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）：侵略性，侵入性乳腺癌将在2007年在美国攻击> 18万名妇女，并将夺走> 40,000名妇女的生命。乳房X线照片检测乳房中的肿块，其中H80％是良性的，H20％是恶性的。团块进行活检以确定它们是良性还是恶性。但是活检并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与雌激素非依赖性乳腺癌。由于癌症基因的突变激活，恶性肿瘤中的细胞经常分裂。我们设计并展示了一种新型技术，可以看到体外外部的多活跃癌基因，我们称之为放射杂交成像（RHI）。 RHI扫描整个乳房以找到癌症基因激活的所有部位，无论是否形成了肿块。 RHI探针是肽核酸（PNA）序列，该序列与从活化的癌症基因复制的Messenger RNA（mRNA）专门杂交。我们添加了一个小的肽类似物，以使RHI探针被乳腺癌细胞吸收。最后，我们螯合放射性核素以通过正电子发射断层扫描（PET）扫描允许外部成像。注射动物模型的CCND1，IRS1，MYCC和KRAS mRNA的RHI探针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（HER2）蛋白与侵略性，侵入性，雌激素无关的乳腺癌有关。 HER2 mRNA的测量表明，HER2+乳腺癌细胞每个细胞表达成千上万的HER2 mRNA，而HER2-乳腺癌细胞的表达较少。我们假设HER2致癌基因表达的外部放射杂交成像将无创攻击性HER2+乳腺癌癌，从而更快，更准确，更精确，更具成本效益。第1阶段：里程碑1：我们将合成并净化HER2 mRNA RHI剂，并匹配不匹配的对照到e95％纯度。里程碑2：我们将确定HER2 mRNA RHI剂是否会显示在培养中人类HER2+乳腺癌细胞中E3倍的积累，与错配对照相比。第2阶段：里程碑1：我们将通过在广泛的范围内改变特异性活性来优化HER2 mRNA RHI剂与失配对照，以使E3倍的PET图像对比正常的对比组织，以实现E3倍的PET图像对比。里程碑2：我们将确定在大环螯合剂，低聚酶和IGF1类似物中的哪种药物将减少E2倍的非特异性器官摄取。里程碑3：我们将确定在HER2+转基因小鼠中化学疗法后HER2 mRNA的放射性杂交成像是否会在肿瘤的PET图像对比度中显示E2倍降低，相对于正常的对比组织，VS. HER2-对照小鼠，作为对化学疗法的响应，是对化学疗法的反应。随着时间的流逝，将将HER2 mRNA水平的RHI测量与FDG测量的代谢活性进行比较。公共卫生相关性：我们建议开发一种遗传核医学程序，以检测体外外部的乳腺癌基因。我们打算在形成肿瘤之前鉴定出乳腺癌。在动物模型中，我们将测试来自真正良性的组织的乳腺癌基因信号，并且由于缺乏真正恶性的组织的乳腺癌基因信号。将来，在没有侵入性手术的情况下，成像多个乳腺癌基因可能诊断雌激素依赖性与雌激素独立的乳腺癌。