Flourine-18 labeled MDM2 antagonists for PET imaging

用于 PET 成像的 Flourine-18 标记的 MDM2 拮抗剂

• 批准号: 9978523
• 负责人: Satish K. Chitneni
• 金额: $ 18.82万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978523
• 关键词: Acute Myelocytic Leukemia; Address; Affinity; Animals; Apoptosis; Binding; Biological Assay; Biology; Breast Adenocarcinoma; Breast Cancer Model; Cancer cell line; Cell Line; Cells; Characteristics; Chemical Structure; Clinical; Clinical Data; DNA Repair; Data; Development; Distant Metastasis; Double Minutes; Drug or chemical Tissue Distribution; Feedback; Fluorescent in Situ Hybridization; Fluorine; Gene Amplification; Genes; Genetic Transcription; Genetically Engineered Mouse; Genome Stability; Glioblastoma; Human; Image; Imaging Techniques; Immunohistochemistry; In Vitro; Investigation; Kinetics; Label; Lead; MCF7 cell; Maintenance; Malignant Neoplasms; Measures; Mesylates; Methods; Molecular; Monitor; Mus; Mutation; Null Lymphocytes; Oncogenic; Oncoproteins; Partition Coefficient; Pathway interactions; Patients; Peptides; Phase I Clinical Trials; Phenols; Play; Positron-Emission Tomography; Property; Protein Overexpression; Protein p53; Proteins; Radiolabeled; Role; Soft tissue sarcoma; Specificity; Stress; Surface Plasmon Resonance; TP53 gene; Technology; Therapeutic; Tracer; Tumor Suppressor Proteins; Tumor Tissue; X-Ray Computed Tomography; affinity labeling; analog; base; cancer cell; clinical development; design; genetic regulatory protein; imaging agent; imaging approach; imaging modality; imaging probe; imaging study; in vivo; lipophilicity; malignant breast neoplasm; molecular imaging; mouse model; neoplastic cell; new therapeutic target; non-invasive imaging; outcome forecast; overexpression; patient population; pre-clinical; predictive marker; prevent; protein expression; response; sarcoma; scaffold; senescence; small molecule; targeted treatment; tool; treatment response; tumor; tumor progression; ubiquitin-protein ligase; uptake

ABSTRACT The tumor suppressor protein p53 plays a critical role in protecting cells against oncogenic transformation. Consistent with this role, nearly 50% of all human cancers have a mutation in the p53 gene, rendering the p53 protein inactive. In tumors that are wild-type p53, the p53 function is often inhibited by the overexpression of its negative regulatory protein, murine double minute 2 (MDM2). Studies suggests that MDM2 is overexpressed in several human cancers, including breast cancer, sarcomas and glioblastoma, although at different rates. MDM2 interacts with p53 in a negative feedback loop and targets the p53 protein for proteasomal degradation, thereby inhibiting the tumor suppressive function of p53 in wild-type p53 tumors. Hence, inhibition of MDM2 with small molecule antagonists or other molecular scaffolds such as stapled peptides is being pursued as a therapeutic strategy for activating the p53 pathway in wild-type p53 cancers. Whilst the preclinical and the early clinical data have demonstrated the promise of this therapeutic approach, recent phase 1 clinical trials with small molecule MDM2 antagonists have indicated significant association between pre-treatment MDM2 expression levels and therapeutic response in patients with acute myeloid leukemia. These data suggest the need for selecting appropriate patients for MDM2 inhibition therapies and the potential usefulness of MDM2 as a predictive biomarker for MDM2 targeted therapies. One of the critical barriers for such studies is the lack of a noninvasive method for determining MDM2 overexpression status in tumors. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), the most commonly used methods for assessing MDM2 gene amplification and MDM2 protein overexpression in tumors, respectively, are invasive and do not permit monitoring the treatment response in vivo. To address these needs, we propose to develop radiolabeled probes for imaging the MDM2 protein expression levels in tumors noninvasively with positron emission tomography (PET), a highly sensitive molecular imaging technique. Building on the preliminary data we obtained in support of the project, we will synthesize fluorine-18 labeled compounds that bind to the MDM2 protein with high affinity (Aim 1). The labeled compounds will be evaluated for their potential to bind on MDM2 expressing tumors cells in vitro (Aim 2) and in mouse models of breast cancer and soft tissue sarcomas in vivo (Aim 3) to identify a lead molecule for MDM2 imaging with PET. To the best of our knowledge, this project would be the first study to develop PET imaging agents for the oncoprotein MDM2. Successful development of a PET imaging approach for the MDM2 protein will provide a valuable tool for studying MDM2-p53 biology in vivo and for investigation of novel therapies targeting MDM2 in wild-type p53 cancers.

抽象的 肿瘤抑制蛋白p53在保护细胞免受致癌转化方面起关键作用。 与该角色一致，近50％的人类癌症在p53基因中具有突变，呈现p53 蛋白质不活跃。在野生型p53的肿瘤中，p53功能通常受到过表达的抑制 其阴性调节蛋白，鼠双分钟2（MDM2）。研究表明MDM2是 在几种人类癌症中过表达，包括乳腺癌，肉瘤和胶质母细胞瘤，尽管 价格不同。 MDM2在负反馈回路中与p53相互作用，并靶向p53蛋白 蛋白酶体降解，从而抑制野生型p53肿瘤中p53的肿瘤抑制功能。 因此，用小分子拮抗剂或其他分子支架（如钉钉）抑制MDM2 肽正在作为一种治疗策略，用于激活野生型p53癌症中的p53途径。 尽管临床前和早期临床数据证明了这种治疗方法的希望，但 最近使用小分子MDM2拮抗剂进行的1期临床试验表明 在治疗前MDM2表达水平和急性髓样患者的治疗反应之间 白血病。这些数据表明需要选择适当的患者进行MDM2抑制疗法和 MDM2作为MDM2靶向疗法的预测生物标志物的潜在有用性。关键之一 此类研究的障碍是缺乏确定MDM2过表达状态的无创方法 肿瘤。荧光原位杂交（FISH）和免疫组织化学（IHC），最常用的 评估肿瘤中MDM2基因扩增和MDM2蛋白过表达的方法 具有侵入性，不允许在体内监测治疗反应。为了满足这些需求，我们 提议开发放射标记的探针，以成像肿瘤中的MDM2蛋白表达水平 与正电子发射断层扫描（PET）无创的，这是一种高度敏感的分子成像技术。 在我们获得支持该项目的初步数据的基础上，我们将合成标记的氟-18 与具有高亲和力的MDM2蛋白结合的化合物（AIM 1）。标记化合物将进行评估 因为它们有可能在体外与MDM2结合表达肿瘤细胞（AIM 2）和乳房模型 体内癌症和软组织肉瘤（AIM 3），以鉴定使用PET的MDM2成像的铅分子。到 我们了解的最好，该项目将是为开发宠物成像剂的第一项研究 癌蛋白MDM2。成功开发MDM2蛋白的PET成像方法将提供 在体内研究MDM2-P53生物学的有价值工具，并研究针对MDM2的新型疗法 野生型P53癌。