Researchers at UCLA under the guidance of Drs. Matthew Rettig and Michael Jung have developed novel molecular compounds that reduce growth of prostate cancer cells. Dr. Jung in collaboration with Dr. Rettig have furthered the development of these compounds by synthesizing a new series of analogues that have similar inhibitory effects.
BACKGROUND: Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Common treatment for prostate cancer includes hormone therapies like androgen deprivation therapy that reduce circulating levels of androgens to prevent androgen receptor (AR) activation in prostate cancer cells. Androgen deprivation therapy, however, is not effective in all patients. Approximately 20-30% of prostate cancer cases will progress to advanced, metastatic disease, with 10-20% of those patients developing castration-resistant prostate cancer (CRPC). CRPC is an advanced form of prostate cancer that no longer responds to hormonal therapies traditionally used, generating more aggressive tumor growth and metastasis. A CRPC diagnosis results in very low survival outcomes, demonstrating a significant clinical challenge and an unmet need for alternative treatment strategies. AR directed therapy may play a pivotal role in addressing CRPC, as AR signaling is a key driver in CRPC progression. Importantly, the AR remains a key driver of castration resistant growth even upon disease progression after treatment with novel AR pathway inhibitors such as abiratereone and enzalutamide.
INNOVATION: Dr. Matthew Rettig, Medical Director of the Prostate Cancer Program of the Institute of Urologic Oncology, and Dr. Michael Jung from the Department of Chemistry & Biochemistry have identified novel compounds (UCLA technology reference number 2017-094) that can inhibit the AR. These compounds inhibit AR activity by covalently binding to the AR N-terminal transactivation domain and inducing its degradation in vitro and in vivo. The degradation inducing effects of these compounds are highly specific; for example, these compounds do not induce degradation of other steroid receptors such as the progesterone, estrogen and glucocorticoid receptors. In addition, these compounds inhibit growth of AR expressing (but not AR null) tumor cells in vitro and in vivo.
POTENTIAL APPLICATIONS:
- Treatment of castration-resistant prostate cancer
- Combination therapy for advanced prostate cancer
- Preventive therapy in high-risk populations
ADVANTAGES:
- Does not inhibit the transcriptional activity of glucocorticoid receptors
- Reduces expression in androgen receptor target genes\
- Androgen receptors are inhibited in a wide range of concentrations
- Several analogues have been identified
DEVELOPMENT-TO-DATE: in-vitro studies
Related paper (by the inventors only): Elshan, N. G. R. D., Rettig, M. B., & Jung, M. E. (2018). Molecules targeting the androgen receptor (AR) signaling axis beyond the AR‐Ligand binding domain. Medicinal Research Reviews, 39(3), 910–960. https://doi.org/10.1002/med.21548