Radium 223 treatment increase immune checkpoint expression in extracellular vesicles from the metastatic prostate cancer bone microenvironment.

Radium-223 prolongs survival in a fraction of men with bone metastatic prostate cancer (PCa). However, there are no markers for monitoring response and resistance to Radium-223 treatment. Exosomes are mediators of intercellular communication and may reflect response of the bone microenvironment to Radium-223 treatment. We performed molecular profiling of exosomes and compare the molecular profile in patients with favorable and unfavorable overall survival.

We performed exosomal transcriptome analysis in plasma derived from our preclinical models (MDA-PCa-118b tumors, TRAMP-C2/BMP4 PCa) and from the plasma of 25 patients (paired baseline and end of treatment) treated with Radium-223. All samples were run in duplicate, and array data analyzed with fold changes +2 to -2 and p < 0.05.

We utilized the pre-clinical models to establish that genes derived from the tumor and the tumor-associated bone microenvironment (bTME) are differentially enriched in plasma exosomes upon Radium-223 treatment. The mouse transcriptome analysis revealed changes in bone-related and DNA damage repair -related pathways. Similar findings were observed in plasma-derived exosomes from patients treated with Radium-223 detected changes. In addition, exosomal transcripts detected immunosuppressive (e.g., PD-L1) that were associated with shorter survival to Radium-223. Treatment of the Myc-CaP mouse model with a combination of Radium-223 and immune checkpoint therapy (ICT) resulted in greater efficacy than monotherapy.

These clinical and co-clinical analyses showed that RNA profiling of plasma exosomes may be used for monitoring the bTME in response to treatment and that ICT may be used to increase the efficacy of Radium-223.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Mar 22 [Epub ahead of print]

Ioulia Vardaki, Paul Corn, Emanuela Gentile, Jian H Song, Namrata Madan, Anh Hoang, Nila U Parikh, Leah D Guerra, Yu-Chen Lee, Song-Chang Lin, Guoyu Yu, Elmer Santos, Marites Melancon, Patricia Troncoso, Nora M Navone, Gary Gallick, Eleni Efstathiou, Sumit K Subudhi, Sue-Hwa Lin, Christopher Logothetis, Theocharis Panaretakis

Department of Genitourinary Medical Oncology,, MD Anderson Cancer Center, The University of Texas., GU Medical Oncology, Unit 1374, MD Anderson., Toracic surgery, The University of Texas MD Anderson Cancer Center., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center., Genitourinary Medical Oncology, UT M. D. Anderson Cancer Center., Department of Cancer Biology, The University of Texas MD Anderson Cancer Center., Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center., Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center., Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center., Nuclear Medicine, The University of Texas MD Anderson Cancer Center., Imaging Physics and Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center., Pathology, The University of Texas MD Anderson Cancer Center., geniturinary medical oncology, The University of Texas MD Anderson Cancer Center., Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center., GU MEdical Oncology, The University of Texas MD Anderson Cancer Center .