PET Imaging of Breast Cancer Using Oncogene Expression

描述(由申请人提供)： 今年，乳腺癌(BC)将发病约210,000人，并将夺走美国40,000名妇女的生命。标准筛查与乳房自我检查和乳房X光检查，建议将乳腺癌的发病率和死亡率降至最低，漏诊10-20%(年轻女性高达40%)的乳腺癌。 此外，如果发现异常，需要进行侵入性诊断程序，以确定乳房是否含有增生、非典型性或癌症。大约80%的侵入性手术可以检测到良性病变。BC细胞表达一种基因产物，细胞表面受体VPAC1，因为内源性生长激素血管活性肠肽(VIP)和垂体腺样囊泡活化肽(PACAP)与VPAC1受体亲和力结合而得名。我们已经用TC-99m标记了两个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，这些试剂正确和明确地成像了所有过度表达VPAC1受体的肿瘤，包括乳腺癌前病变，支持了我们的假设，即VIP和PACAP的有效类似物可以早期发现癌症。我们另外制备了两个类似物(TC-99m-TP3871，EC50，0.45 Nm和TC-99m-TP3475，EC50，1.5 NM)，它们的受体亲和力提高，结构构象更有利，具有更好的体内稳定性。此外，我们还用p+发射极铜标记了血管活性肠肽类似物(TP 3654)，使BC摄取提高了85倍。这些结果，再加上PET的高分辨率和敏感性，促使我们开展了一项系统的研究，以开发一种PET分子成像技术，该技术将1)针对早期BC，2)区分增生性导管上皮(正常图像)与不典型增生和浸润性癌(阳性图像)，3)最大限度地减少不必要的侵袭性手术，以及4)允许临床医生分别使用预防或治疗药物治疗癌前病变(非典型性和原位癌)或浸润性癌，以降低与疾病进展相关的发病率和死亡率。这项研究将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确定先导剂在区分乳腺癌前期和侵袭性乳腺组织与体外正常乳腺组织中的特异性，3)在动物身上进行临床前毒性研究，4)检验其通过PET成像正确识别过度表达VPAC1受体的肿瘤的能力。

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.