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Targeted alpha therapy in a systemic mouse model of prostate cancer - a feasibility study.

ABSTRACT: ²²⁵Ac-PSMA-617 targeted-therapy has demonstrated efficacy in 75-85% of patients; however, responses are not durable. We aimed to establish translatable mouse models of disseminated prostate cancer (PCa) to evaluate effectiveness of ²²⁵Ac-PSMA-617 at various disease stages. Methods: C4-2, C4-2B, or 22Rv1 cells were injected into the left ventricle of male NSG mice. Disease progression was monitored using bioluminescence imaging (BLI). For treatment, mice were injected with 40 kBq ²²⁵Ac-PSMA-617 at one (early treatment cohort) or three weeks (late treatment cohort) post-inoculation. Treatment efficacy was monitored by BLI of whole-body tumor burden. Mice were sacrificed based on body conditioning score. Results: C4-2 cells yielded metastases in liver, lungs, spleen, stomach, bones, and brain - achieving a clinically relevant model of widespread metastatic disease. The disease burden in the early treatment cohort was stable over 27 weeks in 5/9 mice and progressive in 4/9 mice. These mice were sacrificed due to brain metastases. Median survival of the late treatment cohort was superior to controls (13 vs. 7 weeks; p<0.0001) but inferior to that in the early treatment cohort (13 vs. 27 weeks; p<0.001). Late cohort mice succumbed to extensive liver involvement. The 22Rv1 and C4-2B systemic models were not used for treatment due to high kidney metastatic burden or low take rate, respectively. Conclusion: C4-2 cells reproduced metastatic cancer spread most relevantly. Early treatment with ²²⁵Ac-PSMA-617 prevented liver metastases and led to significant survival benefit. Late treatment improved survival without reducing tumor burden in the liver, the main site of metastasis. The current findings suggest that early ²²⁵Ac-PSMA-617 intervention is more efficacious in the setting of widespread metastatic PCa.

SUBMITTER: Stuparu AD

PROVIDER: S-EPMC7052903 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Targeted alpha therapy in a systemic mouse model of prostate cancer - a feasibility study.

Stuparu Andreea D AD Meyer Catherine A L CAL Evans-Axelsson Susan L SL Lückerath Katharina K Wei Liu H LH Kim Woosuk W Poddar Soumya S Mona Christine E CE Dahlbom Magnus M Girgis Mark D MD Radu Caius G CG Czernin Johannes J Slavik Roger R

Theranostics 20200203 6

225Ac-PSMA-617 targeted-therapy has demonstrated efficacy in 75-85% of patients; however, responses are not durable. We aimed to establish translatable mouse models of disseminated prostate cancer (PCa) to evaluate effectiveness of 225Ac-PSMA-617 at various disease stages. Methods: C4-2, C4-2B, or 22Rv1 cells were injected into the left ventricle of male NSG mice. Disease progression was monitored using bioluminescence imaging (BLI). For treatment, mice were injected ...[more]

PMID: 32194823

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Project description:A better assessment of individualized prostate cancer (PrCa) risk is needed to improve screening. The use of the prostate-specific antigen (PSA) level for screening in the general population has limitations and is not currently advocated. Approximately 100 common single nucleotide polymorphisms (SNPs) have been identified that are associated with the risk of developing PrCa. The PROFILE pilot study explored the feasibility of using SNP profiling in men with a family history (FH) of PrCa to investigate the probability of detecting PrCa at prostate biopsy (PB). The primary aim of this pilot study was to determine the safety and feasibility of PrCa screening using transrectal ultrasound-guided PB with or without diffusion-weighted magnetic resonance imaging (DW-MRI) in men with a FH. A secondary aim was to evaluate the potential use of SNP profiling as a screening tool in this population.A total of 100 men aged 40-69 years with a FH of PrCa underwent PB, regardless of their baseline PSA level. Polygenic risk scores (PRSs) were calculated for each participant using 71 common PrCa susceptibility alleles. We treated the disease outcome at PB as the outcome variable and evaluated its associations with the PRS, PSA level, and DW-MRI findings using univariate logistic regression.Of the 100 men, 25 were diagnosed with PrCa, of whom 12 (48%) had clinically significant disease. Four adverse events occurred and no deaths. The PSA level and age at study entry were associated with PrCa at PB (p = .00037 and p = .00004, respectively).The results of the present pilot study have demonstrated that PB is a feasible and safe method of PrCa screening in men with a FH, with a high proportion of PrCa identified requiring radical treatment. It is feasible to collect data on PrCa-risk SNPs to evaluate their combined effect as a potential screening tool. A larger prospective study powered to detect statistical associations is in progress.Prostate biopsy is a feasible and safe approach to prostate cancer screening in men with a family history and detects a high proportion of prostate cancer that needs radical treatment. Calculating a polygenic risk score using prostate cancer risk single nucleotide polymorphisms could be a potential future screening tool for prostate cancer.

Project description:BackgroundActive surveillance (AS) is a preferred management option for men with prostate cancer with favourable prognosis. However, nearly half of men on AS switch to treatment within 5 years, so therapeutic strategies to prevent or delay disease progression could be considered. The androgen receptor is the pre-eminent oncogenic driver in prostate cancer.ObjectiveTo explore image-based tumour responses and the patient impact of short-duration androgen-targeted therapy (ATT) to abrogate disease progression during AS.Design setting and participantsMen on AS with Cambridge Prognostic Group 1 & 2 (low and favourable intermediate risk) prostate cancer and lesions visible on magnetic resonance imaging (MRI) were recruited to an open-label, single-centre, phase 2 feasibility study of short-term ATT (the TAPS01 study).InterventionApalutamide 240 mg was administered for 90 days.Outcome measurements and statistical analysisMRI-measured tumour volume (TV), gland volume (GV), and the TV/GV ratio were calculated at baseline, at day 90 (end of treatment), and at 6- and 18-month follow-up. Quality of life metrics were measured at day 0, day 90, and 6 weeks after ATT.Results and limitationsEleven patients (40% of eligible men approached) agreed to participate, of whom nine completed treatment. At day 90, the median percentage reduction was -38.2% (range -51.8% to -23.5%) for GV, -54.2% (range -74.1% to -13.8%) for TV, and -27.2% (range -61.5% to -7.5%) for TV/GV (all p < 0.0001). At 6 mo, while GV had returned to baseline (p = 0.95) both TV (-31.9%; p = 0.0007) and TV/GV (-28.7%; p = 0.0009) remained significantly reduced. This reduction was sustained at 18 months (TV -18%, TV/GV -23.8%; p = 0.01). European Organization for Research and Treatment of Cancer QoL core 30-item questionnaire scores for global, physical, role, and social functioning decreased during treatment, but all were recovering by 6 weeks. EQ-VAS scores were unchanged compared to baseline.ConclusionsTAPS01 has demonstrated feasibility and patient tolerability for short-term ATT in men on AS. Our data suggest a selective and durable antitumour effect in the short term and support a larger-scale randomised trial.Patient summaryWe investigated the feasibility of short-term treatment with an androgen inhibitor to prevent or delay disease progression for men on active surveillance for prostate cancer. Results for a small group of patients show that 90-day treatment led to a sustained decrease in tumour volume over 18 months. The findings warrant a larger clinical trial for this approach, which could allow patients to delay or even avoid longer-term active treatments.

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Targeted alpha therapy in a systemic mouse model of prostate cancer - a feasibility study.

Publications

Targeted alpha therapy in a systemic mouse model of prostate cancer - a feasibility study.

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