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.

• MeSH
• Apoptosis drug effects   MeSH
• Endocytosis drug effects   MeSH
• Protein Conformation MeSH
• Oleic Acids chemistry   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Urinary Bladder Neoplasms drug therapy   genetics   pathology   MeSH
• Peptides chemistry   pharmacology   therapeutic use   MeSH
• Placebos MeSH
• Proton Magnetic Resonance Spectroscopy MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Amino Acid Sequence MeSH
• Endpoint Determination MeSH
• Thermodynamics MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. Our study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1-oleate, formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intravesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17 mM) on days 3 to 11. A dose-dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor-bearing mice or healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose-dependent therapeutic effect of alpha1-oleate in a murine bladder cancer model.

• MeSH
• Administration, Intravesical MeSH
• Rabbits MeSH
• Oleic Acid administration & dosage   chemistry   toxicity   MeSH
• Lactalbumin administration & dosage   chemistry   toxicity   MeSH
• Humans MeSH
• Urinary Bladder drug effects   pathology   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Cell Line, Tumor transplantation   MeSH
• Urinary Bladder Neoplasms drug therapy   pathology   MeSH
• Antineoplastic Agents administration & dosage   chemistry   toxicity   MeSH
• Drug Screening Assays, Antitumor MeSH
• Toxicity Tests, Subchronic MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH