Periodic Reporting for period 4 - PLEIO-RANK (Pleiotropic treatment of cancer: RANK inhibitors targeting cancer stem cells and immunity) Reporting period: 2021-02-01 to 2022-07-31 Summary of the context and overall objectives of the project Despite the increased knowledge in cancer biology, most breast cancer patients are treated with chemotherapy which has devastating side effects and results in the selection of an aggressive population of tumor cells that disseminate to multiple organs and may end up killing the patient. There is an urgent need to develop targeted therapies in breast cancer that will efficiently kill these metastatic and chemoresistant tumor cells. We have evidences that RANK signaling may promote tumor recurrence and metastasis by expanding this population of aggressive cancer stem cells. We propose to elucidate the mechanisms by which RANK may regulate the expansion of cancer stem cells, their interaction with the microenvironment and the tumor immune response. Anti RANKL drugs may be the next targeted therapy that can significantly reduce breast cancer incidence and mortality based on current results. A selective inhibitor of RANKL, Denosumab, is currently in the clinic for the treatment of osteoporosis and bone metastasis. Provided that the results of our preclinical studies are positive, they will expedite the initiation of new clinical trials to directly address the impact of Denosumab on cancer patients with different solid tumors and ultimately lead to the approval of this drug for the treatment of breast cancer. Our objective is to understand the different functions of RANK protein RANK in various organs and situations. We hypothesized that RANK could act differently on homeostasis or in tumor formation and development, depending on its tissue and cellular context. For our study, we focused on tissues where RANK and RANKL are known to be expressed, at different levels and on different cell types: mammary gland, skin, immune system, intestine and colon. We aim to identify whether RANK is crucial to maintain tissue organization and homeostasis, whether it plays a role in tumor initiation or development and we will analyze the effects of RANK inhibition both during homeostasis and tumorigenesis, with a special focus in the interchange of signals with the immune system. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far We have already established mouse models with which we can eliminate RANK specifically in different subtypes of cells in the mammary gland and skin, in intestinal and colon epithelium, and in myeloid cells, a specific subtype of immune cells known to express high levels of RANK. Currently we are exploring the effects of eliminating RANK in these cells under several contexts: during pregnancy and lactation, breast tumorigenesis, intestinal/colon homeostasis and tumorigenesis. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) We aim to gain insights into the biology of RANK signaling pathway for the maintenance of different epithelia, as well as tumor initiation, recurrence and metastasis. The project is mainly focused on the mammary gland but intestine and skin will also be studied. A second important aim is to elucidate its role in tumor immunity and the communication between tumor and immune cells. Given the pleiotropic effects of RANK signaling pathway in multiple cell types and at different stages of tumor progression, we expect to identify novel indications for an existing drug that is only used in bone metastasis, for prevention and treatment of epithelial carcinomas, which could result may result in real, immediate, benefit for patients. We do expect that, in the medium-long term, our results might prove useful for the development of new therapeutic strategies for solid tumors: novel inhibitors of RANK signaling, or downstream targets. We propose to apply our current knowledge on RANK to explore its real value as therapeutic target given the availability of a drug that, if correctly addressed may result in real, immediate, benefit for patients.
