Characterising the role of RET in breast cancer brain metastasis as a facilitator of colonisation and a novel targeted therapy
Breast Cancer Now
Royal College of Surgeons in Ireland
Brain metastasis occurs in 10-30% of breast cancer patients and is fast becoming the foremost clinical challenge in the management of metastatic disease. Limited therapeutic options exist for patients with brain metastasis and the current treatment paradigm consists of surgical resection, stereotactic radiosurgery and whole-brain radiation. Clearly, there is an urgent need to better understand the mechanisms of breast cancer metastasis to the brain and to define novel therapeutic targets. Recent comprehensive sequencing studies from our group and collaborators have revealed a number of brain metastasis enriched oncogenic alterations with potential clinical significance.  Aims: We aim to determine whether altered aberrant RET signalling in metastatic breast cancer is a key mediator of tumour colonisation of the brain. We also aim to determine the efficacy of RET inhibition to abolish cell growth and survival of breast cancer brain metastatic cells.  Technique and Methodology: To address the suitability of RET as a target we will use both genetic and pharmacological inhibition of RET in comprehensive in vitro, ex vivo and in vivo pre-clinical models of breast cancer brain metastasis representing all three clinical subtypes. In vitro experiments will be accompanied by functional interrogation while in vivo experiments will be complemented by next-generation sequencing of the brain invading tumours.  Impact on breast cancer research: The outcomes of this project have the potential to significantly enhance our understanding of the oncogenic significance of recurrent, acquired aberrations in the RET pathway in breast cancer brain metastasis. This project has the potential to uncover the clinical utility of brain metastasis-acquired clinically actionable alterations that could lay the foundations for a clinical trial utilising RET inhibition for patients with breast cancer brain metastasis.
4.1 Discovery and preclinical testing of markers and technologies