Glucocorticoid Receptor Overexpression as a Mechanism of Cancer Resistance
Glucocorticoids, including cortisol, exert their effects via the glucocorticoid receptor (GR) and regulate multiple normal physiological processes in the body. Over the past decade a body of scientific work has linked GR expression and activity with resistance to cancer therapies, including targeted agents, chemotherapy, and radiation, across a variety of cancers of epithelial origin. Observations include:
- GR is overexpressed in multiple solid tumors, including triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), renal cell carcinoma, ovarian cancer and castration-resistant prostate cancer (CRPC).1
- Higher levels of GR in tumors have been associated with worse outcomes in TNBC, endometrial and ovarian cancer.2
- A disrupted cortisol secretion cycle is correlated with poor survival in ovarian, metastatic breast and lung cancer.
- Stimulating the GR receptor drives resistance to therapy by protecting cancer cells.3
ORIC-101 is an internally-developed, potent and selective antagonist of GR. ORIC’s in vitro and in vivo experiments demonstrate efficacy of ORIC-101 across a broad range of cell lines and tumor types. Below are results of an in vivo study evaluating the activity of ORIC-101 in a human xenograft model of TNBC. Addition of ORIC-101 to chemotherapy reduces the emergence of chemoresistance.
Following the successful completion of a Phase 1a study in over 50 healthy volunteers, which suggested ORIC-101 was well-tolerated, we are undertaking multiple Phase 1b clinical trials in patients with cancer:
- ORIC-101 + Abraxane in solid tumors
- ORIC-101 + an androgen receptor modulator in prostate cancer
- ORIC-101 + a checkpoint inhibitor in solid tumors
More information about our clinical trials is available here.
CD73 and the adenosine pathway as a Mechanism of Cancer Resistance
Adenosine is a naturally occurring metabolite involved in signaling. In patients with cancer, intra-tumoral adenosine levels can become abnormally high as a result of the conversion of ATP—generated by dying tumor cells—into adenosine. The ecto-nucleotidase CD73, expressed on the cell surface of tumor cells is a major factor involved in the production on adenosine.
High levels of extracellular adenosine are linked to impaired anti-tumor immune response and resistance to immunotherapies, including checkpoint inhibitors. In addition, CD73-mediated adenosine production has been associated with resistance to chemotherapy and targeted therapies. Various reports pointing to CD73 as a potentially broad mechanism of treatment resistance across multiple cancers and treatment modalities include:
- High levels of extracellular adenosine have been observed in multiple solid tumors.4
- Increased levels of CD73 are associated with poor prognosis in multiple cancers, including lung, ovarian, and prostate.5
- Elevated CD73 has been observed in tumors resistant to chemotherapy and trastuzumab.6
- In in vivo studies, inhibition of CD73 limited tumor cell metastasis.7
Orally Available Small Molecule Inhibitors of CD73
ORIC is one of the first companies to have discovered and synthesized potent and orally available small molecule inhibitors of CD73. In 2019, we will select one or more of these CD73 inhibitors to begin IND-enabling studies, with a goal of initiating clinical studies in patients with cancer in 2020.
1 ORIC internal data; Glucocorticoid receptor expression in 20 solid tumor types using immunohistochemistry assay. Block et al. Cancer Manag Res (2017) 9: 65–72.
2 Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Pan D et al. Cancer Res (2011 Oct) 71(20):6360-70; Glucocorticoid Receptor confers resistance to anti-androgens by bypassing androgen receptor blockade. Arora VK et al. Cell (2013 Dec 5) 155(6): 1309-1322; High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer. Veneris JT et al. Gynecol Oncol (2017 Jul) 146(1):153-160; Expression of glucocorticoid receptor is associated with aggressive primary endometrial cancer and increases from primary to metastatic lesions. Tangen IL et al. Gynecol Oncol (2017 Dec) 147(3):672-677.
3 ORIC internal in vitro and in vivo studies.
4The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Blay J et al. Cancer Res (1997) 57:2602–5; A2A adenosine receptor protects tumors from antitumor T cells. Ohta A et al. Proc Natl Acad Sci (2006 Aug) 103(35): 13132–13137; 5’-ectonucleotidase mediates multiple-drug resistance in glioblastoma multiforme cells. Quezada C et al. J Cell Physiol (2013) 228(3):602-8.
5 CD73 is associated with poor prognosis in high-grade serous ovarian cancer. Turcotte M et al. Cancer Res (2015 Nov) 75(21):4494-50; Overexpression of CD73 in prostate cancer is associated with lymph node metastasis. Yang Q et al. Pathol Oncol Res (2013) 19(4):811-814. CD73 expression is an independent prognostic factor in prostate cancer. Leclerc BG, et al. Clin Cancer Res (2016 Jan) 22(1):158–66.
6CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Loi S et al. Proc Natl AcadSci (2013 July) 110(27):11091–6; 5’-ectonucleotidase mediates multiple-drug resistance in glioblastoma multiformecells. Quezada C et al. J Cell Physiol (2013) 228(3):602-8; CD73 promotes resistance to HER2/ErbB2 antibody. TurcotteM et al. Cancer Res (2017) 77(20):5652-5663.
7CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Stagg J et al. Cancer Res (2011) 71(8):2892-900.