Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex

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 and Catharina Svanborg ()
Additional contact information
Antonín Brisuda: Charles University Praha
James C. S. Ho: Lund University
Pancham S. Kandiyal: The University of Dublin
Justin T-Y. Ng: Nanyang Technological University
Ines Ambite: Lund University
Daniel S. C. Butler: Lund University
Jaromir Háček: Charles University Praha
Murphy Lam Yim Wan: Lund University
Thi Hien Tran: Lund University
Aftab Nadeem: Lund University
Tuan Hiep Tran: Lund University
Anna Hastings: The University of Dublin
Petter Storm: Lund University
Daniel L. Fortunati: The University of Dublin
Parisa Esmaeili: Lund University
Hana Novotna: Charles University Praha
Jakub Horňák: Charles University Praha
Y. G. Mu: Nanyang Technological University
K. H. Mok: The University of Dublin
Marek Babjuk: Charles University Praha
Catharina Svanborg: Lund University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23748-y

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