PET Imaging of KRAS2 Activation to Guide EGFR Targeting in Cancer Therapy

KRAS2 激活的 PET 成像指导癌症治疗中的 EGFR 靶向

基本信息

批准号：
8457988
负责人：
EDITH P. MITCHELL
金额：
$ 51.99万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457988
关键词：
Address American Antibodies Automobile Driving Benign Biopsy Blood Cancer Cell Growth Cancer Gene Mutation Cancer Model Cancer Patient Cell Proliferation Cells Cessation of life Characteristics Chelating Agents Code Codon Nucleotides Color Contrast Media Cyclic GMP Cytoplasm Diffuse Discipline of Nuclear Medicine Early Diagnosis Early treatment Effectiveness Epidermal Growth Factor Receptor Epithelial Feasibility Studies Future Genetic Growth Factor Receptors IGF1R gene Image Injection of therapeutic agent Insulin-Like Growth Factor I KRAS2 gene Ligands Lung Lung Neoplasms MEKs Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Measurement Measures Mediating Messenger RNA Metabolic Molecular Target Monitor Mus Mutate Mutation Nucleic Acid Probes Oncogenes Pathway interactions Patients Peptide Nucleic Acids Photons Physicians Positron Positron-Emission Tomography Preparation Production Pulmonary Mass RNA Radioisotopes Radiopharmaceuticals Ras/Raf Rattus Sensitivity and Specificity Signal Transduction Site Solid Neoplasm Structure of parenchyma of lung Tail Technology Testing Toxicology Translations Trauma Tyrosine Kinase Inhibitor Veins Xenograft procedure analog cancer cell cancer gene expression cancer therapy chemotherapy design experience improved killings molecular imaging mutant novel overexpression pre-clinical public health relevance receptor response single photon emission computed tomography therapy resistant tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Cancer cell growth depends on high expression of cancer genes. Overexpression of epithelial growth factor receptor (EGFR) stimulates lung cancer cell growth. Anti-EGFR antibodies or tyrosine kinase inhibitors (TKIs) fail in most lung cancer patients. KRAS2 activation makes cancer cell proliferation independent of EGFR activity. As a result, treating lung cancer with anti-EGFR antibodies or TKIs fails when KRAS2 has been mutated. We hypothesize that determining KRAS2 cancer gene mutation status by external genetic PET imaging of mutant KRAS2 mRNA overexpression, as an adjunct to biopsy, will enable physicians to decide on alternatives to EGFR-directed therapies. We have imaged high levels of mutant KRAS2 mRNA and other oncogenes in malignant pancreas cancer xenografts. We designed radionuclide-chelator-spacer- peptide nucleic acid (PNA)-spacer-insulin-like growth factor 1 (IGF1) analogs to enable IGF1R-mediated cellular uptake and genetic radioimaging of mutant KRAS2 mRNA in suspect masses. We demonstrated sequence-specific PNA genetic imaging and quantitation of high levels of mutant KRAS2 mRNA in pancreas cancer xenografts after tail vein injection of 99mTc (SPECT) or 64Cu (PET) PNA-spacer-IGF1 probes. To extend this technology platform to lung cancer, we propose to carry out essential preclinical steps to maximize the sensitivity of imaging multiple mutants of KRAS2 mRNA with a codon 12 redundant chelator-KRAS2 genetic imaging agent in lung cancer xenografts. Our team includes an experienced radiopharmaceutical company, Molecular Targeting Technologies, which will submit an exploratory IND to FDA for a future trial of the KRAS2 genetic imaging agent in patients with suspect lung masses. Specific Aim 1: Test the sensitivity and specificity of a codon 12 multimutant KRAS2 genetic imaging agent in lung cancer xenografts. TJU will synthesize a novel KRAS2 genetic imaging agent designed to detect multiple KRAS2 codon 12 mutations, and control sequences. MTTI will purify and analyze large scale batches of KRAS2 genetic imaging agent and controls. Specific Aim 2: Determine whether genetic imaging of KRAS2 mRNA in lung cancer xenografts provides an early indication of the efficacy of antiproliferative chemotherapy. TJU will determine whether lowered KRAS2 mRNA, measured by genetic imaging, provides an earlier indication of the efficacy of antiproliferative chemotherapy, compared with [18F]FDG measurement of metabolic activity. Specific Aim 3: Obtain an eIND number from FDA for a future feasibility study. MTTI will acquire a dedicated cGMP batch of the KRAS2 genetic imaging agent, direct a microdose toxicology study in rats, compile and submit the eIND application for the KRAS2 genetic imaging agent to FDA, then address FDA questions and concerns. Early external imaging of lung cancer gene activity might (1) improve diagnosis of early lung cancer, (2) avoid biopsy trauma in patients with benign masses, (3) guide EGFR targeted therapy, and (4) ultimately reduce deaths from lung cancer.

描述（由申请人提供）：癌细胞的生长取决于癌症基因的高表达。上皮生长因子受体（EGFR）的过表达刺激肺癌细胞生长。在大多数肺癌患者中，抗EGFR抗体或酪氨酸激酶抑制剂（TKIS）失败。 KRAS2激活使癌细胞增殖与EGFR活性无关。结果，当KRAS2突变时，使用抗EGFR抗体或TKI的肺癌失败。我们假设通过突变体KRAS2 mRNA过表达的外部基因PET成像（作为活检的辅助）确定Kras2癌基因突变状态，将使医生能够决定EGFR指导疗法的替代方法。我们已经在恶性胰腺癌异种移植物中成像了高水平的突变KRAS2 mRNA和其他癌基因。我们设计了放射性核素 - 肽 - 间隙 - 肽核酸（PNA） - 酶 - 胰岛素样生长因子1（IGF1）类似物，以启用可疑质量中突变体KRAS2 mRNA的IGF1R介导的细胞摄取和遗传放射现象。我们证明了在尾静脉注射99mtc（SPECT）或64CU（PET）PNA-Spacer-IgF1探针后，胰腺癌异种移植物中高水平突变的KRAS2 mRNA的序列特异性PNA遗传成像和定量。为了将该技术平台扩展到肺癌，我们建议采取必要的临床前步骤，以最大化用密码子12冗余螯合剂-KRAS2遗传成像肺癌异种移植物中Kras2 mRNA成像的灵敏度。我们的团队包括一家经验丰富的放射线药物，分子靶向技术，该技术将向FDA提交探索性IND，以在可疑肺肿块患者中对KRAS2遗传成像剂的未来试验。具体目标1：测试肺癌异种移植物中密码子12多人KRAS2遗传成像剂的灵敏度和特异性。 TJU将合成一种新型的KRAS2遗传成像剂，旨在检测多个KRAS2密码子12突变和控制序列。 MTTI将纯化和分析KRAS2遗传成像剂和对照组的大规模批次。具体目标2：确定肺癌异种移植物中KRAS2 mRNA的遗传成像是否提供了抗增殖化疗的功效的早期指示。与[18F] FDG测量代谢活性相比，TJU将确定通过遗传成像测量的KRAS2 mRNA是否提供了抗增殖化学疗法的功效的较早指示。特定目的3：从FDA获得一个未来可行性研究的数字。 MTTI将获得KRAS2遗传成像剂的专用CGMP批次，指导大鼠中的微剂毒理学研究，编译并提交KRAS2遗传成像剂的EIND应用程序，然后解决FDA问题和问题。肺癌基因活性的早期外部成像可能会改善早期肺癌的诊断，（2）避免良性肿块患者的活检创伤，（3）引导EGFR靶向治疗，（4）（4）最终减少肺癌死亡。