Abstract
Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. Dysregulation of the androgen receptor pathway is a common feature of castration-resistant PCa, frequently appearing in association with mTOR pathway deregulations. Advanced PCa is also characterized by increased tumor heterogeneity and cancer stem cell (CSC) frequency. CSC-targeted therapy is currently being explored in advanced PCa, with the aim of reducing cancer clonal divergence and preventing disease progression. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18, and LAPC9. We developed in vitro organoids assay and ex vivo tumor slice drug assays to investigate the effects of mTOR- and CSC-targeting compounds. We found that both PDXs could be effectively targeted by treatment with the bivalent mTORC1/2 inhibitor Rapalink-1. Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44+ and ALDEFluorhigh cells, in vitro. Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa.
Highlights
Development of bone metastasis involves 65–75% of breast and prostate cancer patients with advanced, metastatic disease [1] with the axial skeleton as the most common site of bone metastasis [2].The clinical implications revolving around the development of a bone metastatic disease include the development of skeletal-related events, like pathological fractures, spine chord compression or bone pain and represent a common event in advanced breast and prostate patients, greatly affecting their quality of life [1, 3]
We investigated the molecular profile of snap-frozen bone metastasis specimens from patients with advanced breast or prostate cancer
Consistent with the robust inhibition of mTORC2 by RapaLink-1 and previous reports that mTORC2 responds to glutamine catabolites [35], we found that the metabolic enzymes that are linked to glutamine metabolism such as GFAT1, GS, GLS, and CAD were effectively diminished by RapaLink1 (Figures 3C,D)
Summary
Development of bone metastasis involves 65–75% of breast and prostate cancer patients with advanced, metastatic disease [1] with the axial skeleton as the most common site of bone metastasis [2]. The clinical implications revolving around the development of a bone metastatic disease include the development of skeletal-related events, like pathological fractures, spine chord compression or bone pain and represent a common event in advanced breast and prostate patients, greatly affecting their quality of life [1, 3]. The dependence of prostate tissue on androgen receptor (AR) signaling prompted the development of AR-targeting molecules, like abiraterone and enzalutamide, for the treatment of metastatic castration-resistant PCa (mCRPC). A relevant advantage of using PDX models is the possibility of investigating cancer stem cells (CSC), a widely recognized hypothesis that accounts for the establishment of a low-cycling, drug-resistant subpopulation of cells with tumor re-growth potential [10,11,12]
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