Radiohybridization Imaging of HER2 Oncogene to Detect Breast Cancer

HER2 癌基因放射杂交成像检测乳腺癌

• 批准号: 7536308
• 负责人: Brian David Gray
• 金额: $ 11.58万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-02 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536308
• 关键词: All Sites; Animal Experiments; Animal Model; Base Sequence; Benign; Biopsy; Blood; Breast; Breast Cancer Cell; CCND1 gene; Cancer Etiology; Cells; Cessation of life; Chelating Agents; Contralateral; Cytoplasm; Detection; Diagnosis; Diffuse; Discipline of Nuclear Medicine; Doxorubicin; ERBB2 gene; Effectiveness; Epidermal Growth Factor Receptor; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Figs - dietary; Future; Genetic; Human; IGF1 gene; IGF1R gene; IRS1 gene; Image; Injection of therapeutic agent; Insulin-Like Growth Factor I; Invasive; KRAS2 gene; Kidney; Lesion; Life; Liver; MCF7 cell; Malignant - descriptor; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammography; Measurement; Measures; Messenger RNA; Metabolic; Monitor; Mus; Muscle; Nucleic Acid Probes; Nucleic acid sequencing; Oncogenes; Organ; Other Agency or Organization; Peptide Nucleic Acids; Peptides; Phase; Photons; Positron; Positron-Emission Tomography; Procedures; Progesterone Receptors; Proteins; Public Health; RNA; Radioisotopes; Range; Relative (related person); Reporter; Scanning; Signal Transduction; Site; Slide; Staining method; Stains; TP53 gene; Tail; Tamoxifen; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Veins; Week; Woman; Xenograft procedure; analog; base; cancer cell; chemotherapy; cost; design; imaging probe; insulin receptor substrate 1 protein; malignant breast neoplasm; molecular imaging; new technology; peptide analog; receptor; response; tumor; uptake

DESCRIPTION (provided by applicant): Aggressive, invasive breast cancer will attack >180,000 women in the US in 2007, and will take the lives of >40,000 women. Mammograms detect lumps in breasts, H80% of which are benign, and H20% are malignant. Lumps are biopsied to determine whether they are benign or malignant. But biopsies do not determine which oncogenes are activated, and do not reliably diagnose estrogen-dependent vs. estrogen-independent breast cancer. The cells in malignant lumps divide frequently due to mutational activation of cancer genes. We have designed and demonstrated a novel technology to see visualize hyperactive cancer genes from outside the body, which we call radiohybridization imaging (RHI). RHI scans the entire breast to find all sites of cancer gene activation, whether or not a lump has formed. RHI probes are peptide nucleic acid (PNA) sequences that hybridize specifically to messenger RNAs (mRNAs) copied from activated cancer genes. We added a small peptide analog to allow the RHI probes to be taken up by the breast cancer cells. Finally, we chelated radionuclides to permit external imaging by positron emission tomography (PET) scanning. RHI probes for CCND1, IRS1, MYCC, and KRAS mRNAs, injected into animal models, enabled us to visualize breast cancer, pancreas cancer, and prostate cancer xenografts. High levels of human epidermal growth factor receptor 2 (Her2) protein are associated with aggressive, invasive, estrogen-independent breast cancers. Measurements of HER2 mRNA demonstrated that Her2+ breast cancer cells express thousands of HER2 mRNAs per cell, while Her2- breast cancer cells express much less. We hypothesize that external radiohybridization imaging of HER2 oncogene expression will detect aggressive Her2+ breast cancers noninvasively, enabling faster, more accurate, more cost-effective diagnosis. Phase 1: Milestone 1: We will synthesize and purify a HER2 mRNA RHI agent and mismatch controls to e95% purity. Milestone 2: We will determine whether or not the HER2 mRNA RHI agent will show e3-fold greater accumulation in human Her2+ breast cancer cells in culture, vs. mismatch controls. Phase 2: Milestone 1: We will optimize the sensitivity of the HER2 mRNA RHI agent, vs. mismatch controls, in human Her2+ and Her2- breast cancer xenografts by varying the specific activity over a wide range, in order to achieve e3-fold greater PET image contrast in the xenografts, relative to normal contralateral tissue. Milestone 2: We will determine which agent, among macrocyclic chelators, oligolysines, and IGF1 analogs, will reduce nonspecific organ uptake by e2-fold. Milestone 3: We will determine whether radiohybridization imaging of HER2 mRNA following chemotherapy in Her2+ transgenic mice that develop spontaneous breast cancers will show e2-fold decrease in PET image contrast in the tumor, relative to normal contralateral tissue, vs. Her2- control mice, as a response to chemotherapeutic interdiction of proliferation. RHI measurement of HER2 mRNA levels will be compared with FDG measurement of metabolic activity over time. PUBLIC HEALTH RELEVANCE: We propose to develop a genetic nuclear medicine procedure to detect hyperactive breast cancer genes from outside the body. We intend to identify developing breast cancers before they form a tumor. In animal models, we will test for the possibility of breast cancer gene signals from tissues that are really benign, and for lack of breast cancer gene signals from tissues that are really malignant. In the future, imaging multiple breast cancer genes might diagnose estrogen-dependent vs. estrogen-independent breast cancer without an invasive procedure.

