A two-pronged approach towards the development of novel therapeutics for advanced endometrial cancer
Engel, Brian Joseph
Carson, Daniel D
Doctor of Philosophy
Endometrial cancer is the fourth most common cancer among women. The standard of care involves hysterectomy with adjuvant radiation and chemotherapy for advanced disease. Despite these efforts, treatment of advanced and metastatic disease is not very effective. This body of work describes a two-pronged approach to address lack of treatments for advanced endometrial cancer. The first approach was an in-depth study of the mechanism and physiological effect of mucin 1 (MUC1)-driven epidermal growth factor receptor (EGFR) expression and signaling. MUC1 is a large, heavily glycosylated transmembrane protein that functions to lubricate surfaces, provides protection from external insult and plays an important role in embryo implantation. EGFR is a receptor tyrosine kinase that influences cellular proliferation, migration and apoptosis. MUC1 increases EGFR gene expression, mRNA levels, protein levels and signaling in endometrial cancer cell lines. Consequently, MUC1 expression is associated with increased EGF-dependent cellular proliferation, survival and resistance to EGFR inhibitors. In addition, MUC1 and EGFR co-expression is associated with increased cellular proliferation in endometrial tumors. The second approach involved the development and characterization of an advanced three dimensional (3D) hyaluronic acid (HA)-based culture model that is compatible with existing high throughput drug screening methodologies. This system incorporates three layers: an acellular cushion layer; an encapsulated cancer cell layer for growth in 3D; and a collagen-containing layer that supports the growth of stromal cells on top of the hydrogel (2.5D). The robustness of this system was evaluated by incorporating endometrial or prostate cancer cells with associated stromal cells. Both culture systems provided high cancer and stromal cell viability and facilitated paracrine interactions. The response to cytotoxic drugs from cells cultured in 3D HA better matched clinical data than cells grown in 2D and 3D-alginate. These studies provide mechanistic evidence for regulation that occurs in advanced endometrial cancer, as well as an improved platform to screen for effective therapeutics. The 3D culture system could be leveraged to evaluate novel therapeutics for the treatment of advanced endometrial cancer which may include MUC1 and EGF-directed therapies.