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Radium 223-Mediated Zonal Cytotoxicity of Prostate Cancer in Bone.

ABSTRACT: BACKGROUND:Bone-targeting radiotherapy with Radium-223 (Rad-223), a radioisotope emitting genotoxic alpha-radiation with limited tissue penetrance (?100?µm), prolongs the survival of patients with metastatic prostate cancer (PCa). Confoundingly, the clinical response to Rad-223 is often followed by detrimental relapse and progression, and whether Rad-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outcome. METHODS:We tested Rad-223 overall response by PC3 and C4-2B human PCa cell lines in mouse bones (n?=?5-18 tibiae per group). Rad-223 efficacy at subcellular resolution was determined by intravital microscopy analysis of dual-color fluorescent PC3 cells (n?=?3-4 mice per group) in tissue-engineered bone constructs. In vivo data were fed into an in silico model to predict Rad-223 effectiveness in lesions of different sizes (1-27, 306 initial cells; n?=?10-100 simulations) and the predictions validated in vivo by treating PCa tumors of varying sizes in bones (n?=?10-14 tibiae per group). Statistical tests were performed by two-sided Student t test or by one-way ANOVA followed by Tukey's post-hoc test. RESULTS:Rad-223 (385 kBq/kg) delayed the growth (means [SD]; comparison with control-treated mice) of PC3 (6.7?×?105[4.2?×?105] vs 2.8?×?106 [2.2?×?106], P?=?.01) and C4-2B tumors in bone (7.7?×?105 [4.0?×?105] vs 3.5?×?106 [1.3?×?106], P?300?µm distance; P?=?.01).In silico simulations predicted greater efficacy of Rad-223 on single-cell lesions (eradication rate: 88.0%) and minimal effects on larger tumors (no eradication, 16.2% growth reduction in tumors of 27?306 cells), as further confirmed in vivo for PC3 and C4-2B tumors. CONCLUSIONS:Micro-tumors showed severe growth delay or eradication in response to Rad-223, whereas macro-tumors persisted and expanded. The relative inefficacy in controlling large tumors points to application of Rad-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the tumor core.

SUBMITTER: Dondossola E

PROVIDER: S-EPMC6792112 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Radium 223-Mediated Zonal Cytotoxicity of Prostate Cancer in Bone.

Dondossola Eleonora E Casarin Stefano S Paindelli Claudia C De-Juan-Pardo Elena M EM Hutmacher Dietmar W DW Logothetis Christopher J CJ Friedl Peter P

Journal of the National Cancer Institute 20191001 10

<h4>Background</h4>Bone-targeting radiotherapy with Radium-223 (Rad-223), a radioisotope emitting genotoxic alpha-radiation with limited tissue penetrance (∼100 µm), prolongs the survival of patients with metastatic prostate cancer (PCa). Confoundingly, the clinical response to Rad-223 is often followed by detrimental relapse and progression, and whether Rad-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outc ...[more]

PMID: 30657953

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Project description:BackgroundRadium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment.MethodsWe conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues.ResultsWe enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC.ConclusionsOsteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy.

Project description:BackgroundMetastatic prostate cancer in bone is difficult to treat as the tumor cells are relatively resistant to hormonal or chemotherapies when compared to primary prostate cancer. Irreversible electroporation (IRE) is a minimally invasive ablation procedure that has potential applications in the management of prostate cancer in bone. However, a common limitation of IRE is tumor recurrence, which arises from incomplete ablation that allows remaining cancer cells to proliferate. In this study, we combined IRE with radium-223 (Ra-223), a bone-seeking radionuclide that emits short track length alpha particles and thus is associated with reduced damage to the bone marrow and evaluated the impact of the combination treatment on bone-forming prostate cancer tumors.MethodsThe antitumor activity of IRE and Ra-223 as single agents and in combination was tested in vitro against three bone morphogenetic protein 4 (BMP4)-expressing prostate cancer cell lines (C4-2B-BMP4, Myc-CaP-BMP4, and TRAMP-C2-BMP4). Similar evaluation was performed in vivo using a bone-forming C4-2B-BMP4 tumor model in nude mice.ResultsIRE and Ra-223 as monotherapy inhibited prostate cancer cell proliferation in vitro, and their combination resulted in significant reduction in cell viability compared to monotherapy. In vivo evaluation revealed that IRE with single-dose administration of Ra-233, compared to IRE alone, reduced the rate of tumor recurrence by 40% following initial apparent complete ablation and decreased the rate of proliferation of incompletely ablated tumor as quantified in Ki-67 staining (53.58 ± 16.0% for IRE vs. 20.12 ± 1.63%; for IRE plus Ra-223; p = 0.004). Histological analysis qualitatively showed the enhanced killing of tumor cells adjacent to bone by Ra-223 compared to those treated with IRE alone.ConclusionIRE in combination with Ra-223, which enhanced the destruction of cancer cells that are adjacent to bone, resulted in reduction of tumor recurrence through improved clearance of proliferative cells in the tumor region.

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Radium 223-Mediated Zonal Cytotoxicity of Prostate Cancer in Bone.

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Radium 223-Mediated Zonal Cytotoxicity of Prostate Cancer in Bone.

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