Fluciclovine 18F

点击上方蓝字 关注我们 编者按：近年来，去势抵抗性前列腺癌（CRPC）的治疗取得了显著进步；同时，前列腺特异性膜抗原（PSMA）作为前列腺癌分子成像和治疗靶点，也已经取得了突破性进展，如：PSMA-PET成像可显著提高前列腺癌定位精确程度，177Lu-PSMA-617为前列腺癌患者带来全新治疗策略等等。近期，Nature子刊发表了一篇综述，总结了当前PSMA表达、调控及其异质性的研究，并分析了临床应用前景。本刊特别整理，以期为精准治疗提供更多思路。 前列腺中的PSMA表达 前列腺是由上皮组织和纤维肌肉基质组成的外分泌腺（图1）。在微观层面上，PSMA主要在腔上皮的分泌细胞中表达，尤其是在AR阳性的腔上皮细胞中；而基质细胞和少量神经内分泌细胞几乎不表达PSMA。尽管PSMA不在正常血管的内皮细胞中表达，但在多种实体肿瘤的血管生成过程中可以上调，包括乳腺癌、肾癌和前列腺癌等。 图1 前列腺腔上皮中的PSMA表达 靶向PSMA的诊断和治疗方案 通过放射性标记，PSMA-PET/CT可将PSMA表达可视化。但应注意，PSMA假阳性可能出现于软组织病变、异常血管增生、创伤或胸腺瘤等。此外，良性前列腺病变中的PSMA，特别是良性前列腺增生和前列腺上皮内瘤变，需要进一步分析。而通过对PSMA-PET/CT成像进行仔细分析，可提高诊断精度。同时，目前也正在开发多种PSMA放射性配体疗法，如表1所示。 表1 基于GUL的PSMA放射性配体 明确PSMA阳性，改善肿瘤诊断与治疗 对PSMA阳性和同质性的界定，对于筛选合适患者进行PSMA靶向治疗至关重要。研究表明，超过95%的原发性前列腺癌具有中高水平的PSMA表达，但这种PSMA高表达情况仅存在于71%的CRPC患者，而神经内分泌型前列腺癌（NEPC）患者中的比例则下降至32%（图2）。 图2 前列腺癌发展过程中的PSMA表达抑制分析 目前尚无统一的免疫组织化学（IHC）评分系统，临床上主要依赖PSMA-PET成像确定PSMA阳性状态。PSMA-PET/CT图像基于miTNM分类系统中的miPSMA评分（图3），即按照与血液、肝脏和腮腺的摄取量对比进行分级，miPSMA评分为2和3的肿瘤被认为适合PSMA-RLT治疗。 图3 确定PSMA阳性对于选择合适患者至关重要 在PET成像领域，放射性示踪剂的摄取量使用标准摄取值（SUV）进行半定量评估，不同研究使用的SUV标准不同。此外，骨转移在前列腺癌中很常见，SUVmax比值大于2.2通常用于区分恶性和良性病灶。神经内分泌型前列腺癌（NEPC）通常PSMA表达较低，因此在成像中挑战较大，不同的前列腺癌组织学变异也可能影响成像特征。 PSMA影像筛选PSMA-RLT治疗人群 PSMA阴性病灶无法保留PSMA放射性配体，因此PSMA阴性或同时存在PSMA阳性和阴性病灶的患者通常被排除在PSMA-RLT试验之外。虽然基于PSMA-PET识别PSMA阴性病灶的概念较为简单，但实际操作较为复杂，miPSMA评分为0的病灶可能难以识别。为了增强检测，部分试验使用氟脱氧葡萄糖（FDG）PET作为辅助影像方法，因为其可进一步增强筛选精确程度。此外，也有试验数据表明，放射组学与转录组学结果相符，显示RNA-seq数据具有分析PSMA调控的潜力。 区分PSMA异质性与经典肿瘤异质性 最新数据显示，PSMA阳性患者且SUVmean高于10时，177Lu-PSMA-617治疗出现缓解的几率更高。SUVmean用于衡量PSMA异质性，包括细胞、肿瘤、患者个体、空间和时间维度差异（图4）。肿瘤异质性通常是指在原发或转移性肿瘤中存在不同的细胞群，这些细胞具有不同的遗传和表型特征。PSMA的异质性可以通过免疫染色和单细胞RNA测序显示，细胞和肿瘤层面均存在PSMA表达的范围差异。2023年一项研究对52例患者的339个CRPC样本的PSMA表达进行了分类，发现存在低/阴性、异质性和均匀高表达三种模式，部分NEPC亚群也存在PSMA高表达。PSMA在CRPC中表达的谱系内时间异质性也很明显，如雄激素剥夺疗法和AR抑制剂（如恩扎卢胺）可提高AR+肿瘤的PSMA表达水平，表明CRPC在不同时间PSMA异质性的细微差别。 图4 PSMA异质性的复杂性表明需要采用更细致的方案 PSMA异质性在PSMA诊疗中的表现 PSMA-PET/CT结合了核医学与CT影像，其空间分辨率极限通常在4~5 mm，这意味着限制了肿瘤内部PSMA阳性和阴性只有距离＞4~5 mm才有可能进行明确区分。放射学结果称为“影像学层面的PSMA”，而免疫组织化学识别的PSMA称为“病理学层面的PSMA”，分辨率的差异可能导致二者异质性的产生。临床前研究显示，PSMA表达程度和PSMA+细胞比例，与肿瘤摄取与177Lu-/225Ac-PSMA-617相关的DNA损伤有关。因此，评估PSMA-PET放射配体摄取的均一性可能会改善纳入标准。 应承认，目前缺乏对“PSMA阴性”病灶的统一定义。为了提高前列腺癌转移的诊断准确性，PSMA-PET与相应的CT或MRI使用也至关重要，这会直接影响到纳入标准。未来的最佳患者选择可能会受到PSMA成像异质性及其强度的影响。结合其他生物标志物参数，如肿瘤特征、循环肿瘤细胞和循环肿瘤DNA，以及互补的PET成像数据和深度学习图像处理算法，可能有助于进一步改进。 PSMA低表达的分子特征 有研究评估了LuCaP系列PDX模型以及UW-TAN和SU2C-PCF患者队列，发现相比PSMA高表达患者，PSMA低表达患者具有显著的全局表达变化，患者的炎症反应、缺氧、上皮-间质转化以及代谢和糖酵解通路增加。 CRPC中PSMA抑制的出现凸显了寻找PSMA以外靶点的需求。目前已经开发了替代放射性配体以识别靶抗原或改进现有临床配体，包括18F-FDG、胆碱、GRPR、DHT放射性标记物和18F-fluciclovine，以及Zr-DFO-DLL3-scFv和Zr-DFO-MSTP2109A等。成纤维细胞活化蛋白（FAP）也因在CRPC基质中的过表达而成为潜在成像靶点。 PSMA相关的精准医疗未来方向 PSMA作为一种细胞表面蛋白，除了PSMA-RLT之外，还被用作其他治疗的靶点，如PSMA靶向T细胞激活剂、CAR-T细胞治疗和抗体偶联药物。为了优化这些治疗方案，需要深入研究PSMA表达水平和反应、耐药的生物标志物。结合PET成像和液体活检，可评估PSMA表达的动态变化，进行个性化治疗计划，并提前检测耐药。新兴技术如3D组织学、空间转录组学和人工智能，也有助于提高对PSMA在前列腺癌中的生物学理解，并推动更多疗法的开发。 结论 PSMA是前列腺癌的重要生物标志物和治疗靶点，广泛应用于癌症诊断和治疗。PSMA受多重基因组和表观遗传网络调控，尤其是雄激素受体（AR）的影响。然而，部分晚期前列腺癌患者因PSMA表达丧失，影响了PSMA-RLT的疗效。PSMA表达的异质性及其在转移部位以及耐药机制的复杂性，进一步增加了治疗挑战。应探索放射性同位素以外的PSMA靶向治疗途径，以提升前列腺癌治疗效果。 ▌参考文献： Bakht, Martin K., and Himisha Beltran. Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer. Nature Reviews Urology (2024): 1-20. （来源：《肿瘤瞭望-泌尿时讯》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

