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Steroid HormonesSteroid hormone dependent tumoursRational Steroid hormones need to cross the plasma membrane of target cells to exert their biological functions. Until recently, it was believed that these lipophilic hormones enter cells by non-specific diffusion after dissociation from their carrier proteins. However, specialized cell types that require large amounts of steroids for maintenance of normal function or carcinogenesis are likely to require additional mechanisms for specific and efficient uptake of steroid hormones. R&D efforts in ReceptIcon demonstrated that megalin is this uptake pathway used by steroid-dependent cells to actively acquire androgens and estrogens. Evidence for a role of megalin in steroid hormone metabolism is substantial. Firstly, the receptor is expressed in many tissues that take up and respond to steroid hormones, including prostate, mammary gland, epididymis, and uterus. Secondly, the expression of the receptor is up-regulated in steroid-dependent tumours of the breast and prostate. Thirdly, the receptor is able to internalize large amounts of androgens and estrogens bound to carrier proteins, and blocking this receptor by antagonists impairs delivery of steroid hormones to cells (Figure 4). Most importantly, a role for megalin in steroid hormone action is confirmed by the steroid hormone insensitivity of receptor-deficient mouse models. Business concept Most current drugs against steroid dependent tumours block biosynthesis of steroid hormones (aromatase inhibitors) or target the binding of steroids to their intracellular receptors (anti-androgens or anti-estrogens) Preventing the steroids from getting into the cells in the first place through inhibition of megalin offers an alternative point of attack for such tumours (Figure 5). Megalin antagonists may be effective either alone or work synergistically with current drugs, providing two independent strategies in treatment of tumours. Androgen-deprivation or estrogen-antagonist therapies suffer from systemic side effects significantly reducing quality of life for the patients. Inhibition of steroid hormone uptake through inhibition of megalin in specific cell types only is likely to be more selective towards cells requiring active uptake of steroids, and may therefore have fewer systemic side effects than traditional steroid targeting therapies.
The development of megalin antagonists to prevent the delivery of androgens and estrogens to tumors of the breast and prostate represents a second business area for ReceptIcon with significant potential. Compounds capable of inhibiting steroid hormone uptake into tumour cells will be developed as independent medicinal products in line with other anti-neoplastic drugs currently on the market. With respect to this business area, the company pursues two research aims. Firstly, it aims to establish novel test systems in vitro, in cell culture, and in animal models to demonstrate that the megalin pathway is responsible for the delivery of steroid hormones into cancer cells, and that blocking the receptor is a useful strategy to block the growth of steroid-dependent tumors. Secondly, the company aims to identify the binding site on megalin for steroid-hormone-binding proteins in order to facilitate the development of pharmaceutically acceptable megalin antagonists capable of preventing steroid hormone uptake into cells (Figures 4 and 5). |
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ReceptIcon ApS - Fruebjergvej 3, Box 35 -
DK-2100 Copenhagen - Denmark |
Steroid
Hormones 
