Cushing's disease is a debilitating chronic condition caused by ACTH-producing adenomas of the pituitary gland. Because of the lack of an effective medical treatment, surgery is the mainstay of primary therapy. However, persistent or recurrent disease occurs in 30-60% of patients following surgery. The goal of my research is to evaluate a novel medical treatment which targets pituitary adenomas through the disruption of ACTH synthesis and retinoic acid receptor-mediated apoptosis. Protocol 1 is a retrospective, basic science study performed on surgical specimens of corticotroph tumors from Cushing's patients treated with transsphenoidal resection. Immunohistochemistry (IHC) will be performed to analyze the expression of the orphan nuclear receptors COUP-TFI, RARa, RXRa and PPAR-y in normal and adenomatous tissue.
Aim 1 will establish the differential expression of COUP-TFI as a useful adjuvant diagnostic tool for differentiating corticotroph tumor from normal corticotroph cells.
Aim 2 will establish the retinoic acid receptor environment in corticotroph tumors;the RAR subfamily of receptors regulates cellular differentiation in many tissues, while the RXR pathway regulates apoptosis. In addition, the co-expression of PPAR-y in tumor cells may offer the potential for synergy with rexinoids and PPAR-y agonists.
Aim 3 establishes baseline rates of apoptosis as measured by IHC of caspase 3 activity in these surgical specimens. Protocol 2 is a human clinical trial performed through the General Clinical Research Center at the University of Virginia. This inpatient, proof-of-concept pilot study will consist of five days of pre-operative treatment with an RXR agonist. The safety and tolerability of short term rexinoid treatment will be established during these five days which correlate with the highest rates of apoptosis as seen in cell culture studies. Laboratory data including plasma ACTH and cortisol levels will establish the biochemical effects of this therapy, while the post-treatment pathologic specimens will establish cellular morphology, and identify signs of apoptosis and inflammation. Caspase 3 activity, and intranuclear receptor expression will be measured by IHC and compared with control specimens established in protocol 1. This research has the potential to establish a novel medical therapy for Cushing's disease, improving public health by reversing the direct effects of this chronic disease and its associated medical comorbidities, and contributing more broadly to our understanding of retinoic acid signaling in tumor cells, and its potential role as a chemotherapeutic agent in a broad range of cancers.
| Bush, Zachary M; Lopes, Maria-Beatriz S; Hussaini, Isa M et al. (2010) Immunohistochemistry of COUP-TFI: an adjuvant diagnostic tool for the identification of corticotroph microadenomas. Pituitary 13:1-7 |
