PET Imaging of Breast Cancer Using Oncogene Expression

利用癌基因表达对乳腺癌进行 PET 成像

• 批准号: 6927466
• 负责人: MATHEW laxman THAKUR
• 金额: $ 32.18万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927466
• 关键词: athymic mouse; autoradiography; bioimaging /biomedical imaging; biomarker; breast neoplasm /cancer diagnosis; breast neoplasms; cell surface receptors; clinical research; diagnosis design /evaluation; human subject; laboratory rabbit; oncogenes; patient oriented research; polymerase chain reaction; positron emission tomography; radiotracer; receptor binding; vasoactive intestinal peptide

DESCRIPTION (provided by applicant): This year, breast cancer (BC) will attack approximately 210,000 and will take the lives of 40,000 women in the U.S. Standard screening with breast self-examination and mammography, recommended to minimize BC morbidity and mortality, miss 10-20% (up to 40% in young women) of breast cancers. Moreover, if an abnormality is found, an invasive diagnostic procedure is required to determine if the breast contains hyperplasia, atypia, or cancer. Approximately 80% of invasive procedures detect a benign process. BC cells express a gene product, cell surface receptor VPAC1, so named because the endogenous growth hormones Vasoctive Intestinal Peptide (VIP) and Pituitary Adenylate Cylcase Activating Peptide (PACAP) bind to VPAC1 receptors with affinity. We have labeled two VIP analogs with Tc-99m (Tc-99m- TP3654, EC50, 15 nM and Tc-99m-TP3652, EC50, 0.8 nM) and shown in a pilot clinical study that these agents correctly and unequivocally imaged all tumors which overexpress VPAC1 receptors, including precancerous lesions in the breast, supporting our hypothesis that potent analogs of VIP and PACAP candetect cancer at an early stage. We have prepared two additional analogs (Tc-99m-TP3871, EC50, 0.45 Nm and Tc-99m-TP3475, EC50, 1.5 nM) with improved receptor affinity and more favorable structural conformation for better in vivo stability. Furthermore, we have labeled VIP analog (TP3654) with p+ emitter Cu-64, which improved BC uptake by 85-fold. These results, compounded by the high resolution and sensitivity of PET, have prompted us to undertake a systematic investigation to develop a PET molecular imaging technique that will 1) target early BC, 2) distinguish between hyperplastic ductal epithelium (normal image) and atypical hyperplasia and invasive cancer (positive image), 3) minimize the number of unnecessary invasive procedures, and 4) permit clinicians to treat precancerous mastopathy (atypia and in situ cancer) or invasive cancer with preventive or therapeutic agents, respectively, to decrease morbidity and mortality associated with progressing disease. The study will 1) systematically evaluate four analogs for critical imaging parameters, 2) determine the specificity of a lead agent in differentiating pre- and invasive BC from normal breast tissue ex vivo by autoradiography and RT-PCR, 3) perform preclinical toxicity studies in animals, and 4) examine its ability to correctly identify tumors which over express VPAC1 receptors by PET imaging.

描述（由申请人提供）： 今年，乳腺癌 (BC) 将袭击约 210,000 名美国女性，并夺走 40,000 名女性的生命。建议采用乳房自检和乳房 X 光检查进行标准筛查，以尽量减少 BC 发病率和死亡率，漏诊率达 10-20%（高达 40 %（年轻女性）乳腺癌。 此外，如果发现异常，则需要进行侵入性诊断程序以确定乳房是否存在增生、异型性或癌症。大约 80% 的侵入性手术检测到良性过程。 BC细胞表达一种基因产物——细胞表面受体VPAC1，如此命名是因为内源性生长激素血管活性肠肽（VIP）和垂体腺苷酸环化酶激活肽（PACAP）与VPAC1受体具有亲和力结合。我们用 Tc-99m 标记了两种 VIP 类似物（Tc-99m-TP3654，EC50，15 nM 和 Tc-99m-TP3652，EC50，0.8 nM），并在一项试点临床研究中表明，这些药物可以正确、明确地对所有肿瘤进行成像。过度表达 VPAC1 受体，包括乳房癌前病变，支持我们的假设，即 VIP 和 PACAP 的有效类似物可以检测癌症处于早期阶段。我们制备了另外两种类似物（Tc-99m-TP3871，EC50，0.45 Nm 和 Tc-99m-TP3475，EC50，1.5 nM），它们具有改进的受体亲和力和更有利的结构构象，可实现更好的体内稳定性。此外，我们用 p+ 发射体 Cu-64 标记了 VIP 类似物 (TP3654)，这将 BC 吸收提高了 85 倍。这些结果，再加上 PET 的高分辨率和灵敏度，促使我们进行系统研究，开发一种 PET 分子成像技术，该技术将 1) 瞄准早期 BC，2) 区分增生性导管上皮（正常图像）和非典型增生和浸润性癌症（正图），3) 最大限度地减少不必要的侵入性手术的数量，4) 允许临床医生通过预防性治疗癌前乳腺病（异型性和原位癌）或浸润性癌症或治疗剂，以降低与疾病进展相关的发病率和死亡率。该研究将 1) 系统地评估四种类似物的关键成像参数，2) 通过放射自显影和 RT-PCR 确定主要药物在区分前体和侵袭性 BC 与离体正常乳腺组织方面的特异性，3) 进行临床前毒性研究动物，4) 通过 PET 成像检查其正确识别过度表达 VPAC1 受体的肿瘤的能力。