Abstract B025: The proteome of prostate cancer bone metastases

Abstract

Abstract Bone is the most predominant site of distant metastasis in prostate cancer. Patients who develop bone metastases have limited therapeutic options and poor prognosis. Understanding the cellular and molecular changes occurring at this stage is critical to find new treatments and to stratify patients for personalized therapies. In the current study, we used a system-wide quantitative proteomic approach in order to identify (i) cellular alterations occurring during the transition from localized to metastasized prostate cancer and (ii) phenotypic subgroups and potential novel targets for treatment of metastatic prostate cancer. Mass spectrometry-based quantitative proteomic profiling was applied to paraffin-embedded, formalin-fixed bone metastasis tissue from prostate cancer patients (n=22) operated to relieve spinal cord compression. At the time of surgery, 5 patients were previously untreated, 16 had relapsed after androgen-deprivation therapy (ADT), and 1 was under early ADT. Mechanisms behind disease progression were identified through comparative analysis with proteomic profiles of localized prostate cancer (n=26) and adjacent normal tissue (n=8) obtained from radical prostatectomies. Expression levels of selected proteins were verified by immunohistochemical analysis of metastases from our extended bone-metastasis cohort. A mean of 5,067 proteins were identified and quantified per tumor. Compared to primary prostate tumors (1) bone metastases showed increased levels of proteins involved in cell cycle progression, DNA damage response, RNA processing, lipid transport, and fatty acid β-oxidation as well as reduced levels of proteins involved in cell adhesion and carbohydrate metabolism. Based on their proteomes, prostate cancer metastases were more heterogeneous (ρ:0.64±0.077) than localized tumors (ρ:0.8±0.037). We identified two phenotypically different subgroups of metastatic tumors: (i) those expressing higher levels of androgen receptor canonical targets together with elevated levels of mitochondrial and Golgi apparatus resident proteins and (ii) those with increased expression of proliferation and DNA repair-related proteins. Importantly, the two subgroups were seen among both treatment-naïve and castration-resistant cases and thus unrelated to previous treatment. The inverse correlation between tumor cell proliferation and metabolically/secretory active tumor cells was verified by assessment of Ki67 and PSA immunoreactivity in 78 bone metastases (Rs=-0.36, P=0.001). Identification of novel therapeutic targets/strategies for the two subgroups is ongoing. In conclusion, this work describes the first system-wide quantitative characterization of the proteome in prostate cancer bone metastases. By deep proteomic analysis we revealed the existence of at least two different subtypes of prostate cancer bone metastasis according to proliferative and metabolic features, suggesting that personalized therapies could be considered based on molecular signatures in individual cases. Reference: 1. Iglesias-Gato D, et al. The proteome of primary prostate cancer. Eur Urol 2016:69:942-52. Citation Format: Diego Iglesias-Gato, Elin Thysell, Sead Crnalic, Matthias Mann, Anders Widmark, Anders Bergh, Amilcar Flores-Morales, Pernilla Wikström. The proteome of prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B025.