Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates
+ Author Affiliations
- P. Carmeliet, MD, PhD, Vesalius Research Center, VIB, K.U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium Email: peter.carmeliet@med.kuleuven.be
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- Suffice is to say that the concerns mentioned in this review, which is an excellent review, unveils in pretty good details the insufficiency of a monotherapy attacking an essential function of the cells. Not only will the cell have an answer such as dummy receptors, secondary amplification of transcription factors of growth factors, but escape mechanisms that include escape of the area leading to metastasis. I should confess that recruiting other cells to help fight the attacker (Myeloid and endothelial cells) showed clearly how much angiogenesis is globally needed. I would think that the reaction by the NF-kB would be sufficient; with its secondary growth factor production, induction would be the predictable way. But clearly, the cell wants restoration of the angiogenic function and finally wins, making Avastin effects short lived. By inducing Hypoxia, stress becomes a secondary impetus and c-JUN enters the dance and fights again with resulting amplification of growth factor and various dislocation of various cyclins at integrin locations including the Angiopoietins.
- One of the things that needs to be emphasized or not looked at or discussed in your piece are events happening at the MEK. You know by now that MEK is clearly amplified either by the cancerous process or in reaction to the blockage or consumption at VEGF. Tracking MEK is important, because if amplified and mutated it may reverse mesengial transformation and render the cell more omnipotent. It may be at the center of the observation that blocking both EGFR and VEGF reduces the progression free survival. Events at the MEK need to be scrutinized.
- You also realize that, in the long run, MTOR will be secondarily stimulated leading to Telomere preservation (stabilization) and cell surviva
- The quick restoration of the angiogenic function after cessation of the treatment marks the importance of VEGF.
Clearly, Avastin is never meant to be a monotherapy, that is the answer! To all action, there is a reaction. And cells expect action, it is built for them!
