The FGFR (Fibroblast Growth Factor Receptor) signaling pathway has an important role in the embryonic and fetal developmental stages, where it is involved in cell differentiation and proliferation. In adult organisms FGFR is absent (or expressed at very low levels) in most tissues. However, several cancer types (like bladder, prostate, breast and lung for instance) overexpress the receptor and it’s signaling pathway, which contributes to tumor proliferation and metastasis. Considering the very specific binding of its ligand FGF2, we can use this system to deliver a drug payload directly to the cancer cells by conjugating the drug to FGF2. This system has already been tested both in cell lines and in mice. Our results show that FGF2-drug conjugates are internalized by the FGFR, leading to cell death. Also, cells lacking FGFR are unaffected by the FGF2-drug conjugates. Furthermore, we performed experiments in mice with FGF2 conjugated with monomethyl auristatin E (MMAE) that show a clear effect on hindering tumor growth, as well as being rather harmless to the animals.
A possible shortcoming of this method as a therapy is that the cancer cells might eventually be able to escape the effects of the drug – for example by exporting it more efficiently - or by becoming resistant. To overcome this, we have designed FGF2 proteins conjugated with two different drugs simultaneously: auristatin E (microtubule depolymerization) and amanitin (inhibitor of RNA polymerase II and III). These new conjugates can contain 1, 2 or 3 molecules of each drug, giving us drugs of varying potency. The upcoming animal experiments will help us validate the anti-tumor activity of these FGF2-dual-warhead conjugates, as well as the absence of toxicity for healthy tissue.