Professor Simak Ali

Breast Cancer Research

Breast cancer is the most common cancer of women in the western world, with incidence continuing to increase. In most cases, breast cancer is estrogen dependent. Estrogen acts by binding to the estrogen receptor (ER), a transcription regulatory protein that acts by altering gene expression in breast cancer cells. Endocrine therapies are aimed at inhibiting ER activity by competing with estrogen for binding to ER in the case of anti-estrogens such as tamoxifen, or prevent ER activation by inhibiting estrogen biosynthesis (aromatase inhibitors). The use of these endocrine agents has contributed to a significant reduction in breast cancer mortality over the last 10-15 years. Moreover, recent clinical studies have demonstrated that these endocrine agents are also efficacious for breast cancer prevention in women at high risk of developing breast cancer. A major clinical problem, however, is that a substantial proportion of patients presenting with localized disease, and all of the patients with metastatic disease, become resistant to endocrine therapies. In most cases, ER is present in resistant tumours, and in many cases continues to regulate tumour growth, indicating that changes that allow ER activation in the absence of hormone can occur in the development of endocrine resistance.

The purpose of our research is to better understand the molecular mechanisms by which endocrine resistance arises, through the study of the ER and thereby identify and develop new strategies for the treatment of resistant disease. In particular, we have shown that ER phosphorylation at specific sites is important for regulating its activity, and have developed specific antibodies for the detection of ER phosphorylated at specific residue for evaluation of the clinical significance of these phosphorylation events. We have also identified ER-associated proteins that facilitate regulation of gene expression by ER. The focus of current research is the determination of the importance of these and other proteins that modulate ER activity, in endocrine response and resistance in breast cancer. We are also investigating the potential therapeutic importance of ER-regulated genes identified through gene expression profiling using in vitro and in vivo approaches to determine their clinical and mechanistic importance for breast cancer progression, response and resistance to therapies.

 

Prostate Cancer Research 

Prostate cancer is a major disease affecting men. In many cases, prostate cancer growth is stimulated by androgens, acting through the androgen receptor (AR) transcription factor, a protein similar to ER. We have been carrying out gene expression profiling to identify androgen-responsive genes which mediate the growth stimulatory effects of androgens in prostate cancer cells, in order to identify novel diagnostic and predictive markers, and to develop new therapies for the treatment of prostate cancer. This work has identified several potential biomarkers for monitoring prostate cancer progression and response to therapies, and potential therapeutic targets that are being developed through a drug discovery program.

 

Drug Discovery

Some of our recent findings have led to the establishment of drug discovery programs, which are being used to develop new therapies for the treatment of endocrine resistant breast cancer through the Imperial College Cancer Drug Design and Development Group (http://www1.imperial.ac.uk/medicine/about/institutes/drugdiscoverycentre/cd3/).