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... Show moreBone 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 developedin vitroorganoids assay andex vivotumor 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 ALDEFluor(high)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. Show less
Willeumier, J.J.; Wal, C.W.P.G. van der; Schoones, J.W.; Wal, R.J. van der; Dijkstra, P.D.S. 2018
Bone metastases of the long bones often lead to pain and pathological fractures. Local treatment consists of radiotherapy or surgery. Treatment strategies are strongly based on the risk of the... Show moreBone metastases of the long bones often lead to pain and pathological fractures. Local treatment consists of radiotherapy or surgery. Treatment strategies are strongly based on the risk of the fracture and expected survival.Diagnostic work-up consists of CT and biopsy for diagnosis of the primary tumour, bone scan or PET-CT for dissemination status, patient history and blood test for evaluation of general health, and biplanar radiograph or CT for evaluation of the involved bone.A bone lesion with an axial cortical involvement of > 30 mm has a high risk of fracturing and should be stabilised-surgically.Expected survival should be based on primary tumour type, performance score, and presence of visceral and cerebral metastases.Radiotherapy is the primary treatment for symptomatic lesions without risk of fracturing. The role of post-operative radiotherapy remains unclear.Main surgical treatment options consist of plate fixation, intramedullary nails and (endo) prosthesis. The choice of modality depends on the localisation, extent of involved bone, and expected survival. Adjuvant cement should be considered in large lesions for better stabilisation. Show less
Kroon, J.; Buijs, J.T.; Horst, G. van der; Cheung, H.; Mark, M. van der; Bloois, L. van; ... ; Metselaar, J.M. 2015
