TY - JOUR
T1 - Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
AU - Brisuda, Antonín
AU - Ho, James C. S.
AU - Kandiyal, Pancham S.
AU - Ng, Justin T-Y.
AU - Ambite, Ines
AU - Butler, Daniel S. C.
AU - Háček, Jaromir
AU - Wan, Murphy Lam Yim
AU - Tran, Thi Hien
AU - Nadeem, Aftab
AU - Tran, Tuan Hiep
AU - Hastings, Anna
AU - Storm, Petter
AU - Fortunati, Daniel L.
AU - Esmaeili, Parisa
AU - Novotna, Hana
AU - Horňák, Jakub
AU - Mu, Y. G.
AU - Mok, K. H.
AU - Babjuk, Marek
AU - Svanborg, Catharina
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.nature.com/articles/s41467-021-23748-y
U2 - 10.1038/s41467-021-23748-y
DO - 10.1038/s41467-021-23748-y
M3 - Article
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3427
ER -