Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex.

Abstract

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 3427 (06 08 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34103518 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Oleic Acids
• Peptides
• Placebos

Topics

• Amino Acid Sequence
• Apoptosis (drug effects)
• Cell Line, Tumor
• Endocytosis (drug effects)
• Endpoint Determination
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Oleic Acids (chemistry)
• Peptides (chemistry, pharmacology, therapeutic use)
• Placebos
• Protein Conformation
• Proton Magnetic Resonance Spectroscopy
• Thermodynamics
• Urinary Bladder Neoplasms (drug therapy, genetics, pathology)