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Plasma Extracellular-Vesicle Proteomics Nominates Candidate Biomarkers of 177Lu-PSMA-617 Outcomes in Metastatic Prostate Cancer Patients

ABSTRACT: 177Lu-PSMA-617 represents a transformative treatment for metastatic castration-resistant prostate cancer (mCRPC), yet biomarkers of benefit beyond PSMA-PET imaging remain lacking. Here, we present findings from a prospective study of 100 mCRPC patients receiving 177Lu-PSMA-617, using shotgun proteomics to profile plasma-derived extracellular vesicle (EV) proteins alongside PSMA-positive circulating tumor cell (CTC)enumeration. We identify 5,137 EV-derived proteins, including the cell-surface targets PSMA, B7-H3, Trop-2, and STEAP1, with high levels of these proteins associating with worse overall survival (OS). All four EV-proteins positively correlate with molecular tumor volume on PSMA-PET imaging, serum PSA, and serum alkaline phosphatase. CTC subpopulations, including PSMA+/EpCAM+ and PSMA-/EpCAM+ cells, associate with worse progression-free survival (PFS) and OS. Pathway analysis reveals that p53 upregulation associates with poor PFS and OS, while an activated E2F pathway unexpectedly portends better PFS and OS. These findings support the integration of liquid-biopsy proteomics into biomarker-driven mCRPC trials to improve patient stratification

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Emmanuel Antonarakis Ali Arafa Justin Drake

PROVIDER: MSV000098696 | MassIVE | Thu Jul 31 10:33:00 BST 2025

SECONDARY ACCESSION(S): PXD066814

REPOSITORIES: MassIVE

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Project description:Background Identification of the molecular determinants of invasion and metastatic potential may guide the development of a rational strategy for devising specific therapies that target the pathways leading to osteosarcoma. Methods In this study, we used pathway-focused GEarrays to screen for candidate genes related to tumor progression. Expression patterns of the selected genes were validated by real time PCR on 61 osteosarcoma patient tumor samples and correlated with clinical and pathological data. Results THBS3, SPARC and SPP1 were identified with pathway-focused GEarrays as genes differentially expressed in osteosarcoma. In particular, THBS3 was expressed at significantly high levels (p=0.0001) in biopsies from patients with metastasis at diagnosis, which is a predictor of worse overall survival, event-free survival and relapse free survival at diagnosis. After chemotherapy, patients with tumors over-expressing THBS3 have worse relapse free survival. High SPARC expression was found in 51 of 55 (96.3%) osteosarcoma samples and correlated with the worst event-free survival (p=0.03) and relapse free survival (p=0.07). Overexpression of SPP1 was found in 47 of 53 (89%) osteosarcomas correlating with better overall survival, event-free survival and relapse free survival at diagnosis. Conclusion With pathway-focused Gearrays, we identified three genes, which interestingly all encode for proteins involved in extracellular remodeling suggesting potential roles in osteosarcoma progression. This is the first report on the THBS3 gene working as a stimulator of tumor progression. Higher levels of THBS3 maintain the capacity of angiogenesis. High levels of SPARC are not required for tumor progression but are necessary for tumor growth and maintenance. SPP1 is not necessary for tumor progression in osteosarcoma and may be associated with inflammatory response and bone remodeling, functioning as a good biomarker. Keywords: disease state analysis using Superarray Pathway focused arrays

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Plasma Extracellular-Vesicle Proteomics Nominates Candidate Biomarkers of 177Lu-PSMA-617 Outcomes in Metastatic Prostate Cancer Patients

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