About me: Simak Ali

I completed my PhD in 1989 at the Roslin Institute and University of Edinburgh in the laboratory of Profs John Clark and John Bishop. I subsequently received an EMBO fellowship to study mechanisms that control gene expression, in the laboratory of Prof Pierre Chambon, Strasbourg, France. In 1992, I started my own group within Prof Charles Coombes’ laboratory, Charing Cross Medical School, prior to its integration within Imperial College London in 1997. Over the last 25 years, my research has centred on understanding the mechanisms of gene regulation in hormone-dependent cancers, towards the development of new cancer drugs and approaches for identifying patients who would most benefit from new and existing cancer drugs.

What is this project about?

Breast Cancer accounts for one in four of all cancers in women, being responsible for 1.4 million new cases and 460,000 deaths per year worldwide. In the UK, it is responisble for 7% of all deaths from cancer and 15% of female cancer deaths, making the disease a major priority when considering the “health of the nation”.

As the major driver of breast cancer development and progression in the majority, almost 80%, of breast cancers, estrogen receptor-α (ER) is the predominant drug target in breast cancer. ER is activated by binding of the hormone estrogen and estrogen binding allows ER to promote the expression of genes that propel breast cancer growth. Following surgical removal of the tumour, patients with ER-positive breast cancer are treated with drugs that prevent ER activation. This is achieved either with drugs known as antiestrogens, which compete with estrogen for binding to ER, such as Tamoxifen, or with drugs that block the synthesis of estrogen, such as Arimidex and Femara. The use of these drugs have drammatically reduced patient relapse and so have saved millions of lives.

However, at least one-third of patients go on to develop resistance to these therapies. In approximately a quarter of resistant metastatic breast cancer cases, the ER gene is mutated. Importantly, mutations in the ER gene are extremely rare in untreated breast cancer, indicating that hormone treatments that block ER activity impose a strong pressure that results in the selective amplification of rare cancer cells in which mutations in the ER gene pre-exists. Alternatively, the treatment pressure leads to the acquisition of ER mutations by the cancer cells. In either case, resistance would emerge from the selective amplification of breast cancer cells with mutations in the ER gene.

Understanding how these mutations overcome the drug inhibition of ER activity is critical for surmounting resistance to hormonal treatments. This project is using the powerful new technique of CRISPR-Cas9 mediated genome editing to introduce the ER mutations into breast cancer cell lines, in order to determine the mechanisms by which they work. Determining these mechanisms will enable us to determine if switching the type of hormonal treatment could be used to overcome resistance and prevent, or surmount resistance. Importantly, modelling these mutations in breast cancer cell lines will also allow us to perform screens for alternative drugs that would kill breast cancer cells containing ER mutations.

Current state of the project: outcomes and collaborations

We have already generated breast cancer cell lines for 5 mutations, which together account for four-fifths of all ER mutations detected in metastatic breast cancer. We have shown that these mutations result in resistance of the breast cancer cell lines to hormone therapies and are now evaluating the consequences of these mutations for breast cancer cell growth and invasive potential, together with next generation sequencing methods for defining genes in gene expression in the mutated cancer cells.

We are also establishing the potential of other breast cancer drugs for inhibiting the growth and invasive potential of these models of resistant breast cancer. This is being undertaken through additional funding from Cancer Research UK and Breast Cancer Now. We have also established important collaborative programmes for screening these lines for susceptibility to new drugs have been established with groups in the UK (Breast Cancer Now Research Centre at the Institute for Cancer Research; CRUK Cambridge Institute), USA and Canada, and with Astra Zeneca.

Future perspectives for patient care

Hormonal therapies are undoubtedly extremely effective in reducing recurrence in women with breast cancer and their use has saved millions of lives. This project promises a powerful method for modelling resistance arising from ER mutations and has the potential to identify therapeutic approaches, including new drugs, for the treatment of metastatic breast cancer.  ines for 5 mutations, which together account for four-fifths of all ER mutations detected in metastatic breast cancer. We have shown that these mutations result in resistance of the breast cancer cell lines to hormone therapies and are now evaluating the consequences of these mutations for breast cancer cell growth and invasive potential, together with next generation sequencing methods for defining genes in gene expression in the mutated cancer cells.

We are also establishing the potential of other breast cancer drugs for inhibiting the growth and invasive potential of these models of resistant breast cancer. This is being undertaken through additional funding from Cancer Research UK and Breast Cancer Now. We have also established important collaborative programmes for screening these lines for susceptibility to new drugs have been established with groups in the UK (Breast Cancer Now Research Centre at the Institute for Cancer Research; CRUK Cambridge Institute), USA and Canada, and with Astra Zeneca.

Future perspectives for patient care

Hormonal therapies are undoubtedly extremely effective in reducing recurrence in women with breast cancer and their use has saved millions of lives. This project promises a powerful method for modelling resistance arising from ER mutations and has the potential to identify therapeutic approaches, including new drugs, for the treatment of metastatic breast cancer.