Nuclear receptor pharmacology
Anti-oestrogen therapies, while very successful in the treatment of many breast cancers, are not effective for patients whose tumours do not express the oestrogen receptor. Many patients who do respond to these drugs eventually become resistant to their effects. We are identifying alternative molecules related to the oestrogen receptor that could be exploited as novel breast cancer therapeutics.
There are 48 known human nuclear receptors, which work to covert cellular signals into changes in gene expression, and influence virtually all aspects of cell biology. Typified by the steroid hormone and vitamin D receptors, nuclear receptors are ideal targets for drug discovery. Half of all nuclear receptors, however, are “orphans” that have no endogenous ligand to target in a conventional pharmacological sense.
We have shown that one such orphan receptor, LRH-1 induces cell proliferation, invasion and cancer stem cell-like phenotypes, making it an attractive novel target for cancer therapy development.
We also recently demonstrated that LRH-1 interacts strongly with the oestrogen biosynthetic pathway. To verify our findings and aid understanding of the role of LRH-1 in both the normal breast and breast cancer, we have developed a transgenic mouse model in which expression of human LRH-1 is directed specifically to the mammary gland. We have also shown that LRH-1 activity can be inhibited by peptides that block its interactions with co-regulator proteins, and are also currently using in silico and structural approaches to design small drug-like molecules that act in the same manner. This project has received funding from the National Health and Medical Research Council, Victorian Breast Cancer Research Consortium and the US Department of Defence Congressionally Directed Medical Research Programs.
Duke University, NC, USA
St. Vincent’s Institute, Melbourne