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Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex

Brisuda, Antonín ; Ho, James C.S. ; Kandiyal, Pancham S. ; Ng, Justin T.Y. ; Ambite, Ines LU orcid ; Butler, Daniel S.C. LU ; Háček, Jaromir ; Wan, Murphy Lam Yim LU ; Tran, Thi Hien LU and Nadeem, Aftab LU , et al. (2021) In Nature Communications 12.
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
12
article number
3427
publisher
Nature Publishing Group
external identifiers
  • pmid:34103518
  • scopus:85107675774
ISSN
2041-1723
DOI
10.1038/s41467-021-23748-y
language
English
LU publication?
yes
id
704fa103-122d-4946-8180-e13a9f6ddf23
date added to LUP
2021-07-01 13:45:40
date last changed
2024-06-15 13:07:16
@article{704fa103-122d-4946-8180-e13a9f6ddf23,
  abstract     = {{<p>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.</p>}},
  author       = {{Brisuda, Antonín and Ho, James C.S. and Kandiyal, Pancham S. and Ng, Justin T.Y. and Ambite, Ines and Butler, Daniel S.C. and Háček, Jaromir and Wan, Murphy Lam Yim and Tran, Thi Hien and Nadeem, Aftab and Tran, Tuan Hiep and Hastings, Anna and Storm, Petter and Fortunati, Daniel L. and Esmaeili, Parisa and Novotna, Hana and Horňák, Jakub and Mu, Y. G. and Mok, K. H. and Babjuk, Marek and Svanborg, Catharina}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-23748-y}},
  doi          = {{10.1038/s41467-021-23748-y}},
  volume       = {{12}},
  year         = {{2021}},
}