Combinatorial effect of radium-223 and irreversible electroporation on prostate cancer bone metastasis in mice

Rojo, Raniv D.; Perez, Joy Vanessa D.; Damasco, Jossana A.; Yu, Guoyu; Lin, Song-Chang; Heralde, Francisco M.; Novone, Nora M.; Santos, Elmer; Lin, Sue-Hwa; Melancon, Marites P.

doi:10.1080/02656736.2021.1914873

Cited by 4 publications

(5 citation statements)

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“…After 3 weeks, mice bearing MDA PCa-118b tumors with similar tumor size were treated with ATRA, Palo, or LDN as previously described (20). Treatment of C4-2b-BMP4 tumors with Rad223 was as previously described (60).…”

Section: Generation Of Mda Pca-118b Tumors Treat With Atra Palovarote...mentioning

confidence: 99%

Prostate cancer-induced endothelial-to-osteoblast transition generates an immunosuppressive bone tumor microenvironment

Yu,

Corn,

Mak

et al. 2023

Preprint

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Immune checkpoint therapy has limited efficacy for patients with bone metastatic castrate-resistant prostate cancer (bmCRPC). In this study, we revealed a novel mechanism that may account for the relative resistance of bmCRPC to immune checkpoint therapy. We found that prostate cancer (PCa)-induced bone via endothelial-to-osteoblast (EC-to-OSB) transition causes an ingress of M2-like macrophages, leading to an immunosuppressive bone tumor microenvironment (bone-TME). Analysis of a bmCRPC RNA-seq dataset revealed shorter overall survival in patients with an M2-high versus M2-low signature. Immunohistochemical (IHC) analysis showed CD206+M2-like macrophages were enriched in bmCRPC specimens compared with primary tumors or lymph node metastasis. In osteogenic PCa xenografts, CD206+macrophages were enriched adjacent to tumor-induced bone. FACS analysis showed an increase in CD206+cells in osteogenic tumors compared to non-osteogenic tumors. Genetic or pharmacological inhibition of the EC-to-OSB transition reduced aberrant bone and M2-like macrophages in osteogenic tumors. RNAseq analysis of tumor-associated macrophages from osteogenic (bone-TAMs) versus non-osteogenic (ctrl-TAMs) tumors showed high expression of an M2-like gene signature, canonical and non-canonical Wnt pathways, and a decrease in an M1-like gene signature. Isolated bone-TAMs suppressed T-cell proliferation while ctrl-TAMs did not. Mechanistically, EC-OSB hybrid cells produced paracrine factors, including Wnts, CXCL14 and LOX, which induced M2 polarization and recruited M2-like TAMs to bone-TME. Our study thus links the unique EC-to-OSB transition as an “upstream” event that drives “downstream” immunosuppression in the bone-TME. These studies suggest that therapeutic strategies that inhibit PCa-induced EC-to-OSB transition may reverse immunosuppression to promote immunotherapeutic outcomes in bmCRPC.SignificanceThe insight that prostate cancer-induced bone generates an immunosuppressive bone tumor microenvironment offers a strategy to improve responses to immunotherapy approaches in patients with bone metastatic castrate-resistant prostate cancer.

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Section: Generation Of Mda Pca-118b Tumors Treat With Atra Palovarote...mentioning

confidence: 99%

Prostate cancer-induced endothelial-to-osteoblast transition generates an immunosuppressive bone tumor microenvironment

Yu,

Corn,

Mak

et al. 2023

Preprint

Self Cite

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“…Alpha radiation is unlikely to present an external hazard due to its low penetrating power, but becomes a concern if an alpha-emitting radionuclide (e.g. Ra-223 or other targeted alpha therapies; Gupta et al., 2017; Tafreshi et al., 2019; Rojo et al., 2021) is inhaled, ingested, or gets in the eyes. Depending on the energy, beta radiation may have a range of up to a few metres in air, and can penetrate tissue on the millimetre scale.…”

