRCC1,4
Tyrosine kinase inhibitors (TKIs) are small molecules that block the action of TKR by inhibiting the kinase on the inside of the receptor.Ā The tyrosine kinase inhibitors used in the treatment of mRCC inhibit the VEGF receptor (and possibly other tyrosine kinase receptors) located on the endothelial and tumour cells, inhibiting:
- Formation of new blood vessels (angiogenesis)
- Tumour proliferation
TKI can inhibit other TKRs, includingĀ platelet-derived growth factor receptor (PDGFR), rearranged during transfection (RET), FMS-like tyrosine kinase (FLT3), fibroblast growth factor receptor (FGFR), and KIT, all important regulators of normal cellular processes, but also have a crucial role in the development and progression of many types of cancer.Ā 2,3,4
Some TKIs also inhibit AXL and MET, both thought to be involved in the development of resistance to VEGFR.
Medicinal products:
Efficacy of monoclonal antibody against VEGF-A
BevacizumabĀ is an anti-VEGF-A recombinant monoclonal antibody that binds and neutralises all isoforms of circulating VEGF-A. Thus, the mechanism of action is angiogenesis inhibition.
Bevacizumab is approved in combination with interferon-Ī± as first-line treatment for patients with clear-cell histology mRCC.
Bevacizumab has been studied with other combinations, includingĀ IL-2/interferon and in combination with checkpoint inhibitor.
Medicinal products:
References
- Delacroix SE, Wood CG, Jonasch E. Renal neoplasia. In: Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu ASL, et al., eds. Brenner & Rectorās The Kidney. 9th ed. Philadelphia, PA: Elsevier Saunders; 2012:1508ā1535.
- Ljungberg B, Bensalah K, Bex A, et al. EAU guidelines on renal cell carcinoma: 2016 update. European Association of Urology. https://uroweb.org/guideline/renal-cell-carcinoma/. Accessed June 25, 2016.
- Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO Clinical Practise Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 suppl 3:iii49-iii56,
- Pili R, Kauffman E, Rodriguez R. Cancer of the kidney. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloffās Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2014:1416-1444.e5. Chapter 82.
- Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373: 1119-1132.
- Banumathy G, Cairns P. Cancer Biol Ther 2010;10:658ā64
