Cinzia Allegrucci - Discovering drivers of breast cancer recurrence to overcome metastatic disease 2021 Pilot Grant
Lay abstract
Background: Metastatic breast cancer is common and the primary cause of death in cancer patients. Metastatic (or secondary) breast cancer is caused by cancer cells spreading to other parts of the body, with the disease becoming incurable. The time when a secondary tumour becomes apparent is variable, from months to many years after treatment. This is due to cancer cells surviving therapy and remaining in a dormant state. What makes them reawaken is still not understood. Predicting the risk of disease relapse is difficult and this causes paramount concern for cancer patients who live under constant threat of the cancer reoccurring.
Aims: This project aims to understand how dormant breast cancer cells reawaken to give rise to secondary tumours. We aim to discover new 2 genes that can drive this transition and use them as predictors of disease relapse.
Techniques and methodology: We will determine the role of a class of genes, called HOX genes, in breast cancer dormancy and reawakening. The expression of these genes will be studied using a new model where cancer cells grow in a gel to form mini-tumours that mimic the ones found in patients. By changing the rigidity of the gel and level of oxygen that cells are exposed to, we will produce a state of dormancy. This state will then be reversed to allow cancer cells to start growing again. The expression of those HOX genes found involved in this switch will be validated looking at data of breast cancer patients’ survival to determine their value as prognostic markers.
Impact on breast cancer research: Our vision is to discover novel markers for prediction of cancer relapse, as well as possible targets for new therapies targeting dormant and disseminated cells. The impact of this project is to improve prognosis and survival of breast cancer patients.
Scientific abstract
Background: Metastatic breast cancer remains a significant clinical challenge and a leading cause of cancer-related death. Breast cancer metastatic recurrence is variable and unpredictable, with a window of time 3 spanning few months to decades. Currently, there is a significant lack of knowledge of the molecular events involved in disease recurrence and therefore the risk of relapse is difficult to predict. Therefore, the identification of drivers of recurrence is of paramount clinical importance as early prediction can improve patient outcome
Aims: This project aims to investigate the role of HOX genes as regulators of breast cancer dormancy and recurrence to determine their value as novel prognostic markers and therapeutic targets.
Techniques and methodology: We will use a clinically relevant synthetic peptide hydrogel to establish 3D cultures of breast cancer cells to model the switch from dormancy to recurrence by modulating the gel stiffness and oxygen tension. We will then analyse the expression of HOX genes in the dormant and recurrence state and validate them using patients’ tumour samples and clinical data to determine their prognostic value.
Impact on breast cancer research: This project will provide new knowledge about the molecular events involved in disease recurrence. Our vision is to discover novel biomarkers for detection and treatment of residual disease and recurrence. The impact of this project is to improve clinical outcome of breast cancer patients.