描述（由申请人提供）：2007年，侵袭性、浸润性乳腺癌将侵袭美国> 180，000名妇女，并将夺去> 40，000名妇女的生命。乳房X光检查发现乳房肿块，其中H80%为良性，H20%为恶性。对肿块进行活组织检查以确定它们是良性的还是恶性的。但是活组织检查不能确定哪些癌基因被激活，也不能可靠地诊断雌激素依赖性乳腺癌和雌激素非依赖性乳腺癌。恶性肿块中的细胞由于癌基因的突变激活而频繁分裂。我们已经设计并展示了一种新的技术，可以从体外观察过度活跃的癌症基因，我们称之为放射性杂交成像（RHI）。RHI扫描整个乳房，以找到癌症基因激活的所有位点，无论是否形成肿块。RHI探针是肽核酸（PNA）序列，其与从活化的癌基因复制的信使RNA（mRNA）特异性杂交。我们添加了一个小肽类似物，使RHI探针被乳腺癌细胞吸收。最后，我们螯合放射性核素，允许外部成像的正电子发射断层扫描（PET）扫描。将CCND 1、IRS 1、MYCC和KRAS mRNA的RHI探针注射到动物模型中，使我们能够可视化乳腺癌、胰腺癌和前列腺癌异种移植物。高水平的人表皮生长因子受体2（Her 2）蛋白与侵袭性、侵袭性、雌激素非依赖性乳腺癌相关。HER 2 mRNA的测量表明，HER 2+乳腺癌细胞表达数千HER 2 mRNA每个细胞，而HER 2-乳腺癌细胞表达少得多。我们假设，HER 2癌基因表达的外部放射性杂交成像将检测侵略性HER 2+乳腺癌非侵入性，使更快，更准确，更经济有效的诊断。第1阶段：里程碑1：我们将合成并纯化HER 2 mRNA RHI试剂和错配对照，使其纯度达到95%。里程碑二：我们将确定HER 2 mRNA RHI试剂在培养的人Her 2+乳腺癌细胞中的积累是否比错配对照高出e3倍。第二阶段：里程碑1：我们将通过在宽范围内改变比活性来优化HER 2 mRNA RHI试剂与错配对照相比在人Her 2+和Her 2-乳腺癌异种移植物中的灵敏度，以实现异种移植物中相对于正常对侧组织的e3倍更高的PET图像对比度。里程碑二：我们将确定大环螯合剂，寡聚赖氨酸和IGF 1类似物中的哪种药物将减少非特异性器官摄取E2倍。里程碑3：我们将确定在发生自发性乳腺癌的Her 2+转基因小鼠中化疗后HER 2 mRNA的放射杂交成像是否显示肿瘤中PET图像对比度相对于正常对侧组织与Her 2对照小鼠降低e2倍，作为对化疗阻断增殖的响应。将HER 2 mRNA水平的RHI测量值与代谢活性随时间的FDG测量值进行比较。公共卫生相关性：我们建议开发一种遗传核医学程序，从体外检测乳腺癌基因。我们打算在乳腺癌形成肿瘤之前识别它们。在动物模型中，我们将测试乳腺癌基因信号是否来自真正良性的组织，以及是否缺乏乳腺癌基因信号来自真正恶性的组织。在未来，对多个乳腺癌基因进行成像可能会在没有侵入性手术的情况下诊断雌激素依赖性乳腺癌与雌激素非依赖性乳腺癌。