Targeted Inhibition of Prostate Cancer Metastases with an RNA Aptamer to Prostate-specific Membrane Antigen

Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed to effectively treat some cancers. However, many cancers such as metastatic prostate cancer (PC) have yet to be treated with current smart drug technology. Here, we describe the thorough preclinical characterization of an RNA aptamer (A9g) that functions as a smart drug for PC by inhibiting the enzymatic activity of prostate-specific membrane antigen (PSMA). Treatment of PC cells with A9g results in reduced cell migration/invasion in culture and metastatic disease in vivo. Importantly, A9g is safe in vivo and is not immunogenic in human cells. Pharmacokinetic and biodistribution studies in mice confirm target specificity and absence of non-specific on/off-target effects. In conclusion, these studies provide new and important insights into the role of PSMA in driving carcinogenesis and demonstrate critical endpoints for the translation of a novel RNA smart drug for advanced stage PC.     

血清前列腺特异性抗原在前列腺癌筛查中的价值

目的:探讨血清前列腺特异性抗原筛查前列腺癌的价值。方法:采用化学发光免疫分析技术检测4 255名珠海市50岁以上男性的血清PSA含量,对PSA值>4.0μg/L的被检者进行穿刺活检或手术。结果:随着年龄增加,血清PSA浓度的增高,前列腺癌的发病率提高。通过血清PSA筛查,可以检出早期前列腺癌,占检出前列腺癌的94.4%。结论:应用血清PSA筛查前列腺癌可以早期、敏感发现可治愈的局限性的前列腺癌,临床意义重大。     

Prostate Cancer Theranostics Targeting Gastrin-Releasing Peptide Receptors

Gastrin-releasing peptide receptors (GRPRs), part of the bombesin (BBN) family, are aberrantly overexpressed in many cancers, including those of the breast, prostate, pancreas, and lung, and therefore present an attractive target for cancer diagnosis and therapy. Different bombesin analogs have been radiolabeled and used for imaging diagnosis, staging, evaluation of biochemical recurrence, and assessment of metastatic disease in patients with prostate cancer. Recently, interest has shifted from BBN-like receptor agonists to antagonists, because the latter does not induce adverse effects and demonstrate superior in vivo pharmacokinetics. We review the preclinical and clinical literatures on the use of GRPRs as targets for imaging and therapy of prostate cancer, with a focus on the newer developments and theranostic potential of GRPR peptides.     

前列腺特异性膜抗原PET/MRI在前列腺癌中的应用现状与前景

前列腺癌(prostate cancer, PCa)是常见的老年男性恶性肿瘤,并是其主要致死原因之一。前列腺特异性膜抗原(prostate specific membrane antigen, PSMA)是一种PCa组织特异性高表达的跨膜蛋白,这使得PSMA成为PCa良好的特异性分子影像靶点。目前,PSMA PET/CT在PCa诊断、分期等方面的价值已被广泛认可。随着PET/MRI逐步进入临床,PSMA PET与MRI两种诊断PCa的重要影像学方法的有机结合成为可能。本文就PSMA PET/MRI在PCa中的应用现状与前景进行阐述,以期为临床诊疗提供借鉴。     

复合前列腺特异性抗原在前列腺癌诊断中的应用

目的探讨复合前列腺特异性抗原（cPSA）及cPSA/tPSA比值在前列腺癌（PCa）诊断中的应用价值。方法分析PCa患者22例、前列腺增生（BPH）患者48例及前列腺正常对照组50例患者的tPSA、cPSA及cPSA/tPSA比值,并进行统计学分析。结果 PCa组的tPSA和cPSA浓度明显高于BPH组,差异具有统计学意义（P〈0.05）;cPSA/tPSA比值在对照组与PCa组及BPH组与PCa组之间的差异均具有统计学意义（P〈0.01）。结论 cPSA与tPSA均可筛选及早期发现PCa,结合cPSA/tPSA比值可以更有效地提高对PCa诊断的准确率。     

游离与总前列腺特异抗原检测在前列腺癌诊断中的应用

目的研究血清游离前列腺特异抗原(FPSA)与总前列腺特异抗原(TPSA)比值对前列腺癌患者的诊断价值。方法用电化学发光免疫分析法检测54例前列腺增生(BPH),32例前列腺癌(Pca)和38例正常男性的血清FPSA、TPSA含量,并计算FPSA/TPSA比值,讨论它们对前列腺癌的诊断意义。结果单独以血清TPSA大于4.0μg/L作为前列腺癌的诊断标准,其敏感性和特异性分别为85.0%,76.2%。以FPSA/TPSA小于0.11作为前列腺癌的诊断限定值,当血清TPSA小于4.0μg/L时,FPSA/TPSA比值的敏感性和特异性分别为98.0%,68.1%;当血清TPSA大于10.0μg/L时,FPSA/TPSA比值的敏感性和特异性分别为68.5%,69.1%;而当血清TPSA在4.0￣10.0μg/L时,FPSA/TPSA比值的敏感性和特异性分别为95.3%,90.5%。结论当血清TPSA在4.0￣10.0μg/L时,FPSA/TPSA比值可大大提高前列腺癌诊断的准确率。     

