NIEUWS - A Sister's Hope for Breast Cancer Research

PROJECT TITLE: Testing and development of a novel drug for tamoxifen resistant breast cancer

# PATIENTS IN PROJECT: 20
ASSIGNED SUBSIDY: 20.000 euro

PROJECT PROGRESS
Project background
Around 75% of all breast cancer patients present with hormone receptor-positive disease. This implies the tumor cells are positive for a protein called the Estrogen Receptor; a hormone-binding protein in the nucleus of the tumor cell. Importantly, tumor growth is thought to be dependent on the activity the Estrogen Receptor. This renders the Estrogen Receptor a prime drug target in the treatment of breast cancer, but resistance to hormonal treatment is frequently observed. Importantly, most tumors that are resistant to hormonal treatment still remain positive for the Estrogen Receptor, and still dependent on this protein for tumor growth.
Would it be possible to target the Estrogen Receptor indirectly in this setting, and with that effectively treating hormone-resistant tumors? Previously, we identified all proteins that interact with the Estrogen Receptor in breast cancer cells, and identified a previously-unknown interaction partner for the Estrogen Receptor in tumors. This protein appeared critical for Estrogen Receptor function, also in hormone-resistant conditions. With this, we are exploring the possibility of targeting Estrogen Receptor-interacting proteins rather than the receptor itself, as a novel strategy to treat hormone-resistant breast cancer.

Progress over the last year
In collaboration with researchers from the USA (prof. Anton Simeonov, NIH, Bethesda), we identified a chemical inhibitor of our newly-identified Estrogen Receptor interacting protein. In cell lines, this inhibitor blocked proliferation of all Estrogen Receptor-positive cells we tested, and completely eradicated Estrogen Receptor activity. Also breast cancer cells that were resistant to all known hormonal therapies were effectively killed with this new compound.
Next, we tested whether this new compound would also be successful in treating tumors in mice. Even though the compound was not toxic, well-tolerated and stable in the blood of the mouse, no major effect on tumor growth was observed. With this, we conclude that the compound would require additional optimization before further clinical testing.
To determine whether drugging this specific protein would have potential in the human setting, we analysed drug efficacy on human surgical material from breast tumors, in collaboration with prof. Wayne Tilley (University of Adelaide, Australia). In this approach, surgical resection material from breast cancers is put on a small sponge and taken into culture. This way, the human tumor tissue can be kept alive for multiple days outside of the body, and exposed to different medications to determine whether the drug would be suitable to kill the tumor cells. Using this novel technology, we treated the tissue for 5 days with our inhibitor. Thereafter, we test whether the drug had an effect on the tumor cells, by looking at tumor cell proliferation. This approach was performed for 20 human breast tumors. We could show that the new compound successfully blocked tumor cell proliferation in this setting, illustrating that this approach is feasibly, and inhibition of Estrogen Receptor interacting proteins may have therapeutic potential.

Plans for the coming period
We identified a novel drug target in the treatment of hormone receptor-positive breast cancer, and developed a chemical inhibitor that has potential to block proliferation in hormone-resistant tumor cell lines. However, currently all experimental analyses on human tumor tissue has been limited to cultures from primary surgery.

In the next year, we will further test whether our novel therapeutic strategy would be applicable for metastatic breast cancer as well. For this, we will collect tumor cells derived from malignant pleural effusions. These are tumor cells that have metastasized to the pleura surrounding the lungs. As most of the patients from whom pleural fluids are removed have developed a relapse after treatment, we will be able to assess whether our novel therapeutic approach would also be effective in this setting. With this, we aim to further improve treatment of metastatic breast cancer.