GLUCOCORTICOID AXIS AS A MEDIATOR OF RESISTANCE
Over the past decade numerous laboratories have reported a link between GR expression and/or activity and resistance to targeted agents, chemotherapy and radiation across a variety of cancers of epithelial origin.
Studies in TNBC, CRPC and ovarian cancer have shown a correlation between high levels of GR in tumors and poor outcome (Pan et al, 2011; Arora et al 2013; Veneris et al 2017). Published accounts have shown that a disrupted cortisol secretion cycle correlate with poor survival in ovarian, metastatic breast and lung cancer.
At ORIC we have furthered the work on GR as a mechanism of resistance, and have demonstrated in-vitro and in-vivo that stimulating the GR receptor drives resistance to therapy.
ORIC-101 ACTIVITY IN RESISTANT CANCERS
The ORIC-101 molecule is a potent GR antagonist discovered in-house. We have shown across a variety of GR-expressing human cancer cell lines that ORIC-101 can overcome resistance driven by GR activation. Furthermore, we have demonstrated that in triple-negative breast cancer (TNBC) (Fig. 1) and ovarian cancer human xenografts, the addition of ORIC-101 to chemotherapy reduces the emergence of chemoresistance.
At ORIC we have furthered the work on GR as a mechanism of resistance and have demonstrated in preclinical models that stimulating the GR receptor protects cancer cells from various therapies.
Figure 1. In-vivo TNBC xenograft model shows that (i) GR activation ameliorates the activity of chemotherapy (green), and (ii) the addition of ORIC-101 prevents the emergence of – resistant tumor cells (red).
ORIC-101 ACTIVITY ON IMMUNE CELLS
Both natural (cortisol) and synthetic (dexamethasone) glucocorticoids are immune suppressive agents. Internal ORIC experiments suggest that ORIC-101 treatment drives an immune stimulatory response that can potentially be leveraged to sensitize tumors to immunotherapies. Further combination studies will help elucidate how blocking the immune suppressive effects of cortisol may enhance response to these immunotherapies.
PIPELINE AND PLATFORM
ORIC is interested in developing novel drugs targeting mechanisms of therapy resistance.
Our second undisclosed drug discovery project is focused on targeting a mechanism of resistance with potential broad commercial opportunity due to its relevance across therapies and cancer types. ORIC also continues to look for novel targets to overcome mechanisms of therapy resistance, based on its functional genomics platform.