PET Imaging of Breast Cancer Using Oncogene Expression

利用癌基因表达对乳腺癌进行 PET 成像

基本信息

批准号：
7213242
负责人：
MATHEW laxman THAKUR
金额：
$ 43.38万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213242
关键词：
Adult Affinity Animals Antibodies Anxiety Atypia Atypical hyperplasia Autoradiography Benign Binding Biological Biological Assay Biopsy Blood Breast Breast Cancer Cell Breast Cancer Early Detection Breast Self-Examination Cancerous Carcinoma in Situ Cell Line Cell Surface Receptors Cell surface Cells Characteristics Chemopreventive Agent Classification Clinical Research Complex Condition Correlation Studies Data Diagnosis Diagnostic Diagnostic Procedure Disease Drug Kinetics Drug or chemical Tissue Distribution Ductal Epithelium Early Diagnosis Enrollment Epithelium Evaluation Excision biopsy Feasibility Studies Future Gene Expression Goals Gold Hematoma Hen Egg Lysozyme Histologic Histology Hormones Human Hyperplasia Image Imaging Techniques Immunohistochemistry In Vitro Infection Inhibitory Concentration 50 Injection of therapeutic agent Intestines Invasive Invasive Lesion Investigation Knowledge Label Lead Lesion Life Malignant - descriptor Malignant Neoplasms Mammary Gland Parenchyma Mammography Mastectomy Measures Molecular Conformation Molecular Genetics Morbidity - disease rate Mus Muscle relaxation phase Myomatous neoplasm Names Nature Neoplasm Metastasis Normal tissue morphology Numbers Oncogenes Oryctolagus cuniculus Palpable Pathologic Pathologist Pathology Patients Peptides Pituitary Gland Population Positron-Emission Tomography Premalignant Preventive Principal Investigator Procedures Process Protein Overexpression Proteins Puncture biopsy Purpose Quantitative Autoradiography Radiation Radioactivity Radiometry Receptor Gene Research Ethics Committees Resolution Reverse Transcriptase Polymerase Chain Reaction Risk Sampling Score Screening procedure Somatotropin Specificity Specimen Staging Standards of Weights and Measures TP 3654 Tail Technetium 99m Techniques Testing Therapeutic Agents Thick Time Tissue Sample Tissues Toxic effect Urine Vasoactive Intestinal Peptide Woman adenylate analog base cancer cell cell transformation chemotherapeutic agent cost human study improved in vivo malignant breast neoplasm molecular imaging mortality novel peptide analog pituitary adenylate cyclase activating polypeptide pre-clinical programs receptor receptor density receptor expression tumor uptake vasoactive intestinal peptide receptor 1 volunteer

项目摘要

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）将攻击约210,000人，并通过乳房自我检查和乳房X线摄影术中40,000名妇女的生命，建议最大程度地减少BC的发病率和死亡率，乳房癌症的10-20％（年轻女性最高40％）的乳房癌症。此外，如果发现异常，则需要进行侵入性诊断程序，以确定乳房是否含有增生，非洲裔或癌症。大约80％的入侵程序检测到良性过程。 BC细胞表达基因产物细胞表面受体VPAC1，之所以命名，是因为内源性生长激素血管闭塞性肠道肽（VIP）和垂体腺苷酸胞裂激活肽（PACAP）与亲和力结合VPAC1受体。 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早期的VIP和PACAP糖果癌的类似物。我们已经准备了两个其他类似物（TC-99M-TP3871，EC50、0.45 nm和TC-99M-TP3475，EC50、1.5 nm），具有改善的受体亲和力和更有利的结构构象，可更好地体内稳定性。此外，我们用P+发射极CU-64标记了VIP模拟（TP3654），该铜的摄入量提高了85倍。这些结果是由PET的高分辨率和敏感性加剧的，促使我们进行系统的研究，以开发一种PET分子成像技术，该技术将以1）为目标。分别具有预防或治疗剂的乳腺病（异型和原位癌）或侵入性癌症，以降低与进展疾病相关的发病率和死亡率。该研究将1）系统地评估四个类似物的关键成像参数，2）确定铅剂在区分前和侵入性BC与正常乳腺组织与正常乳腺组织的特异性通过自放射摄影和RT-PCR的体外，3）3）3）3）进行彻底毒性研究，以及在动物中进行抗pepAccectors pet teper vpaC 1的能力。