RET a novel therapeutic target to treat breast cancer brain metastasis

Metastatic disease recurrence occurs in up to 30% of breast cancer patients with approximately 20% of these tumours metastasising to the brain. With the advent of better systemic therapies, brain metastases are increasing in incidence and confer poor prognosis, which is compounded by limited treatment options. Breast cancer brain metastases are defined by complex adaptations to both adjuvant treatment regimens and the brain microenvironment. Consequences of these alterations remain poorly understood, as does their potential for clinical targeting. Previous research using experimental models and primary tumour datasets has proposed some mechanisms of disease progression relating to brain metastasis. Mutational analysis on longitudinal breast and metastatic samples by our group and others illustrated acquired mutations affecting HER2 and the PI3k/AKT/mTOR pathway. Although current emphasis for longitudinal profiling of tumours is on mutation-level alterations, these approaches have failed to uncover genomic alterations for site-specific metastasis or the molecular determinants that drive adaptation to treatment. Conversely, transcriptional and epigenetic re-programming develops with higher frequency and has been observed to functionally affect oncogenes and related signalling pathways.

In preliminary studies, we have characterized the brain metastatic-altered transcriptome across 21 patient-matched primary breast tumours and their associated brain metastases to identify new therapeutic targets. Considerable shifts in breast cancer cell-specific gene expression profiles were observed upon brain colonization, which had a large degree of metastatic selectivity.

Bioinformatic analysis for readily druggable targets revealed recurrent gains in expression of the tyrosine kinase receptors RET and HER2. In preliminary studies, ex vivo patient explants and PDX brain metastatic studies demonstrated significant anti-tumour activity for therapies directed against both RET and HER2.

This project as part of the StAR International Training Programme will address clinically relevant questions arising from these observations.
• What is the molecular profile of the primary tumour of patients at risk of developing brainmetastasis?
• How does enhanced tyrosine kinase signalling and in particular RET contribute to brain metastasis?
• What is the efficacy of cabozantinib to inhibit progression to brain metastatic disease?
• Can we use next generation sequencing in multiple models of brain metastasis to define a gene signature to predict response to RET treatment?

A multidisciplinary approach, with input from molecular biologists, bioinformaticians, clinicians and industrial partners, will be taken to address these questions. Retrospective and on-going prospective clinical trials will be used to profile at risk patients. In vitro, ex vivo and in vivo models will be used for mechanistic and
functional studies, bioinformatics and biostatistics will be employed for advanced data analysis and computational modelling.
The output of this research will be:
Full evaluation of RET as a new therapeutic target to treat breast cancer patients at risk of and with overt brain metastatic disease ready for commercial partnership.
Publications in high-impact journals In combination with structured StAR PhD training modules, this research will provide a breath of experience in clinically relevant advanced technologies providing the candidate with a competitive advantage for international post-doctoral and/or industrial placements.