Section: Basic Concepts Of Radiological Protectionmentioning

confidence: 99%

ICRP Publication 153: Radiological Protection in Veterinary Practice

2022

Ann ICRP

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Veterinary use of radiation in the diagnosis, management, and treatment of disease has expanded and diversified, as have the corresponding radiological protection concerns. Radiological exposure of personnel involved in veterinary procedures and, where applicable, members of the public providing assistance (e.g. owners or handlers) has always been included within the system of radiological protection. Veterinary practice is now addressed explicitly as the modern complexities associated with this practice warrant dedicated consideration, and there is a need to clarify and strengthen the application of radiological protection principles in this area. The Commission recommends that the system of radiological protection should be applied in veterinary practice principally for the protection of humans, but with explicit attention to the protection of exposed animals. Additionally, consideration should be given to the risk of potential contamination of the environment associated with applications of nuclear medicine in veterinary practice. This publication focuses primarily on justification and optimisation in veterinary practice, and sets the scene for more detailed guidance to follow in future Recommendations. It is intended for a wide-ranging audience, including radiological protection professionals, veterinary staff, students, education and training providers, and members of the public, as an introduction to radiological protection in veterinary practice. © 2022 ICRP. Published by SAGE.

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“…Rojo et al [96] stated that metastatic prostate cancer within bone is difficult to treat in view of the fact that the tumour cells tend to be relatively resistant to hormonal or chemotherapies in comparison with primary prostate cancer. They also stated that Irreversible electroporation (IRE) is a minimally invasive ablation treatment procedure which has potential applications in the management of prostate cancer within bone.…”

Section: Absmentioning

confidence: 99%

“…Nevertheless, a common limitation of IRE is recurrence of tumour, which does arise from incomplete ablation which does allow the remaining cancer cells to proliferate. Rojo et al [96] in their study, combined IRE with radium-223 (Ra-223), a bone-seeking radionuclide which does emit short track length alpha particles and thus tends to be associated with reduced damage to the bone marrow and evaluated the impact of the combination treatment on bone-forming prostate cancer tumours. With regard to the methods of their study, Rojo et al [96] stated that they had tested the antitumor activity of IRE and Ra-223 as single agents and in combination in vitro against three bone morphogenetic protein 4 (BMP4)-expressing prostate cancer cell lines (C4-2B-BMP4, Myc-CaP-BMP4, and TRAMP-C2-BMP4).…”

Section: Absmentioning

confidence: 99%

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Irreversible Electroporation of Carcinoma of the Prostate Gland with a Focus on Localized Carcinoma of the Prostate Gland: A Review and Update

