Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Antonín Brisuda
  • James C.S. Ho
  • Pancham S. Kandiyal
  • Justin T.Y. Ng
  • Jaromir Háček
  • Aftab Nadeem
  • Tuan Hiep Tran
  • Anna Hastings
  • Daniel L. Fortunati
  • Hana Novotna
  • Jakub Horňák
  • Y. G. Mu
  • K. H. Mok
  • Marek Babjuk
Enheter & grupper
Externa organisationer
  • University Hospital Motol
  • Trinity College Dublin
  • School of Biological Sciences, Singapore
  • Lund University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Mikrobiologi inom det medicinska området
  • Immunologi inom det medicinska området
Originalspråkengelska
Artikelnummer3427
TidskriftNature Communications
Volym12
StatusPublished - 2021 dec
PublikationskategoriForskning
Peer review utfördJa