Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Uncovering molecular mechanisms involved in metastasis to the brain (#83)

Jodi M Saunus 1 , Majid Momeny 1 , Leonard da Silva 1 2 , Ana Cristina Vargas 1 , Fares Al-Ejeh 3 , Brian Morrison 3 , Kum Kum Khanna 3 , Sean Grimmond 4 , Georgia Chenevix-Trench 3 , Rosalind L Jeffree 5 , Nic Waddell 4 , Peter T Simpson 1 , Sunil R Lakhani 1 2 6
  1. The University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia
  2. University of Queensland School of Medicine, The University of Queensland, Herston, Queensland, Australia
  3. XXX, Queensland Institute of Medical Research, Herston 4029, Qld, AUSTRALIA
  4. Queensland Centre for Medical Genomics, The Institute for Molecular Bioscience, University of Queensland, St Lucia 4072, Qld, AUSTRALIA
  5. XXX Department of Neurosurgery, The Royal Brisbane and Women's Hospital, Herston 4029, Qld, AUSTRALIA
  6. XXX Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Queensland, Australia

Brain metastasis is a fatal complication of invasive cancer, affecting 25-40% of patients with advanced solid tumours (most commonly lung, breast, melanoma, renal, and colon cancers). This is a major unmet clinical need associated with morbidity, neurological decline and 100% mortality1. It is also a major economic burden (~$7B USD/year2), mainly due to the high costs of clinical management and palliative care.

No targeted agents have been developed based on the direct study of clinical or experimental brain metastasis samples. Drug development has been hampered by a lack of clinical specimens, the impermeability of the blood-brain-barrier (BBB) and an historic view that development of brain metastases marks end-stage, incurable disease. In order to expand the available therapeutic options, it is essential to understand more about the molecular pathways that enable the metastatic process. There is a growing body of evidence that brain metastasis can be an early event in progression, implying parallel clonal evolution in primary and secondary tumours, consistent with our previous observations that brain metastases are divergent from matched primary breast tumours3. Focussing on processes that promote colonisation and regulate dormancy may therefore be the most promising in terms of clinical translation.

Using gene expression array analysis of archival matched pairs of primary breast tumours and brain metastases, we discovered that some metastases achieve activation of ErbB signalling by up-regulating HER33, raising the possibility that this pathway could be targeted therapeutically. We are now performing functional validation of these findings using in vitro and mouse models. We are also extending the breadth of the original studies to characterise the genomes and transcriptomes of a discovery cohort of prospectively collected, fresh frozen human brain metastasis tissues from melanoma, breast and lung cancer patients using next generation sequencing. Latest developments will be presented.

  1. Maher, E.A., et al. Cancer Res, 2009. 69(15): p. 6015-20.
  2. Nieder, C., et al. Oncology, 2010. 78(5-6): p. 348-55.
  3. Da Silva, L., et al. Breast Cancer Research, 2010. 12(4): p. R46.