SUMMARY
Breast cancer is still a leading cause of death in the female population. Some patients do not react to available drugs: this resistance to treatment is due to mutations in the cancer cells, which have to be studied. Once the relevant DNA mutations are determined, it will be possible to seek alternative treatments to cure the patient.
SOCIAL RELEVANCE OF THE PROJECT
Breast cancer is the most frequent tumour within the female population, the estimate being that one in ten Spanish women will suffer from it during their life. 25% of breast tumours over-express the HER2 protein. Therapies to combat this protein, including trastuzumab or lapatinib, have shown a survival increase in patients with breast cancer. Unfortunately, not all treated patients respond; however, out of those who do, a significant amount improves after receiving treatment for a certain period of time.
The end goal of this project is to identify the causes associated with resistance to this treatment and to develop new drugs to improve prognosis and cure.
PROJECT OVERVIEW
Breast cancer is one of the main causes of death by cancer for women in developed countries. Despite having made important progress in its prevention and treatment, metastatic breast cancer is still an unresolved clinical problem.
From a clinical-pathological point of view, breast cancer has been classified into three groups:
- Tumours that present expression of hormone receptors,
- Tumours that over-express the HER2 kinase transmembrane protein.
- Tumours with no high expression of those markers, classified as triple-negative tumours.
Tumours with HER2 over-expression are characterised by an aggressive clinical course, and an unfavourable prognosis. Even though the development of targeted therapies against HER2 has improved the disease’s prognosis, resistance to these therapies poses a relevant clinical problem. In this research project, we intend to further knowledge of the mechanisms responsible for the development of resistance to anti-HER2 therapies.
With these goals in mind, we hope to:
- Create in-vitro and in-vivo models of resistance to said therapies.
- Create cells resistant to trastuzumab and lapatinib by continuous treatment with these drugs
- Carry out a detailed analysis of the mechanisms responsible for this resistance using genomic and proteomic techniques.
- Screen inhibitors and RNAi libraries, for the purpose of identifying targets and drugs that can be used to fight the resistance mechanisms.
RESULTS
Using these cellular models, a stable cell line resistant to anti-HER2 treatment has already been identified; now the genes which may be implicated in the development of this resistance to anti-HER2 therapy will be studied. Several candidates have already been identified. The latest techniques are being employed in this study, such as genomic and proteomic analysis.
Going forward, there is a focus on the development of new therapies to combat resistance to anti-HER2 therapies. In this context, we will use knowledge gained about molecules that may be involved in this resistance, working with compounds which neutralise these molecules.
We will also carry out an analysis of several hundred molecules to see if they revert to resistance to these anti-HER2 therapies, using the resistance models generated in the study.