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 Aß than
their NBM counterparts. In xenograft models, genetic or pharmacological inhibition of Aß secretion dramatically
inhibited BM formation without affecting metastasis to other organs, exposing a critical role for Aß in BM. We
hypothesize that therapeutic agents targeting Aß, 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 Aß 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 Aß on the brain microenvironment using single-cell resolution
techniques.
Our studies will detail if/how Aß 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 Aß inhibition as a novel therapeutic strategy against BM and possibly brain tumors.