MONROE TOWNSHIP, N.J. & OXFORD, England--( BUSINESS WIRE )--Bracco and Blue Earth Diagnostics Ltd, a Bracco company and recognized leader in the development and commercialization of innovative PET radiopharmaceuticals, welcomes proposed changes announced on July 10, 2024, by the Centers for Medicare & Medicaid Services (CMS) for the Hospital Outpatient Prospective Payment System (OPPS) Rule. The rule is designed to improve payments for diagnostic radiopharmaceuticals for U.S. Medicare patients, and has the potential to increase access to innovative radiopharmaceuticals that have lost, or will lose, their Transitional Pass-Through payment status. Blue Earth Diagnostics has been a pioneer in championing the discussions with CMS to secure this rule change. “ We are excited about this proposed CMS rule, which will increase patient access to advanced diagnostic imaging products to inform patient management, and, at the same time, enhance industry innovation and sustainability,” said Marco Campione, Chief Executive Officer of Blue Earth Diagnostics. “ Adoption of innovative radiopharmaceutical products, and importantly, patient access to these products, has been hampered for years by limitations of the CMS payment methodology,” added Terri Wilson, President, Blue Earth Diagnostics, Inc. “ In the case of Blue Earth Diagnostics, this new proposed rule will support our entire portfolio of diagnostic imaging agents. POSLUMA ® (flotufolastat F 18) will maintain its Pass-Through payment status for diagnostic imaging radiopharmaceutical reimbursement until September 30, 2026. Upon passage of the proposed rule, Axumin ® (fluciclovine F 18), which previously lost Pass-Through status in January 2020, will gain separate payment.” The proposed OPPS rule requires further refinement over a 60-day comment period. Blue Earth Diagnostics is looking forward to continued cooperation with CMS to determine necessary details to identify the new separate payment rates (which are proposed to differ from those under Transitional Pass-Through), build a model for future adjustments and ensure successful implementation of the rule. The final rule will be issued in early November 2024 and take effect January 1, 2025. Indication and Important Safety Information About Axumin INDICATION Axumin ® (fluciclovine F 18) injection is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated blood prostate specific antigen (PSA) levels following prior treatment. IMPORTANT SAFETY INFORMATION Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out recurrent prostate cancer and a positive image does not confirm its presence. The performance of Axumin seems to be affected by PSA levels. Axumin uptake may occur with other cancers and benign prostatic hypertrophy in primary prostate cancer. Clinical correlation, which may include histopathological evaluation, is recommended. Hypersensitivity reactions, including anaphylaxis, may occur in patients who receive Axumin. Emergency resuscitation equipment and personnel should be immediately available. Axumin use contributes to a patient’s overall long-term cumulative radiation exposure, which is associated with an increased risk of cancer. Safe handling practices should be used to minimize radiation exposure to the patient and health care providers. Adverse reactions were reported in ≤ 1% of subjects during clinical studies with Axumin. The most common adverse reactions were injection site pain, injection site erythema and dysgeusia. To report suspected adverse reactions to Axumin, call 1-855-AXUMIN1 (1-855-298-6461) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Full Axumin prescribing information is available at https://www.axumin.com/prescribing-information.pdf . Indication and Important Safety Information About POSLUMA INDICATION POSLUMA ® (flotufolastat F 18) injection is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level IMPORTANT SAFETY INFORMATION Image interpretation errors can occur with POSLUMA PET. