Molecular Imaging of CD46

CD46 的分子成像

• 批准号: 10218509
• 负责人: Youngho Seo
• 金额: $ 20.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218509
• 关键词: Adenocarcinoma; Affinity; Amides; Animal Model; Antibodies; Antibody-drug conjugates; Antigens; Attention; Binding; Biological Assay; Biopsy; CD46 Antigen; Cancer Patient; Cells; Characteristics; Clinic; Clinical Trials; DU145; Detection; Development; Dose; Drug Kinetics; Epithelial; Goals; Human; Immunoglobulin Fragments; Immunohistochemistry; In Vitro; LNCaP; Length; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Metastatic breast cancer; Methods; Modeling; Molecular; Mus; Neoplasm Metastasis; Neurosecretory Systems; Normal tissue morphology; PC3 cell line; PET/CT scan; Pancreas; Patients; Play; Pregnancy; Prognosis; Property; Prostate; Protein Engineering; Radiolabeled; Radiopharmaceuticals; Recombinants; Research; Research Personnel; Role; Site; Specificity; Staging; Techniques; Testing; Tissue Sample; Translating; Xenograft procedure; advanced prostate cancer; base; castration resistant prostate cancer; clinical translation; clinically relevant; dosimetry; experimental study; imaging platform; imaging probe; immunoreactivity; in vivo; malignant breast neoplasm; microPET; molecular imaging; mouse model; new therapeutic target; non-invasive imaging; novel; novel therapeutics; overexpression; patient derived xenograft model; phase I trial; radiotracer; trophoblast; tumor; tumor growth; tumor xenograft; uptake

PROJECT SUMMARY CD46 is highly expressed in multiple cancers, including both adenocarcinoma and neuroendocrine types of metastatic castration resistant prostate cancer (mCRPC). Its expression on normal tissue is generally low except for placental trophoblasts during pregnancy and to a lesser degree the prostate epithelium. An anti-CD46 antibody-drug conjugate (ADC) originally developed in the Liu lab is now in phase I trials at five US centers for mCRPC. UCSF is the leading test site (led by significant contributor Dr. Rahul Aggarwal) and the first patient has been dosed. An important challenge for this type of therapy is the appropriate selection of CD46-positive patients who will likely respond to therapy. One method to assay CD46 positivity would be through tissue sampling. However, biopsies do not reflect target expression in all lesions but rather the characteristic of a specific tumor metastatic lesion. In contrast, non-invasive molecular imaging using anti-CD46 radiotracers will allow for whole body assessment of antigen expression and consequently identification of patients who are likely to respond to this novel therapy. CD46 has been very recently discovered as a novel target of advanced prostate cancer; therefore, there is a gap in fundamental information about whole body expression of CD46, relationship between its expression and tumor growth and metastasis formation. Moreover, as a recently discovered target, molecular imaging of CD46 could contribute to understand specific molecular alterations related to CD46 expression. The goal of this proposal is the technical development of a platform for molecular imaging of CD46. We will develop a panel of radiopharmaceuticals capable of non-invasively imaging CD46. This platform will not only has the potential to identify mCRPC patients that will likely respond to CD46 ADC and other emerging therapies but also to explore CD46 expression in other tumor types with special attention to those that currently has very poor prognosis and survival. The information gather in this project may play an important role in the development on new therapies.

项目摘要 CD46在多种癌症中高度表达，包括腺癌和 神经内分泌类型的转移性cast割前列腺癌（MCRPC）。它的表达 在正常组织上，除了怀孕期间胎盘滋养细胞和 较小的前列腺上皮。抗CD46抗体 - 药物结合物（ADC） 现在在刘实验室开发的是在美国五个美国MCRPC中心的I期试验中。 UCSF是领先 测试地点（由重要贡献者Rahul Aggarwal博士领导），第一位患者已服用。 这种类型的疗法的重要挑战是适当选择CD46阳性 可能会对治疗做出反应的患者。一种测定CD46阳性的方法是通过 组织采样。但是，活检并不反映所有病变中的靶标表达 特定肿瘤转移性病变的特征。相反，非侵入性分子成像 使用抗CD46放射性示例将允许全身评估抗原表达和 因此，鉴定可能对这种新疗法有反应的患者。 CD46具有 最近被发现是晚期前列腺癌的新目标。因此，有 关于CD46的全身表达的基本信息的差距，其之间的关系 表达和肿瘤生长和转移形成。而且，正如最近发现的 目标，CD46的分子成像可能有助于了解特定的分子改变 与CD46表达有关。 该提案的目的是用于分子成像平台的技术开发 CD46。我们将开发一组能够非侵入性成像CD46的放射性药物。 该平台不仅有可能识别可能会做出反应的MCRPC患者 CD46 ADC和其他新兴疗法，但也探索其他肿瘤中的CD46表达 类型的类型特别关注那些目前的预后和生存率非常低的类型。这 该项目中收集的信息可能在新疗法的开发中发挥重要作用。