Research

For the past 15 years the Robson Lab has focused it’s entire research efforts on elucidating the biological role of a novel protein called FK506 Binding Protein Like (or abbreviated to FKBPL).

FKBPL is a member of a family of proteins known as immunophilins. Immunophilins are characterised by the presence of a prolyl isomerases (PPIase) and in the case of larger protein family members the additional presence of a tetratricopeptide repeat (TPR) domain. However FKBPL is divergent member of this family with shared homology only in the C-terminal TPR domain which is important for the interactions with the chaperone protein Hsp90, involved in protein folding.

Early research from the Robson lab revealed that FKBPL, and in particular it’s N-terminal region, had anti-angiogenic activity, i.e. it could inhibit the formation of new blood vessels. Angiogenesis is critical to the sustained growth of a tumour, and thus a unique opportunity to develop a new anti-cancer therapy arose. In collaboration with Almac Discovery, a peptide therapeutic (AD-01) was developed and it was found to robustly inhibit vessel formation in murine models. Following further pharmacokinetic testing, a next generation peptide was developed coined ALM201. Both AD-01 and ALM201 massively reduced tumour volume and the number of blood vessels in the tumour mass of murine xenograft models. Importantly the therapeutic peptides did not indicate any toxicity in the models tested.

Fig.2: Development of a biological FKBPL peptide. A 24 mer was synthesised (AD-01) which robustly inhibited vessel formation in mouse models.  Following deletion of a single glutamine residue, a 23 mer (ALM201) was synthesised and became the peptide of choice for clinical testing.

Following promising preclinical work, ALM201 completed a Phase I trial that was published in 2017, with the primary aim of checking safety and identifying phase II dose. Importantly the drug was well tolerated by patients and no dose limiting toxicities were recorded (NCT03427073).

In addition to being found in the cytoplasm, FKBPL is also secreted from numerous cell types, including endothelial cells, immune cells and cancer cells. In addition to it’s anti-angiogenic role, full length FKBPL protein and it’s therapeutic peptide mimetics have been shown to regulate cancer stem cell differentiation, and most recently it has been shown to have a role in inflammation and obesity, and these are now major research themes within the Robson Lab.

Fig. 3 FKBPL has been shown to have a protective role in cancer, obesity, and inflammation, indicating it’s far reaching therapeutic implications to treat numerous conditions.

Recently the Robson Lab have been investigating alternative therapeutic strategies to deliver full length FKBPL into cells to overcome possible limitations with peptide based therapies such as the potentially truncated activity of the protein. These investigations, in collaboration with pHion Therapeutics, involve complexing the FKBPL gene (pFKBPL) with an amphipathic peptide called RALA, to form a nanoparticle, which we have shown to strongly inhibit angiogenesis and subsequent tumour growth in mouse xenograft models.