超声测量移行区前列腺特异性抗原密度对前列腺癌的诊断价值

目的阐明移行区前列腺特异性抗原密度(PS ATZ)对前列腺癌(Pca)的诊断价值.方法对于血清前列腺特异性抗原(PSA)值处于灰值区的54例Pca和114例前列腺增生(BPH)患者进行经直肠超声检查,并穿刺活检.通过与血清PSA和前列腺特异性抗原密度(DPSA)对比,分析PSATZ和PSA指数(PSAI)的敏感性和特异性.结果 (1)与血清PSA 、DPSA 、PSAI相比,PSATZ是最佳的Pca检测指标, 具有最大的约登指数、ROC曲线下面积和最高的特异性;(2)PSATZ的最佳临界值是0.5 ng/ (ml·cm3),可作为疑似Pca的穿刺活检指标.结论 PSATZ法明显优于血清PSA、DPSA和PSAI法.在进行早期Pca筛选时, 应在经直肠超声检查的基础上,对于PSATZ大于0.5 ng/(ml·cm3) 的病例进行穿刺活检.     

经直肠前列腺超声造影靶向活检诊断前列腺癌的可行性研究

目的评价超声造影对前列腺癌(PCa)的诊断价值,探讨PCa靶向活检(TB)的可行性。方法对164例前列腺特异度抗原(PSA)水平≥4ng/ml患者,在接受前列腺活检前行前臂静脉注射声诺维2.4ml (29.5μg),经直肠超声(TRUS)前列腺超声造影(CEUS)检查,评估CEUS的声像图表现。对92例CEUS显示前列腺异常灌注区行TB;并对260例PSA≥4ng/ml患者行前列腺系统活检(SB),然后对TB和SB的病理结果进行对比分析。结果 92例CEUS显示前列腺异常灌注区的患者于TRUS引导下行TB,平均每位患者取活检标本12.6条,病理诊断PCa阳性率66.3%(61/92),未见癌细胞33.7%(31/92);SB病理诊断PCa 19.6%(51/260),未见癌细胞199例76.5%(199/260),TB对PCa检出率明显高于SB的19.6%(优势比=3.3,P=0.002 7)。CEUS提示PCa的声像图表现多种多样:强对比增强、快速对比增强、血管灌注异常和低对比增强。结论 TRUS引导下CEUS靶向活检,可提高组织材料的质量,使患者避免不必要的穿刺,减少穿刺次数,从而提高PCa的诊断率,超声造影TB和SB结合,可以获得PCa较高的检出率,有较高的临床应用价值。     

Accurate Use of Prostate-Specific Antigen in Determining Risk of Prostate Cancer

Measuring the level of prostate-specific antigen (PSA) in serum is used as a screening tool for prostate cancer. As more research results on improving the specificity and sensitivity of PSA testing become available, primary care providers will be provided with other methods to indicate when a urology referral is needed. The belief that the normal range is 0 to 4 ng/mL has not been supported by research. Multiple factors such as age, medication, and inflammatory processes can affect PSA level. Risk factors increase the patient's probability of developing prostate cancer. With no standard screening recommendations for prostate cancer, the provider has a greater responsibility to interpret results properly. Implications for practice are discussed.     

低血清前列腺特异抗原型高危前列腺癌的临床特征

目的:提高对低血清前列腺特异抗原(PSA)型高危前列腺癌的认识及诊疗水平。方法:回顾分析8例低PSA型高危前列腺癌患者的临床资料。结果:8例患者入院平均PSA值为2.14ng/mL;7例患者肛指检查异常;穿刺病理诊断腺癌6例(其中1例为导管腺癌),小细胞癌2例;行Gleason评分者5例,均>7分;T3期以上患者占75%,5例有远处转移。对2例前列腺小细胞癌行内分泌治疗,其中1例再行化疗;对6例前列腺癌,1例行内分泌治疗加根治性放疗,1例行前列腺癌根治术加内分泌辅助治疗,其余4例均行内分泌治疗。平均随访19.5个月,8例患者中3例死亡,4例病情进展,1例病情无进展。结论:低PSA型高危前列腺癌起病隐匿,恶性程度较高,诊断及监测不依赖于PSA,治疗效果不佳,需引起足够重视。     

Prostate Stem Cell Antigen DNA Vaccination Breaks Tolerance to Self-antigen and Inhibits Prostate Cancer Growth

