Investigating a Potential Source of Tumor Intrinsic Glucocorticoid Production in Ovarian Carcinoma

Pahul Hanjra (Advisor: Anil K. Sood, MD)

Patients with epithelial ovarian cancer (EOC) are known to experience hypothalamic-pituitary-adrenal (HPA) axis disturbances. Importantly, these disturbances have been shown to affect survival in patients with EOC. Our laboratory has previously shown that patients with EOC have elevated night-time cortisol levels, and that high cortisol levels correlate with shorter survival in patients with EOC. We have shown that cortisol levels normalize in patients following cytoreductive surgery, but it is not known if tumors can contribute to these cortisol elevations. In this study, the enzyme, 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1) is studied as a potential source of tumor intrinsic glucocorticoids, using a combination of bioinformatics analyses, in vitro experiments, and mouse models of ovarian cancer. 11b-HSD1 is expressed in a subpopulation of cancer-associated fibroblasts (CAFs) that are enriched in expression of pathways related to inflammation. Lab experiments show that 11b-HSD1 activity can activate GR signaling. In animal models, 11b-HSD1 silencing leads to tumor growth inhibition of a syngeneic ovarian cancer mouse model, changes in immune cell activation, and compensatory systemic increases in glucocorticoids. This work increases our understanding of glucocorticoid production in the setting of ovarian cancer and reveals a potential novel therapeutic target to improve efficacy of immunotherapy in ovarian cancer.

Advisory Committee:

• Anil K. Sood, MD, Chair
• Robert Dantzer, DVM, PhD
• Nicholas Justice, PhD
• Jinsong Liu, MD, PhD
• Wendy Woodward, MD, PhD