Metastatic cancers are the deadliest of diseases with a low chance of survival. In women, metastatic breast cancer is the most frequent causes of cancer death. Breast cancers constitute a heterogeneous group of malignant diseases associated with multiple genetic alterations. Currently, chemotherapies are the most effective strategy for improving patient survival, although these are only effective in a low proportion of patients with metastatic disease. Although immune therapies provide promise to treat cancer, the efficacy in metastatic breast cancer is limited. There is a clear need to develop new treatments which are effective in tackling aggressive, metastatic cancers. Elevated glucocorticoid (GC) activity has been implicated in the pathophysiology of breast cancer. Patients administered GC prior to immune checkpoint inhibitor therapy are reported to experience worse outcomes across multiple oncology indications. In our laboratory, we have used syngeneic in vivo tumour models and recently developed an immune cell cancer spheroid model that closely mimic disease. To better understand the process underlying tumour progression, we hypothesize that the broad immunosuppressive effects of GC may limit tumour immune response and drug efficacy, which may be improved by glucocorticoid receptor (GR) antagonism.
This project is in collaboration with Corcept Therapeutics and will leverage the specificity of their proprietary selective GR antagonists, including relacorilant. Relacorilant does not bind to the androgen receptor or the progesterone receptor (Ki >10 μM). Newer selective GR modulators with distinct potency or tissue-specific effects will be included.
For this PhD studentship, the candidate will use cells that model breast cancer (4T1) or antigen-expression tumour immune response (EG7). A combination of confocal microscopy, genomics and proteomic strategies coupled with cutting-edge in vivo and co-culture technologies, will be used to investigate the effects of GR antagonism on metastatic expression profiles specifically targeting genes and protein pathways that play a critical role in tumour spread. This work will build on the prior observation that relacorilant promoted an antigen-specific immune response to the EG7 tumours in combination with immune therapies. To study the effects of cortisol, 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1, an enzyme which converts inactive cortisone to active cortisol and regulates GR activation, will be modulated using CRISPR and/or lentiviral strategies in our models. Additionally, the combination therapies of relacorilant and immune therapies will be tested for the reduction of tumour burden and promoting the immune response. More specifically, the effects of tumour cell 11BHSD1 expression +/- relacorilant on immune infiltration, cytokine production, lymphocyte activation, and exosome biology will be examined. The successful candidate will work with a multidisciplinary team of supervisors and this project uses cutting-edge technologies with the potential for clinical impact.
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