Terje Sundstrøm PhD project

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Molecular biology of melanoma brain metastasis: Potential new therapeutic targets

Terje Sundstrøm

Terje Sundstrøm is a MD from the University of Bergen in 2005, and a resident in neurosurgery at Haukeland University Hospital from 2007. As a medical student he started clinical research in neurosurgery under the supervision of Professor Knut Wester. He has published 8 articles on different neurosurgical topics (http://www.uib.no/persons/Terje.Sundstrom and http://www.neurotrauma.nu). Sundstrøm has during neurosurgical training been recruited to neuro-oncology and translational cancer research. He started his PhD project in January 2011 after being awarded a 3-year scholarship from the Western Norway Regional Health Authority (Helse Vest). His project on melanoma brain metastasis is a part of the Melanoma Metastasis Project headed by Professor Frits Thorsen, Translational Cancer Research Group, Department of Biomedicine, University of Bergen (http://www.uib.no/persons/Frits.Thorsen and https://wikihost.uib.no/mriwiki/index.php/Frits_Thorsen´s_group).

Project background

Metastases are responsible for the vast majority of cancer mortality, and brain metastases occur in 1/3 of adults suffering from cancer. Metastases to the brain are 10 times more frequent than primary brain tumors. The number of patients with brain metastases is increasing because treatments for primary cancers are continually improving, and patients are surviving with these diseases longer. The treatment of brain metastases is troublesome and inadequate due to limited effects of cytostatic medications and difficult compromises with respect to consequences of radiation and surgery on surrounding brain structures.

Melanoma has the highest propensity to metastasize to the brain of all cancers. The median survival time with brain metastases is 6 months. The incidence of melanoma has increased over the last 3 decades, and the death rate continues to rise faster than the rate with most cancers. Recent results have shown that it is possible to develop genetically tailored therapy to various sub-populations of patients with metastatic melanoma (1-4).

Unfortunately, the mechanisms for metastatic spread of melanoma to the brain are largely unknown. This is due to the lack of relevant in vivo model systems. Patients with brain metastases are often excluded from larger clinical trials, leaving us uncertain about the effect of new therapeutic modalities. New research approaches and treatment strategies are clearly needed to improve the outcome for these patients.

Project overview

We have developed competitive animal models to study cancer metastasis and especially to the brain. This project includes extensive use of advanced imaging technology (e.g. 7 Tesla MRI, PET and bioluminescence imaging), as well as state of the art genetic and proteomic analyses through close collaboration with national and international core facilities. Our model system has unique translational possibilities in characterizing cancer metastasis and developing new target specific treatment. Biological and therapeutical considerations have motivated us to study melanoma, but any cancer can in principle be studied.

In our experimental model, cell lines from human melanoma brain metastases and cell lines from primary, cutaneous melanomas are injected into the left cardiac ventricle of immunodeficient mice. In our spontaneous model, the same cell lines are injected into the skin. We have been able to show that these cells form tumors in the mice, and that the metastatic cell populations more aggressively target the brain. Some of this work has already been published (5). Preliminary results were recently presented at the AACR in the USA, and as a consequence of this, we are now in the process of establishing a cooperation with the manufacturer of one of the most promising new drugs for metastatic melanoma (Vemurafenib/PLX4032; http://www.plexxikon.com) (3).

It has previously been shown that breast cancer cells prelabelled with micron-sized iron oxide particles (MPIOs) and thereafter injected intracardially into mice, can be tracked by MRI as single cells in the mouse brain (6). We are currently doing comprehensive MRI studies to elucidate the metastatic patterns and growth potentials of our cell lines by using a similar particle, called Fedex (7). This work is done in collaboration with Professor Arvid Lundervold at our department. We are able to visualize single cells labelled with Fedex in the animal brains, and through mathematical modelling we can quantify the brain cell load and follow the development of brain metastases, as well as the interesting aspects of tumor dormancy in the brain. This model system gives us a reliable tool, both quantitatively and qualitatively, to study the efficacy of new treatments.

We are now working to characterize functional and structural differences in the metastatic patterns of cell lines derived from primary tumors and metastases (e.g. by 7 Tesla MRI, PET and bioluminescence imaging). This work will provides us with a groundwork for a more target specific identification and validation of genetic and epigenetic alterations responsible for melanoma disbursement and growth in the brain. Through functional assessments of candidate genes by overexpression and knockout studies, we hope to contribute to the development of more target specific and effective anti-tumor therapy. We are also in the process of investigating the significance of miRNAs in the metastatic process, by selective insertion of candidate miRNAs into the tumor cells.

Figure

Figure 1.jpg

Modeling melanoma brain metastasis in the mouse A. MRI T1 with contrast 6 weeks after intracardial injection showing a contrast-enhancing tumor in the right hemisphere. B. 3D brain model of the same animal as in A illustrating multiple metastases. C. Optical imaging 3 weeks after intracardial injection demonstrating both abdominal and brain tumors. D. Mathematical modeling with automatic quantification of single Fedex labeled cells in the brain based on MRI T2*/MGE sequences.

Movie

File:3D movie met.mov 3D movie showing multiple melanoma brain metastases in a mouse brain

References

(1) Beadling et al. Clin Cancer Res 2008. (2) Carvajal et al. JAMA 2011. (3) Chapman et al. N Engl J Med 2011. (4) Flaherty et al. N Engl J Med 2010. (5) Wang et al. Neuropathol Appl Neurobiol 2011. (6) Bos et al. Nature 2009. (7) Babic et al. Bioconjug Chem 2008.