A new type of cancer-killing molecule, not previously described

All medical research, especially cancer research, has two simultaneous visions: The first is to make new and unexpected discoveries that creates new knowledge about conditions regarding life and health. The second is to reveal how diseases arise, what interrupts normal body functions and how cancer can cause the extensive damages that affect seriously ill patients.

The two visions within cancer research coincides in HAMLET

The two visions coincides in Hamlet. The discovery of HAMLET identified a new type of cancer-killing molecule, which has not previously been described. Many properties of HAMLET are unexpected and challenging: the protein´s changed structure and the presence of a oleic acid, the broad effect against many kinds of tumor cells and the high degree of selectivity for tumor cells. At the same time these properties make HAMLET to a new drug candidate, that so far has shown high efficacy in clinical studies and animal models. HAMLET has so far shown no side effects and the substance could be produced with a relatively simple production method.

HAMLET can therefore be the type of drug that is needed to better treat cancer patients. Despite the progress in cancer care, the need for new drugs remains very large and biologicals with cancer-killing effects start to become increasingly common.

Two natural molecules

HAMLET is a biological substance formed by two molecules naturally present in breast milk. Molecules that are naturally present in humans is usually called GRAS (Generally Regarded As Safe).

The substance is extracted from human breast milk and has shown to be effective against a variety of tumor cells. The substance, which kills cancer cells without harming healthy cells, has shown impressive results in both animal models and in trials on humans. As HAMLET is based on natural and endogenous molecules, it is likely that the substance as such does not generate any toxic effects and by that the side effects that has become generally accepted as being a part of the cancer treatments that are available today.

Research

HAMLET effectively kills tumor cells but has also proven to be safe in the proof-of-concept studies done on humans. The compound has demonstrated therapeutic effect on skin papillomas in a placebo-controlled clinical trial. HAMLET resulted in rapid shedding of dead tumor cells and a decrease in tumor size in patients with bladder cancer. Therapeutic effects have also been demonstrated in several studies performed in animal models, including effect against glioblastoma (brain cancer), bladder cancer, and colon cancer.

HAMLET (red) binds to a cancer cell marker (green) which provides a yellow color.

Trials on both animals and humans

Studies have been made both in animals and in humans, indicating that HAMLET could have an effect on a number of common cancers but also on less frequent and hard cured tumor types such as glioblastoma, a form of brain tumor that usually strike relatively young people.

Phase II trials: colon and bladder cancer

Hamlet Pharma plans to conduct Phase II studies on colon cancer and bladder cancer, common and hard cured cancers. The goal with the studies is to create a basis for further development of HAMLET to a registered drug, which may require collaboration with major pharmaceutical companies.

Effective treatment missing

Colon cancer is one of the most common cancers in the world with few treatment alternatives and where patients have a relatively poor prognosis.

Bladder cancer, which is the sixth most common cancer in Sweden, also lacks modern and effective treatment, giving space for the new type of tumor-specific cancer treatment that HAMLET could be.

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R1.       Svensson, M., C. Duringer, O. Hallgren, A. K. Mossberg, A. Hakansson, S. Linse, and C. Svanborg. 2002. Hamlet–a complex from human milk that induces apoptosis in tumor cells but spares healthy cells. Adv Exp Med Biol 503:125.

R2.       Svanborg, C., H. Agerstam, A. Aronson, R. Bjerkvig, C. Duringer, W. Fischer, L. Gustafsson, O. Hallgren, I. Leijonhuvud, S. Linse, A. K. Mossberg, H. Nilsson, J. Pettersson, and M. Svensson. 2003. HAMLET kills tumor cells by an apoptosis-like mechanism–cellular, molecular, and therapeutic aspects. Adv Cancer Res 88:1.

R3.       Duringer, C., Hallgren, O., Gustafsson, L., Pettersson, J., Mossberg, A. K., Manolov, T. and Svanborg, C. 2005. HAMLET; a novel tool to identify apoptotic pathways in tumor cells. in Sluyser, M. (Ed), Application of apoptosis to cancer treatment., Springer, pp. 223-246.

R4.       Gustafsson, L., Hallgren, O., Mossberg, A. K., Pettersson, J., Fischer, W., Aronsson, A. and Svanborg, C. 2005. HAMLET Kills Tumor Cells by Apoptosis: Structure, Cellular Mechanisms, and Therapy. J Nutr 135:1299.

R5.       Mok, K. H., Pettersson, J., Orrenius, S. and Svanborg, C. 2007. HAMLET, protein folding, and tumor cell death. Biochem Biophys Res Commun 354:1.

 R6.       Hallgren, O., Aits, S., Brest, P., Gustafsson, L., Mossberg, A. K., Wullt, B. and Svanborg, C. 2008. Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells). Adv Exp Med Biol 606:217.

R7.       Pettersson-Kastberg, J., Aits, S., Gustafsson L., Mossberg A., Storm, P., Trulsson, M., Persson, F., Mok, K. H. and Svanborg, C. 2009. Can misfolded proteins be beneficial? The HAMLET case. Ann med 41:162.

R8.       Svanborg, C., Aits, S., Brest, P., Gustafsson, L., Mok, K., Moreillhon, C., Mossberg, A., Pettersson, J., Storm, P. and Trulsson, M. 2009. HAMLET, a tumoricidal molecular complex from human milk. BMC Proceedings 3(Suppl 5):S11

R9.       Mossberg, A. K., Mok, K. H., Morozova-Roche, L. A. and Svanborg, C. 2010. Structure and function of human a-lactalbumin made lethal to tumor cell (HAMLET)-type complexes. FEBS Journal 277:4614.

P10.     Min S, Meehan J, Sullivan LM, Harte NP, Xie Y, Davey GP, Svanborg C, Brodkorb A, Mok KH. (2012) Alternatively folded proteins with unexpected beneficial functions. Biochem Soc Trans. 40(4):746-751.

P11.     Ho CS J, Rydström A, Trulsson M, Bålfors J, Storm P, Puthia M, Nadeem A and Svanborg C. 2012. HAMLET: functional properties and therapeutic potential. Future Oncol. 8(10), 1301-1313.

P12.    Ho JCS, Nadeem A and Svanborg C. 2017. HAMLET – A protein-lipid complex with broad tumoricidal activity. Biochem Biophys Res Commun 482 (3), 454–458.

SM1.