MassIVE MSV000086408

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Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer

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Description

Purpose: Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA-RLT. Experimental Design: Therapeutic efficacy of PSMA-RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53-knockout tumor-bearing Nod scid gamma mice. Two days post-RLT, the (phospho)proteome was analyzed by mass spectrometry. Results: PSMA-RLT significantly improved disease control in a dose-dependent manner. (Phospho)proteomic datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, PI3K/AKT, and MYC signaling. C4-2 TP53-knockout tumors were less sensitive to PSMA-RLT than parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusions: We identified signaling alterations that may mediate resistance to PSMA-RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients. [doi:10.25345/C5V78Q] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: 225Ac-PSMA ; 177Lu-PSMA ; prostate cancer ; proteomics/phosphoproteomics ; DNA damage

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Principal Investigators:
(in alphabetical order) 		Caius Radu, UCLA, USA
Submitting User: tmle

Publications

Stuparu AD, Capri JR, Meyer C, Le TM, Evans-Axelsson SL, Current K, Lennox M, Mona CE, Fendler WP, Calais J, Eiber M, Dahlbom M, Czernin J, Radu CG, Lückerath K, Slavik R.
Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer.
J Nucl Med. Epub 2020 Dec 4.

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