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
- apoptóza účinky léků MeSH
- endocytóza účinky léků MeSH
- konformace proteinů MeSH
- kyseliny olejové chemie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory močového měchýře farmakoterapie genetika patologie MeSH
- peptidy chemie farmakologie terapeutické užití MeSH
- placeba MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- sekvence aminokyselin MeSH
- stanovení cílového parametru MeSH
- termodynamika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
