Protein Kinases and Molecular Oncology

Cancer therapy response biomarkers based on protein kinases.

Director: Dr. Virginia Novaro.

Our laboratory’s perspective is to advance the understanding of the mechanisms mediated by the PI3K/AKT/mTOR and cyclin D1/CDK4/6/Rb pathways in the progression of luminal-type and HER2+ breast cancer and eventually define new markers associated with disease evolution. The impact of our research relies in the fact that activation of these signaling pathways is proposed as fundamental tumor escape routes, especially during resistance to conventional systemic therapies. In the last 5 years, new specific inhibitors targeting these pathways have been introduced into clinical practice, such as PI3K, mTOR, and CDK4/6 inhibitors. However, there is still no consensus on which are the molecular markers of activation of each pathway that are best associated with the clinical evolution of patients. It is also not known how the activation of these pathways is modified after exposing patients to targeted therapies. For this reason, we want to deepen our knowledge of the role of PI3K/AKT/mTOR and cyclin D1/CDK4/6/Rb in the mechanisms involved in the progression of the disease and in the response of breast cancer to available therapeutic agents. To this end, we evaluate tumors from patients undergoing the disease to find molecular markers and use experimental models of breast tumors induced in mice, as well as xenografts of tumor cell lines, to test the most beneficial therapeutic options according to the markers found.

The sublines of work we develop are:

1) Use of AKT1 and AKT2 isoforms as prognostic factors in breast cancer;

2) Study of the interaction between the PI3K/AKT/mTOR and CDK4-6/Rb/cyclin D1 pathways as a predictor of tumor response;

3) Determination of specific microRNAs involved in the differential regulation of protein kinases to provide diagnostic and/or prognostic circulating markers.

Liquid biopses base don miRNAs as response predictors and follow up in breast cancer.

Director: Dr. Adriana De Siervi.

miRNAs are promising molecules to be used as biomarkers because of their ability to be released by a tumor (even when it is undetectable) and circulate in the patient’s blood at an early stage, even differentially with various treatments. Therefore, they can be used in “liquid biopsies”, meaning the detection of miRNAs in blood or other body fluids for disease diagnosis. This is a very promising tool for diagnosis, prognosis, and patient follow-up, as it is a non-invasive method for the patient.

On the other hand, neoadjuvancy is the treatment given prior to surgical treatment for cancer in general. Neoadjuvant therapy has allowed for re-staging of patients, reducing tumor progression, and even assessing treatment response in vivo. Considering that the use of liquid biopsies based on miRNAs for the follow-up and prognosis of breast cancer patients in neoadjuvant therapy has not yet been established, we are currently researching circulating miRNAs in patients with breast cancer before and after neoadjuvant therapy to generate new biomarkers for breast cancer prognosis and to define a specific therapeutic strategy. Furthermore, preclinical studies on resistance to neoadjuvant treatment will allow us to characterize miRNAs that can be used to improve the therapeutic response in breast cancer patients.

Biomarkers for Triple-Negative Breast Cancer Therapy Based on miRNAs.

Director: Dr. Paola De Luca.

Our laboratory has been studying the role of miRNAs in the development and progression of breast cancer, as well as their potential in the diagnosis, prognosis, and therapy of this disease, for years. The triple-negative molecular subtype has the worst prognosis and the fewest therapeutic options. Additionally, non-hereditary factors have a high impact on the risk and progression of cancer. Metabolic syndrome is a risk factor for breast cancer that increases its aggressiveness and metastasis and is more prevalent in triple-negative breast cancer. The aim of this research line is to generate miRNA-based targeted therapies for triple-negative breast cancer, whether or not associated with metabolic syndrome. To do this, we conduct expression microarrays and bioinformatics analysis to identify key miRNAs involved in the growth and progression of triple-negative breast cancer, whether or not associated with metabolic syndrome. We are currently carrying out preclinical studies to understand the function of these miRNAs in triple-negative breast cancer, with the aim of developing therapies based on them.