Radiohybridization Imaging of HER2 Oncogene to Detect Breast Cancer

HER2 癌基因放射杂交成像检测乳腺癌

基本信息

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
项目类别：
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

项目摘要

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、浸润性乳腺癌将袭击美国超过 180,000 名女性，并将夺走超过 40,000 名女性的生命。乳房X光检查可检测乳房肿块，其中80%是良性，20%是恶性。对肿块进行活检以确定它们是良性还是恶性。但活检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。由于癌基因的突变激活，恶性肿块中的细胞频繁分裂。我们设计并展示了一种新技术，可以从体外观察高度活跃的癌症基因，我们称之为放射杂交成像（RHI）。 RHI 扫描整个乳房以查找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，可与从激活的癌症基因复制的信使 RNA (mRNA) 特异性杂交。我们添加了一个小肽类似物，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通过正电子发射断层扫描（PET）扫描进行外部成像。将 CCND1、IRS1、MYCC 和 KRAS mRNA 的 RHI 探针注射到动物模型中，使我们能够观察乳腺癌、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- 乳腺癌细胞表达量要少得多。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 1 阶段：里程碑 1：我们将合成并纯化 HER2 mRNA RHI 试剂和错配对照，使其纯度达到 e95%。里程碑 2：我们将确定 HER2 mRNA RHI 试剂是否会在培养的人 Her2+ 乳腺癌细胞中显示出与错配对照相比高 3 倍的积累。第 2 阶段：里程碑 1：我们将通过在大范围内改变比活性，优化 HER2 mRNA RHI 试剂相对于错配对照在人类 Her2+ 和 Her2- 乳腺癌异种移植物中的敏感性，以实现 e3 倍的提高异种移植物相对于正常对侧组织的 PET 图像对比度。里程碑 2：我们将确定大环螯合剂、寡聚赖氨酸和 IGF1 类似物中的哪一种药物能够将非特异性器官摄取减少 e2 倍。里程碑 3：我们将确定，与 Her2- 对照小鼠相比，发生自发性乳腺癌的 Her2+ 转基因小鼠化疗后 HER2 mRNA 的放射杂交成像是否会显示肿瘤中 PET 图像对比度相对于正常对侧组织下降 e2 倍，作为对化疗抑制增殖的反应。 HER2 mRNA 水平的 RHI 测量值将与代谢活动随时间的 FDG 测量值进行比较。公共健康相关性：我们建议开发一种遗传核医学程序，以从体外检测过度活跃的乳腺癌基因。我们打算在乳腺癌形成肿瘤之前识别出它们。在动物模型中，我们将测试来自真正良性组织的乳腺癌基因信号的可能性，以及来自真正恶性组织的乳腺癌基因信号的缺乏的可能性。将来，对多个乳腺癌基因进行成像可能可以在不进行侵入性操作的情况下诊断雌激素依赖性乳腺癌和雌激素非依赖性乳腺癌。