Drug Repurposing To Treat Melanoma Brain Metastases

Despite recent therapeutic advances in the management of patients with metastatic melanoma, brain metastases remain an intractable problem. It has proven difficult to identify and target single genes or pathways critical to brain metastasis formation. In this work we set out to explore a more global and preventive treatment approach to melanoma brain metastases within an established xenograft model of human melanoma. Mice were injected intracardially under ultrasound guidance and followed for six weeks with whole-body BLI and brain MRI. Tumor-bearing brains, adrenals, ovaries, and femurs were harvested and enzymatically dissociated before three tumor cell samples from each organ were flow-sorted and subjected to RNA sequencing. We developed a combined workflow of several independent computational and statistical analyses based on differential expression, and defined a brain metastasis gene signature of 54 upregulated and 54 downregulated genes. We then queried the Connectivity Map database using our 108-gene signature for candidate drugs, i.e. drugs that induce an opposite gene expression profile in various cancer cell lines. Three of the top ten drugs, already in use for other clinical conditions, showed significant efficacy in monolayer proliferation assays and colony forming assays with two brain-tropic melanoma cell lines and one brain-tropic lung cancer cell line. To examine these results in vivo, we used a highly standardized and predictive model system with automated MRI-based quantification of nanoparticle-labeled cells in the mouse brain following intracardiac injection of human melanoma cells. Treatment was started shortly after verification of comparable tumor cell exposure in the mouse brains and animals were monitored with whole-body BLI and brain MRI. Preliminary results showed promising therapeutic effects with respect to brain metastatic burden and survival, as well as acceptable toxicity profiles. We are currently validating these results on a larger scale in vivo, in other models, as well as applying systems biology and network modeling approaches to explore the fundamental mechanisms of action. Together, our results demonstrate a previously unrecognized potential for drug repurposing in the treatment of patients at risk of developing melanoma brain metastases or with clinically occult micrometastatic disease. Finding new uses for old drugs can greatly expedite translation to clinical practice; thus, further investigations are warranted to determine the safety, tolerability, and efficacy of these therapies. Citation Format: Terje Sundstrom, Jobin K. Varughese, Francisco Azuaje, Kjell Petersen, Clifford G. Tepper, Elizabeth Ingham, Lisa Even, Sarah Tam, Kai Ove Skaftnesmo, Morten Lund-Johansen, Rolf Bjerkvig, Katherine W. Ferrara, Frits A. Thorsen. Drug repurposing to treat melanoma brain metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4036. doi:10.1158/1538-7445.AM2014-4036