Novel targeted therapy based on dual warhead conjugates against FGFR-dependent cancers DUALDRUG NOR/POLNOR/DUALDRUG/0058/2019 (2020-2024), projekt finansowany ze środków Polsko-Norweskiego Programu Badawczego, kierownik: prof. dr hab. Jacek Otlewski we współpracy z grupami prof. Antoniego Więdłochy i firmą Pure Biologics S.A.
Effective cancer therapy is the most important goal in oncology. The progress in antibody drug conjugates encouraged us to verify here if attachment of two different cytotoxins to a targeting protein will lead to a more efficient conjugate. The Project stems from our findings that fibroblast growth factor 2 (FGF2) can replace antibody as a targeting protein. FGF2 conjugated with monomethyl auristatin E (MMAE) can be internalized and destroy cancer cells overexpressing FGF receptor 1. We will produce FGF2 conjugates containing two extremely cytotoxic warheads: MMAE and α-amanitin (AMN). Simultaneous application of two drugs is an alternative for conventional combination therapy. MMAE blocks microtubule formation and AMN is RNA polymerase II and III inhibitor. Both warheads should act in concert in a single cancer cell. Further, MMAE can be secreted from cancer cell and via so called bystander effect destroy neighboring cells and AMN shows outstanding activity in cells expressing multi-drug resistant transporters. To develop conjugates we will apply: thiol-maleimide conjugation and synthesis of PEGylated peptide with auristatin and amanitin attached to FGF2. These methods will allow to produce homogenous conjugates of defined stoichiometry containing from 1 up to 3 molecules of each drug. Dual-warhead conjugates will be compared with two respective single warhead conjugates in biochemical and cell culture studies. The most promising dual conjugate will be tested in animal models, including FGFR-dependent xenographs and patient-derived tumor models. The approach is highly original and addresses trends in anti-cancer drug development: specific delivery, high level of drug loading combined with defined stoichiometry and overall homogeneiety of conjugate. Most importantly our proposed targeted strategy will have not only the potential to efficiently kill tumor cells reducing the side effects on healthy cells, but also to limit their ability to develop resistance.