Venyo¹

2022

JCRR

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Even though adenocarcinoma of the prostate gland could be lethal in its advanced stage, adenocarcinoma of the prostate gland can be effectively treated when the carcinoma is localized to the prostate gland and when the localized adenocarcinoma is a low-risk or intermediate-risk localized adenocarcinoma of the prostate gland. it is localized. Traditionally, radical prostatectomy (RP) or radical radiotherapy (RT) in the form of either external beam radiotherapy or brachytherapy were utilized to treat all men who have localized adenocarcinoma of the prostate gland as treatment of curative intent. Nevertheless, Radical prostatectomy and radical radiotherapy do tend to be associated with significant risks of post-treatment side effects. Some patients who have localized prostate cancer may not be medically fit as a result of their comorbidities to undergo radical prostatectomy or radical radiotherapy to their prostate cancers. Over recent years a number of less-invasive treatment options are being utilized for the treatment of some localized adenocarcinomas of the prostate gland and some of the treatment options include: Cryotherapy of prostate Cancer; Radiofrequency ablation of prostate cancer, High Intensity Focused Ultrasound Treatment of Prostate Cancer and Irreversible Electroporation of prostate cancer as focal ablation or whole gland ablation. Focal therapy has emerged as a potential form of treatment that can achieve similar oncological outcomes to radical treatment while preserving functional outcomes and decreasing rates of adverse effects. Irreversible electroporation (IRE) is one such form of focal therapy which utilizes pulsatile electrical currents to ablate tissue. This modality of treatment is still in an early research phase, with studies showing that IRE is a safe procedure that can offer good short-term oncological outcomes whilst carrying a lower risk of poor functional outcomes. Irreversible Electroporation (IRE) is a new radiology image-guided tissue ablation which does induce cell death through very short but strong electric fields. IRE had been demonstrated to have preserving properties towards vessels, nerves, as well as the extra-cellular matrix. For this reason, IRE could represent an ideal treatment option for adenocarcinoma where other treatment options including radical prostatectomy and radical radiotherapy tend to unselectively destroy that encompass the prostate cancer and inducing side effects including urinary incontinence as well as sexual dysfunction / impotence. Some results of studies in which IRE had been utilized for the treatment of curative intent of localized low-risk and intermediate-risk adenocarcinomas of the prostate gland had indicated complete efficacy of IRE to the standard of radical prostatectomy and standard radical radiotherapy with regard to the 5-year tumour recurrence rate as well as better preservation of genitourinary function which did prove the safety as well as suitability of IRE for the treatment of localized low-risk and intermediate risk adenocarcinoma of the prostate gland. Some data pertaining to IRE besides focal treatment of early adenocarcinoma of the prostate gland had shown that IRE besides focal treatment of early prostate cancer could also be utilized for whole prostate gland ablations in patients who develop recurrent prostate cancer as well as a problem-solving treatment for the control of local tumour within the prostate gland that are not amenable to surgery or radiotherapy anymore. Some studies had demonstrated comparable short-term and medium-term functional outcomes functional outcomes with radical prostatectomy and radical radiotherapy but following longer surveillance assessments those underwent IRE were found tom have superior genitourinary function in that a number of the sexual dysfunction and urinary incontinence had resolved but with regard to the oncology outcome repeat follow-up biopsy of the prostate had demonstrated a higher positive tumour biopsy upon pathology examination for which either further IRE, or radical radiotherapy, or radical prostatectomy was required as subsequent treatment of curative intent in that radical prostatectomy of curative intent had superior medium-term to long-term outcome in comparison with IRE. IRE can also be utilized to treat locally recurrent prostate cancer following: (a) radical radiotherapy and (b) following the finding of persistent or locally recurrent adenocarcinoma of the prostate gland pursuant the undertaking of IRE as treatment of curative intent of localized adenocarcinoma of the prostate gland. Following failure of IRE treatment for localized adenocarcinoma of the prostate, the persistent carcinoma of the prostate gland could also be treated by means of radical prostatectomy, or radical radiotherapy or any other minimally invasive treatment of curative intent including cryotherapy, radiofrequency ablation of the prostate and high intensity focused ultrasound treatment. Considering that IRE tends to be associated with good short-term and medium-term outcome which also tends to be generally superior to the outcome following radiotherapy as well as radical prostatectomy, and the fact that the medium-term to long-term oncology outcome tends to be good but the oncology outcome following radical prostatectomy as well as radiotherapy would tend to be a bit superior to IRE, it could be suggested that patients who have low-risk and intermediate-risk localized adenocarcinoma who prefer to maintain their genitourinary function could be offered IRE as first line treatment of curative intent which should be followed up with regular frequent assessments which would enable early identification of treatment failures at an early stage. The individuals who are found to have IRE failure could then be offered radical prostatectomy or radical radiotherapy as second line treatment of curative intent. Finally, there is need for a global multi-centre trial of IRE in the treatment of curative intent of localized low-risk, intermediate-risk, as well as high risk groups and those who have high risk group localized prostate cancer could be offered adjuvant therapy and all these treatments should be compared with radical radiotherapy and radical prostatectomy with a long period of follow-up to enable a consensus opinion to be established as well as guidelines to be formulated.

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Combinatorial effect of radium-223 and irreversible electroporation on prostate cancer bone metastasis in mice

Cited by 4 publications

References 88 publications

Prostate cancer-induced endothelial-to-osteoblast transition generates an immunosuppressive bone tumor microenvironment

Prostate cancer-induced endothelial-to-osteoblast transition generates an immunosuppressive bone tumor microenvironment

ICRP Publication 153: Radiological Protection in Veterinary Practice

Irreversible Electroporation of Carcinoma of the Prostate Gland with a Focus on Localized Carcinoma of the Prostate Gland: A Review and Update

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