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. The performance of POSLUMA for imaging metastatic pelvic lymph nodes in patients prior to initial definitive therapy seems to be affected by serum PSA levels and risk grouping. The performance of POSLUMA for imaging patients with biochemical evidence of recurrence of prostate cancer seems to be affected by serum PSA levels. Flotufolastat F 18 uptake is not specific for prostate cancer and may occur in other types of cancer, in non-malignant processes, and in normal tissues. Clinical correlation, which may include histopathological evaluation, is recommended. Risk of Image Misinterpretation in Patients with Suspected Prostate Cancer Recurrence: The interpretation of POSLUMA PET may differ depending on imaging readers, particularly in the prostate/prostate bed region. Because of the associated risk of false positive interpretation, consider multidisciplinary consultation and histopathological confirmation when clinical decision-making hinges on flotufolastat F 18 uptake only in the prostate/prostate bed region or only on uptake interpreted as borderline. POSLUMA use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Advise patients to hydrate before and after administration and to void frequently after administration. Ensure safe handling to minimize radiation exposure to the patient and health care providers. The adverse reactions reported in ≥0.4% of patients in clinical studies were diarrhea, blood pressure increase and injection site pain. Drug Interactions: androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F 18 in prostate cancer. The effect of these therapies on performance of POSLUMA PET has not been established. To report suspected adverse reactions to POSLUMA, call 1-844-POSLUMA (1-844-767-5862) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Full POSLUMA prescribing information is available at www.posluma.com/prescribing-information.pdf . About Blue Earth Diagnostics Blue Earth Diagnostics, an indirect subsidiary of Bracco Imaging S.p.A., is a growing international molecular imaging company focused on delivering innovative, well-differentiated diagnostic solutions that inform patient care. Formed in 2014, the Company’s success is driven by its management expertise and supported by a demonstrated track record of rapid development and commercialization of positron emission tomography (PET) radiopharmaceuticals. Blue Earth Diagnostics’ expanding oncology portfolio encompasses a variety of disease states, including prostate cancer and neuro-oncology. Blue Earth Diagnostics is committed to the timely development and commercialization of precision radiopharmaceuticals for potential use in imaging and therapy. For more information, please visit: www.blueearthdiagnostics.com . About Bracco Imaging Bracco Imaging S.p.A., part of the Bracco Group, is a world-leading diagnostic imaging provider. Headquartered in Milan, Italy, Bracco Imaging develops, manufactures and markets diagnostic imaging agents and solutions. It offers a product and solution portfolio for all key diagnostic imaging modalities: X-ray imaging (including Computed Tomography-CT, Interventional Radiology, and Cardiac Catheterization), Magnetic Resonance Imaging (MRI), Contrast Enhanced Ultrasound (CEUS), and Nuclear Medicine through radioactive tracers and novel PET imaging agents to inform clinical management and guide care for cancer patients in areas of unmet medical need. Our continually evolving portfolio is completed by a range of medical devices, advanced administration systems and dose-management software. In 2019 Bracco Imaging enriched its product portfolio by expanding the range of oncology nuclear imaging solutions in the urology segment and other specialties with the acquisition of Blue Earth Diagnostics. In 2021, Bracco Imaging established Blue Earth Therapeutics as a separate, cutting-edge biotechnology vehicle to develop radiopharmaceutical therapies. Visit: www.braccoimaging.com . This press release is for U.S. audiences only