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: 7681555
• 负责人: Brian David Gray
• 金额: $ 34.21万
• 依托单位: MOLECULAR TARGETING TECHNOLOGIES, INC.
• 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/7681555
• 关键词: 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; Gene Activation; Genetic; Human; IGF1 gene; IGF1R gene; IRS1 gene; Image; Injection of therapeutic agent; 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; Peptide Nucleic Acids; Peptides; Phase; Photons; Positron; Positron-Emission Tomography; Procedures; Progesterone Receptors; Proteins; RNA; Radioisotopes; Relative (related person); Reporter; Scanning; Signal Transduction; Site; Slide; Staining method; Stains; TP53 gene; Tail; Tamoxifen; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Veins; Woman; Xenograft procedure; analog; base; cancer cell; chemotherapy; cost; design; effective therapy; imaging probe; malignant breast neoplasm; molecular imaging; new technology; peptide analog; public health relevance; 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、侵袭性乳腺癌在美国将侵袭18万名妇女，并将夺去4万名妇女的生命。乳房x光检查发现乳房肿块，其中80%为良性，20%为恶性。通过活检来确定肿块是良性的还是恶性的。但是活组织检查并不能确定哪些致癌基因被激活，也不能可靠地诊断雌激素依赖型和非雌激素依赖型乳腺癌。恶性肿块中的细胞由于癌基因的突变激活而频繁分裂。我们设计并展示了一种新的技术，可以从体外看到过度活跃的癌症基因，我们称之为放射杂交成像（RHI）。RHI扫描整个乳房，找到所有癌症基因激活的部位，无论肿块是否已经形成。RHI探针是肽核酸（PNA）序列，与从活化的癌症基因复制的信使rna （mrna）特异性杂交。我们添加了一个小的肽模拟物，使RHI探针能够被乳腺癌细胞吸收。最后，我们螯合放射性核素，以允许外部成像的正电子发射断层扫描（PET）扫描。将CCND1， IRS1， 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，胰腺癌和前列腺癌的异种移植。高水平的人表皮生长因子受体2 （Her2）蛋白与侵袭性、侵袭性、不依赖雌激素的乳腺癌有关。HER2 mRNA的测量表明，HER2 +乳腺癌细胞每个细胞表达数千个HER2 mRNA，而HER2 -乳腺癌细胞表达较少。我们假设HER2癌基因表达的外部放射杂交成像将无创地检测侵袭性HER2 +乳腺癌，从而实现更快、更准确、更具成本效益的诊断。第一阶段：里程碑1：我们将合成并纯化HER2 mRNA RHI试剂和错配对照，纯度为95%。里程碑2：我们将确定HER2 mRNA RHI制剂是否会在培养的人类HER2 +乳腺癌细胞中显示比错配对照高e3倍的积累。第2阶段：里程碑1：我们将优化HER2 mRNA RHI剂在人类HER2 +和HER2 -乳腺癌异种移植物中与错配对照相比的敏感性，通过在大范围内改变特异性活性，以实现与正常对侧组织相比，异种移植物的PET图像对比度提高3倍。里程碑2：我们将确定在大环螯合剂、低聚氨酸和IGF1类似物中，哪种药物将使非特异性器官摄取减少2倍。里程碑3：我们将确定HER2 +转基因小鼠发生自发性乳腺癌化疗后的HER2 mRNA放射杂交成像是否会显示肿瘤PET图像对比度降低2倍，相对于正常的对侧组织，与HER2对照小鼠相比，作为化疗抑制增殖的反应。RHI测量的HER2 mRNA水平将与FDG测量的代谢活性随时间的变化进行比较。公共卫生相关性：我们建议发展一种遗传核医学程序，从体外检测过度活跃的乳腺癌基因。我们打算在发展中的乳腺癌形成肿瘤之前识别出来。在动物模型中，我们将测试从真正良性的组织中获得乳腺癌基因信号的可能性，以及从真正恶性的组织中缺乏乳腺癌基因信号的可能性。在未来，多种乳腺癌基因成像可能会诊断雌激素依赖型和雌激素依赖型乳腺癌，而无需侵入性手术。