BM-34NEW USES OF OLD DRUGS FOR THE CLINICAL TREATMENT OF BRAIN METASTASES

Metastatic brain tumors are ten times more common than that of all other primary brain tumors combined. Since it is not likely that the metastatic process is based on single genetic events alone, there is a need to find out whether a combination of multiple genes could be responsible for malignant disbursement of cancer cells from the primary site to the brain, in order to develop new treatment strategies. Here, we explored a more global and preventive treatment approach to brain metastases using an established xenograft model. Mice were injected intracardially under ultrasound guidance and followed for eight weeks with whole-body BLI and brain MRI. Tumor-bearing brains, adrenals, ovaries, and femurs were harvested and enzymatically dissociated before sorting out tumor cells by flow cytometry. By using RNA sequencing followed by bioinformatics analysis, we were able to determine a set of 108 genes that were specific for brain metastases, as compared to the metastases from the other organs. We then queried the Connectivity Map database using our 108-gene signature for drugs that could 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 assays on several metastatic cell lines. We then tested these drugs in vivo, after injecting brain metastatic cell lines intracardially into nod/scid mice. Daily treatment was started immediately, and the animals were followed with whole-body BLI and brain MRI for 10 weeks. The treated animals showed decreased brain metastasis burden, increased survival, and acceptable toxicity profiles. Our results demonstrate a previously unrecognized potential for drug repurposing in the treatment of patients at risk of developing brain metastases or with clinically occult micrometastatic disease. Finding new uses for old drugs can greatly expedite translation to clinical practice.