Growth Factor and Angiogenesis Inhibitors

Chapter 12 - Emerging Targets and New Agents in Squamous Head and Neck Tumours

Growth Factor Angiogenesis Inhibitors Figure 1 - You do not have permission to view this object.

c-Met is overexpressed and mutated in 75% and 14% of HNSCC, respectively. Excessive activation of c-Met is implicated in cetuximab resistance.


Two tyrosine kinase inhibitors (TKIs), dasatinib and saracatinib, targeting the non-receptor tyrosine kinase Src are currently under evaluation in cetuximab-pretreated HNSCC patients.

Silencing of tumour suppressor genes caused by hypermethylation is an epigenetic mechanism implicated in HNSCC. Demethylating agents such as decitabine are under investigation.

The phosphatidylinositol 3 phosphate (PI3K)/Akt/ mechanistic target of rapamycin (mTOR) pathway is frequently activated in HNSCC.

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PI3KCA amplification/mutations are found in 34% and 56% of HPV-negative and -positive HNSCC, respectively. Around 20% of HPV-positive HNSCC have an activating PI3KCA mutation.

PI3K inhibitors (BKM120, BYL19, PX-866), perifosine (PI3K and AKT inhibitor), and mTOR inhibitors (everolimus, temsirolimus) are examples of agents under investigation.

Increased expression of vascular endothelial growth factor (VEGF) is associated with resistance to EGFR inhibitors and with poor prognosis in HNSCC, suggesting that angiogenesis is a reliable target.

Growth Factor Angiogenesis Inhibitors Figure 3 - You do not have permission to view this object.

Combination strategies against the EGFR family and angiogenesis are being investigated. Vandetanib targets EGFR, RET and VEGFR2, and was shown in vitro and in vivo to overcome cisplatin and radioresistance in HNSCC.

Anti-VEGF agents that are being or have been evaluated: the mAb bevacizumab targeting VEGF, and different TKIs such as sunitinib, sorafenib and cediranib. Bleeding, ulceration and fistulae are known adverse events of these compounds.

Revision Questions

  1. Why could Met inhibitors be interesting to use in HNSCC therapeutics?
  2. Which pathway is frequently altered in HPV-positive HNSCC?
  3. What are the risks of anti-VEGF therapy in HNSCC?
Last update: 26 July 2017