The Brockman Foundation Medical Research Grant Program has provided support for research being conducted by Dr. Jan-Ake Gustafsson and his team at the Center for Nuclear Receptors and Cell Signalling at the University of Houston.
Dr. Gustafsson is the Founding Director of the Center, as well as the Robert A. Welch Professor in the Department of Biology and Biochemistry at the university.
The Center’s focus is on cell signalling in cancer (of the prostate, breast, pancreas, lung and cervix), neurodegenerative diseases, and immunotherapy for cancer.
Since its creation in 2009, the Center has become nationally recognised for its scientific advances in the areas of prostate cancer, diabetes, degenerative neurological diseases, and cancer immunotherapy.
Working from the Center’s world-class labs, researchers combine interdisciplinary research and dynamic collaboration with the Texas Medical Center and industry partners.
The grant by the Brockman Foundation Medical Research Grant Program supports the conduct of research, basic and clinical, into a new approach for the treatment of prostate cancer utilising an estrogenic receptor-Beta agonist.
Hypothesis and Research Approach
The Brockman grant was used to explore the role of Estrogen Receptor beta (ERb) in prostate cancer (PCa) with the overall aim of targeting this receptor to treat PCa. The need for a new approach to the current clinical practice, which is to target the androgen receptor (AR), is that AR antagonists have good short-term benefit but lead to the fatal disease outcome in castration-resistant PCa. The goal is to repress AR signaling by using ERb agonists to repress the transcription of the AR gene, removing it from the prostate and avoiding the development of AR-mediated signaling which is independent of androgens.
Drs. Gustafsson’s and Warner’s research has used four approaches to achieve the stated goal, with the following results:
1) They created a mouse in which the ERb gene was completely removed from the genome. This mouse allowed the definitive conclusion that ERb is necessary for control of proliferation in the prostate and mammary gland;
2) Clinical prostate cancer samples from MD Anderson demonstrated that androgen deprivation therapy (ADT) leads to EGFR-driven proliferation of the basal cells of the prostate which could lead to castration-resistant PCa;
3) Benign Prostate Hypertrophy (BPH) samples revealed that soya isoflavones, which are ERb agonists, can prevent proscar-induced basal cell proliferation;
4) Prostate cell lines in culture revealed that ERb regulates INPP4, a phosphatase that can compensate for loss of the tumor repressor gene, PTEN, which is frequently lost in prostate cancer.
The clinical implication of these studies is that ERb agonists should be used to control early stages of prostate cancer to prevent progression to higher grades and that ADT can be made safer by combination with ERb agonists.
Publications (supported by the Brockman Foundation-sponsored research):
1. Margaret Warner, Wan-fu Wu, Leticia Montanholi, Ivan Nalvarte, Per Antonson, and Jan-Ake Gustafsson. In press 2020. Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene. Proceedings of the National Academy of Sciences.
2. Michelle Faria, Peter Shepherd, Yinghong Pan, Sujash S. Chatterjee, Nora Navone, Jan-Åke Gustafsson and Anders Strom. 2018. The estrogen receptor variants β2 and β5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling. Oncotarget. 9(91):36273 – 36288.
- Overview: Cell signalling in cancer
- Conclusion: Agonists should be used to control early stages of prostate cancer; ADT can be made safer by combination with ERb agonists