Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex.

Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials. gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.

Nature communications. 2021 Jun 08*** epublish ***

Antonín Brisuda, James C S Ho, Pancham S Kandiyal, Justin T-Y Ng, Ines Ambite, Daniel S C Butler, Jaromir Háček, Murphy Lam Yim Wan, Thi Hien Tran, Aftab Nadeem, Tuan Hiep Tran, Anna Hastings, Petter Storm, Daniel L Fortunati, Parisa Esmaeili, Hana Novotna, Jakub Horňák, Y G Mu, K H Mok, Marek Babjuk, Catharina Svanborg

Department of Urology, Motol University Hospital, 2nd Faculty of Medicine, Charles University Praha, Prague, Czech Republic., Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden., Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin, Ireland., School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Department of Pathology and Molecular Medicine, Motol University Hospital, 2nd Faculty of Medicine, Charles University Praha, Prague, Czech Republic., Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden. .