Prostate stem cell antigen (PSCA) is a cell surface antigen expressed in normal human prostate and over expressed in prostate cancer. Elevated levels of PSCA protein in prostate cancer correlate with increased tumor stage/grade, with androgen independence and have higher expression in bone metastases. In this study, the PSCA gene was isolated from the transgenic adenocarcinoma mouse prostate cell line (TRAMPC1), and a vaccine plasmid construct was generated. This plasmid PSCA (pmPSCA) was delivered by intramuscular electroporation (EP) and induced effective antitumor immune responses against subcutaneous TRAMPC1 tumors in male C57 BL/6 mice. The pmPSCA vaccination inhibited tumor growth, resulting in cure or prolongation in survival. Similarly, the vaccine inhibited metastases in PSCA expressing B16 F10 tumors. There was activation of Th-1 type immunity against PSCA, indicating the breaking of tolerance to a self-antigen. This immunity was tumor specific and was transferable by adoptive transfer of splenocytes. The mice remained healthy and there was no evidence of collateral autoimmune responses in normal tissues. EP-assisted delivery of the pmPSCA evoked strong specific responses and could, in neoadjuvant or adjuvant settings, provide a safe and effective immune control of prostate cancer, given that there is significant homology between human and mouse PSCA.     

Repeatability of [<Superscript>68</Superscript>Ga]DKFZ11-PSMA PET Scans for Detecting Prostate-specific Membrane Antigen-positive Prostate Cancer

Purpose

We studied the effect of varying specific activity of [⁶⁸Ga]DKFZ-PSMA11 ([⁶⁸Ga]DP11) on repeated imaging of prostate-specific membrane antigen-positive (PSMA+) xenograft tumors.

Procedures

Athymic nude mice bearing PC3-PIP (PSMA+) and PC3 (PSMA?) bilateral flank tumors were assessed to study intra- and inter-day repeatability of [⁶⁸Ga]DP11 imaging in mice administered [⁶⁸Ga]DP11 or [⁶⁷Ga]DP11 (as a dilution tracer) using imaging and biodistribution studies.

Results

Region of interest (ROI) analysis of the [⁶⁸Ga]DP11 imaging study indicated that the uptake was constant on the same day or consecutive days. Prior imaging with [⁶⁸Ga]DP11 did not significantly influence the subsequent uptake of [⁶⁸Ga]DP11. Uptake of [⁶⁸Ga]DP11 (60 min) and [⁶⁷Ga]DP11 (24 h) in PC3-PIP tumors was 12.37 ± 4.19 %ID/g and 12.49 ± 6.88 %ID/g, respectively; [⁶⁸Ga]DP11 was 13.83 ± 3.77 and 17.76 ± 1.84 on same-day and 15.98 ± 5.82 %ID/g on second-day imaging.

Conclusions

This study demonstrates that [⁶⁸Ga]DP11, in a given PSMA+ lesion, is constant under several same-day or serial-day imaging conditions.

     

复合PSA测定对前列腺癌诊断的临床应用价值

目的　化学发光法对复合 PSA( c PSA)测定方法的建立与应用。方法　采用化学发光技术对 1 5 8例经病理组织活检报告验证的前列腺增生 ( 5 8例 )及前列腺癌患者 ( 1 0 0例 )进行了总 PSA( t PSA)、游离PSA( f PSA)及 c PSA检测。同时选取健康成年男性 ( 90例 )作为正常对照组 ,确定了该地区健康男性 c PSA参考范围。结果　试验组 1 0 0例前列腺癌患者 c PSA和 t PSA两种指标经配对资料 χ2检验具有显著性差异 (χ2 =8.1 ,P<0 .0 1 ) ;c PSA与 f PSA/t PSA比率相比具有显著性差异 (χ2 =9.39,P<0 .0 1 )。t PSA在 4.0～ 1 0 .0 ng/ml灰区内的前列腺增生组与前列腺癌组相比 ,两组 t PSA之间无差异 ( t=1 .1 37,P>0 .0 5 ) ;两组 f PSA/t PSA百分比率相比具有一定的差异 ( t=2 .86,0 .0 1 相似文献   

Additional Targeted Biopsy in Clinically Suspected Prostate Cancer: Prospective Randomized Comparison between Contrast-Enhanced Ultrasound and Sonoelastography Guidance

Our aim was to improve the detection of prostate cancer by evaluating whether contrast-enhanced ultrasound (CEUS) or sonoelastography (SE) is more helpful in guiding targeted biopsy (TB) performed before systematic biopsy (SB). A total of 52 patients suspected of having prostate cancer were prospectively included and randomly assigned to either the CEUS or SE group. Different, independent radiologists performed TB and twelve-core SB. Within each group, cancer detection rates based on core number were compared between SB and TB. We evaluated the effect of TB on core-based cancer detection rates between the CEUS and SE groups. Cancer detection was higher in overall TB cores 16.4% (28/171) than SB cores 11.4% (71/624) in both groups. In the SE group, TB cores revealed higher cancer detection than did SB cores from 4.49% (14/312) to 12.86% (9/70) (p = 0.01). Compared with CEUS, SE may improve detection rates when considering additional TB guidance methods.     

Novel Gastrin-Releasing Peptide Receptor Targeted Near-Infrared Fluorescence Dye for Image-Guided Surgery of Prostate Cancer

Molecular Imaging and Biology - Prostate cancer (PCa), the most widespread male cancer in western countries, is generally eradicated by surgery, especially if localized. However, during surgical...