Developing new therapeutic strategies for brain metastasis

PROJECT SUMMARY Most cancer patients that develop brain metastasis succumb to the disease. Brain metastasis occurs in patients with melanoma (8-11%), lung (17-39%), and breast (5-17%) adenocarcinoma. Of all melanoma patients with metastatic disease, 40-50% develop brain metastasis and this percentage raises to 70% in autopsy studies. Despite its importance, mechanisms that mediate brain metastasis are largely unknown. We developed a new BM model of patient-derived short-term cultures (STCs), which consist of a brain metastasis (BM) and a non-brain metastasis (NBM)-derived STC from the same patient, and showed that matched pair BM retain greater brain-specific metastatic capability than NBM STCs. Through proteomics and in vitro assays, we showed that BM STCs have higher levels of APP-specific gamma secretase activity and secrete more Aβ than their NBM counterparts. In xenograft models, genetic or pharmacological inhibition of Aβ secretion dramatically inhibited BM formation without affecting metastasis to other organs, exposing a critical role for Aβ in BM. We hypothesize that therapeutic agents targeting Aβ, developed for the treatment of Alzheimer’s, can be repurposed for the treatment of brain metastasis, as single agents or combined with approved therapies. This proposal leverages the complementary expertise of Drs. Hernando (molecular mechanisms of melanoma and metastasis), Schober (cell biology, single cell RNAseq), and Ruggles (computational biology) to: 1) assess the therapeutic potential of clinical-grade antibodies and small molecules against Aβ in syngeneic preclinical models of brain metastasis, 2) investigate if our findings apply to other tumor types with tropism to the brain, like lung and breast adenocarcinoma, and brain tumors such as glioblastoma; and 3) investigate cell-autonomous and non-cell autonomous effects of targeting Aβ on the brain microenvironment using single-cell resolution techniques. Our studies will detail if/how Aβ functions as a critical mediator of BM. Characterizing this novel mechanism will provide important insights into BM, establish an intriguing link with neurodegeneration, and provide proof of principle of Aβ inhibition as a novel therapeutic strategy against BM and possibly brain tumors.