Molecular Imaging of CD46

项目总结 CD46在多种肿瘤中高表达，包括腺癌和 神经内分泌型转移性去势抵抗前列腺癌(MCRPC)。其表达方式 在正常组织上，除妊娠期间胎盘滋养层细胞外，一般都很低 程度较轻的前列腺上皮。抗CD46抗体-药物结合物(ADC) 在刘实验室开发的mCRPC目前正在美国五个中心进行第一阶段试验。加州大学旧金山分校是领先的 测试地点(由重要贡献者Rahul Aggarwal博士领导)和第一名患者已被注射。 这种治疗的一个重要挑战是适当地选择CD46阳性的患者 可能对治疗有反应的患者。检测CD46阳性的一种方法是通过 组织取样。然而，活组织检查并不反映所有皮损中的靶向表达，而是反映了 具有特定肿瘤转移性病变的特征。相比之下，非侵入性分子成像 使用抗CD46放射性示踪剂将允许全身评估抗原表达和 因此，确定可能对这种新疗法有反应的患者。CD46有 最近被发现为晚期前列腺癌的新靶点；因此，有 CD46全身表达的基本信息差距及其与其之间的关系 表达与肿瘤生长和转移形成的关系。此外，正如最近发现的那样 CD46的靶向分子成像有助于了解特定的分子变化 与CD46的表达有关。 这项提议的目标是开发一个分子成像平台的技术 CD46。我们将开发一种能够对CD46进行非侵入性成像的放射性药物小组。 该平台不仅有可能识别mCRPC患者可能对 CD46、ADC等新兴疗法也在探索CD46在其他肿瘤中的表达 特别注意那些目前预后和存活率非常差的类型。这个 在这个项目中收集的信息可能在新疗法的开发中发挥重要作用。

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.