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, Catharina Svanborg, 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
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.
Conflict of interest statement
C.S. holds shares in HAMLET Pharma, as a representative of scientists in the HAMLET group. Patents protecting the use of the alpha1 peptide were filed previously (Biologically active complexes and therapeutic uses thereof; GB 201707715 priority date 14/05/2017, PCT/EP2018/062396 filing date 14/05/2018; inventors: C.S., A.N., J.Ho). No specific patents have been filed based on this study. Other authors declare no competing or conflicts of interests.
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