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: 7355546
• 负责人: MATHEW laxman THAKUR
• 金额: $ 40.4万
• 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 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355546
• 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

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人，并将在美国夺走40，000名妇女的生命。标准筛查包括乳房自我检查和乳房X光检查，建议将BC发病率和死亡率降至最低，错过10-20%（年轻女性高达40%）的乳腺癌。 此外，如果发现异常，则需要进行侵入性诊断程序以确定乳腺是否含有增生、肥大或癌症。大约80%的侵入性手术检测到良性过程。 BC细胞表达基因产物，细胞表面受体VPAC 1，如此命名是因为内源性生长激素血管收缩肠肽（VIP）和腺苷酸环化酶激活肽（PACAP）以亲和力结合VPAC 1受体。我们用Tc-99 m标记了两种VIP类似物（Tc-99 m-TP 3654，EC 50，15 nM和Tc-99 m-TP 3652，EC 50，0.8 nM），并在初步临床研究中显示，这些试剂正确且明确地使所有过表达VPAC 1受体的肿瘤成像，包括乳腺癌前病变，支持我们的假设，VIP和PACAP的有效类似物可以在早期阶段检测癌症。我们已经制备了另外两种类似物（Tc-99 m-TP 3871，EC 50，0.45 nM和Tc-99 m-TP 3475，EC 50，1.5 nM），其具有改善的受体亲和力和更有利的结构构象，以获得更好的体内稳定性。此外，我们用p+发射体Cu-64标记VIP类似物（TP 3654），其将BC摄取提高了85倍。这些结果，加上PET的高分辨率和灵敏度，促使我们进行系统的研究，以开发PET分子成像技术，1）靶向早期BC，2）区分增生的导管上皮，（正常图像）和不典型增生及浸润癌（正像），3）最小化不必要的侵入性程序的数量，以及4）允许临床医生治疗癌前乳腺病在一些实施方案中，本发明的组合物分别与预防剂或治疗剂一起用于治疗恶性肿瘤（原位癌和原位癌）或侵袭性癌症，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确定先导剂在离体区分前和侵袭性BC与正常乳腺组织中的特异性，3）在动物中进行临床前毒性研究，以及4）通过PET成像检查其正确识别过表达VPAC 1受体的肿瘤的能力。

项目成果

PET imaging of VPAC1 expression in experimental and spontaneous prostate cancer.

实验性和自发性前列腺癌中 VPAC1 表达的 PET 成像。

• DOI: 10.2967/jnumed.107.043703
• 发表时间: 2008
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Zhang,Kaijun;Aruva,MohanR;Shanthly,Nylla;Cardi,ChristopherA;Rattan,Satish;Patel,Chirag;Kim,Christopher;McCue,PeterA;Wickstrom,Eric;Thakur,MathewL
• 通讯作者: Thakur,MathewL

99mTc-Fanolesomab: affinity, pharmacokinetics and preliminary evaluation.

99mTc-Fanolesomab：亲和力、药代动力学和初步评估。

• 发表时间: 2006
• 期刊: The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...
• 作者: Shanthly,N;Aruva,MR;Zhang,K;Mathew,B;Thakur,ML
• 通讯作者: Thakur,ML

VPAC1 receptors for imaging breast cancer: a feasibility study.

用于乳腺癌成像的 VPAC1 受体：可行性研究。

• DOI: 10.2967/jnumed.112.114876
• 发表时间: 2013
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Thakur,MathewL;Zhang,Kaijun;Berger,Adam;Cavanaugh,Barbara;Kim,Sung;Channappa,Chaitra;Frangos,AndreaJ;Wickstrom,Eric;Intenzo,CharlesM
• 通讯作者: Intenzo,CharlesM