Authors: Mossberg AK1, Wullt B, Gustafsson L, Månsson W, Ljunggren E, Svanborg C.
BACKGROUND
This study introduces HAMLET, as a new molecular approach to bladder cancer therapy. The HAMLET molecule is a protein-lipid complex, first identified in human milk. HAMLET kills >40 different tumour cells in vitro by affecting membrane integrity, metabolism, proteasome function and chromatin structure. In animal studies, local HAMLET treatment limited the progression of bladder cancer, suggesting that HAMLET could be used to delay tumour development. Toxic effects on healthy tissue were not observed, suggesting that HAMLET selectively removes cancer cells in vivo.
AIMS
To examine the response of bladder cancers to intravesical HAMLET instillation in patients with non-muscle invasive transitional cell carcinomas.
METHODS
Nine patients were included. During the week preceeding scheduled transurtheral resection, each patient received five HAMLET instillations (25 mg/ml) on consecutive days and the tissue response was evaluated at surgery. In addition, urine samples were collected for quantification of cell shedding and analysis of apoptosis.
RESULTS
1. HAMLET was well tolerated. The patients did not report subjective discomfort and no toxic effects were recorded by urinalysis or tissue analysis.
2. HAMLET caused rapid and massive shedding of dead tumour cells into the urine. Control instillations with inactive protein or vehicle did not induce shedding.
3. HAMLET instillations caused a reduction in tumour size or change in tumour character in most of the patients. Biopsies from the remaining tumour showed abundant apoptotic changes, but there was no evidence of apoptosis in healthy tissues surrounding the tumour.
CONCLUSIONS
The results show that bladder cancers respond to HAMLET within a few hours of instillation into the bladder and suggest that the therapeutic efficacy should be evaluated in controlled trials. Based on these fndings, we have developed a synthetic, second generation drug candidate comprising the alpha-helical, N-terminal domain of α-lactalbumin, the protein constituent of HAMLET. When mixed with oleic acid, alpha1 forms a complex that kills a wide range of tumour cells in vitro including bladder cancer cells. We have demonstrated therapeutic efficacy of this molecule and selectivity for bladder cancer in animal models. We are currently producing GMP material for a controlled trial in this patient group.
