Derivados Silanol do Ácido Litocólico como Super Agonistas do Recetor da Vitamina D para a Aplicação na Terapia do Cancro da Mama

In Portugal, cancer is the leading cause of death before the age of 70, being the second cause of death for all ages nationwide.[30] Cancer diagnosis and treatment are complex and imply relevant costs. For Portugal, cancer treatment was estimated to account for an annual cost of 867 million euros in 2017, representing 5.5% of total health expenditure.[31] According to the International Agency for Research on Cancer, in 2022 there have been approximately 69,567 new cases and 33,762 deaths from cancer in Portugal.[32] As of 2022, the most prevalent cancer in Portugal per 100,000 (5-year prevalence, both sexes, and all ages) was breast cancer (36,117 cases, 17.7%), followed by colorectum (31,861 cases, 15.7%), and prostate (29,216 cases, 14.4%) cancers.[32] Over the last decade, breast cancer mortality has been dropping as a result of improved screening (mammograms), with the five-year survival rate increasing from 78% in 1983-1985 to 88% in 1995-2001.[33] To further improve this already optimistic outlook, more research is compulsory to halt the progression of breast cancer, through the development of new effective, selective, and safer chemotherapeutics thereby contributing to enhanced life expectancy and quality of life for oncologic patients. The expression of the VDR has been demonstrated in the human mammary gland.[34] Using mammary tumoral cell lines, Muñoz and coworkers have shown that calcitriol treatment induces profound changes in phenotype (morphology, cytoarchitecture, size), proliferation, sensitivity to apoptotic stimuli, adhesiveness, migration, invasion, and the expression of marker genes associated with the inhibition of myoepithelial characteristics and with decreased malignancy in triple-negative breast cancer (TNBC) cells.[35] However, at pharmacological doses, the administration of calcitriol induces hypercalcemic toxic effects, which can even be lethal. This has led researchers to attempt the development of vitamin D analogs with reduced calcemic properties. To our knowledge, however, only two clinical trials using vitamin D analogs for the treatment of breast cancer have been published in the literature. The first trial was carried out in 1991 with calcipotriol (Fig. 1), with beneficial results in stabilizing locally advanced and cutaneous metastatic breast cancer,[36] and the second clinical trial was carried out using another vitamin D analog, seocalcitol (Fig. 1).[37] In this sense, considering the importance of VDR as a therapeutical target in breast cancer and the lack of VDR agonists described in the literature, the main aim of this project is to explore the development of new VDR ligands for application in breast cancer therapy with potent antiproliferative activity devoid of toxic hypercalcemic effects. Contrary to previous studies focused on secosteroid-based calcitriol derivatives, herein an unprecedented series of metabolic stable VDR ligands is proposed based on potent LCA derivative I (Fig. 2), which is a more potent VDR ligand than calcitriol and is devoid of hypercalcemic effects. Moreover, the chemical diversity envisioned in this project is expected to enlighten the structural determinants of non-calcemic effects and explore biased antiproliferative effects using a panel of tumoral breast cell lines. In this sense, the invention described in the SILANOL project is highly ambitious and goes beyond the state of the art of VDR research with great potential application in breast cancer therapy.