Targeting Pancreatic Cancer

描述（由申请人提供）：抗癌治疗和诊断成像的共同目标是开发能够特异性靶向肿瘤细胞且与正常组织的交叉反应性最小的分子构建体。细胞表面受体和表位是这类试剂的有吸引力的靶标，因为它们比细胞内靶标更容易接近，从而在靶向试剂的设计中允许更多的自由度。目前的提案旨在开发胰腺癌PaAdo的靶向药物，PaAdo是一种具有高死亡率且没有有效疗法的毁灭性疾病。来自我们小组和其他人的数据表明，这个问题的一个可能的解决方案可以来自使用同时靶向一个以上受体的多聚体药物。多聚体配体是一类含有多拷贝结合部分的新型靶向剂。因此，它们以协同亲和力结合，并且结合相对于靶蛋白表达水平可以是非线性的。此外，它们提供了将多种不同的结合配体混合到同一化学构建体上的可能性，提供了进一步的区分水平。该项目围绕3个独立的具体目标进行组织，以解决我们知识中的基本空缺：人类癌症的适当靶点未得到充分识别。在过去的一年中，我们分析了28例患者和103例正常组织的RNA表达数据。从这些数据中，我们已经确定了29个基因的产品，可以潜在的区别PaAdo从正常组织中作为单一的代理或在3和4基因组合。其中三个靶标已通过免疫组织化学、IHC进行了验证。目标1的重点将是使用组织阵列的IHC检查剩余的26种基因产物。小配体是有用的，但不容易获得。虽然抗体是有用的靶向剂，但将它们组装成多聚体复合物可使它们大得令人望而却步。因此，我们正在确定和迭代开发更小的靶向配体与可溶相和固相支持高通量方法。这些方法将在目标2中应用于多达五个经验证的目标。多聚体构建体的构效关系（SAR）是不明确的。由于这是一种相对较新的方法，支架和连接体的SAR并不为人所知。我们和其他人在过去几年的工作已经开始形成更坚实的理解，但在这种结构的从头工程变得可行之前，还需要更多的数据。在目标3中，我们将研究聚合物支架和线性连接器作为不同的方法来系统地定义工程系统中固有的自由度。这项工作的长期目标是开发适用于人体体内使用的靶向药物，这些药物将携带适用于诊断成像和治疗的有效载荷。

DESCRIPTION (provided by applicant): A common goal of anti-cancer therapy and diagnostic imaging is the development of molecular constructs that can specifically target the tumor cells with minimal cross-reactivity to normal tissues. Cell surface receptors and epitopes are attractive targets for such agents as they are more accessible than are intracellular targets, allowing many more degrees of freedom in the design of the targeting agents. The current proposal seeks to develop targeting agents for Pancreatic Adenocarcinoma, PaAdo, a devastating disease with high mortality and no effective therapies. Data from our group and others suggest that a possible solution to this problem can come from the use of multimeric agents that are targeted to more than one receptor simultaneously. Multimeric ligands are a new class of targeting agents that contain multiple copies of binding moieties. Hence, they bind with cooperative affinity and binding can be non-linear with respect to target protein expression levels. In addition, they provide the possibility of mixing multiple different binding ligands onto the same chemical construct, providing a further level of discrimination. This project is organized around 3 independent specific aims that address fundamental vacancies in our knowledge: Appropriate targets on human cancers were inadequately identified. Over the past year, we have analyzed RNA expression data from 28 PaAdos and 103 normal tissues. From these data, we have identified 29 gene products that can potentially discriminate PaAdo from normal tissues in as single agents or in 3- and 4-gene combinations. Three of these targets have been validated by immunohistochemistry, IHC. The focus of Aim 1 will be to examine the remaining 26 gene products using IHC of tissue arrays. Small ligands are useful but not readily available. Although antibodies are useful targeting agents, assembling them into multimeric complexes can make them prohibitively large. Hence, we are identifying and iteratively developing smaller targeting ligands with soluble-phase and solid-support high-throughput methods. These methods will be applied in aim 2 for up to five of the validated targets. The structure-activity relationships (SAR) for multimeric constructs are ill-defined. Since this is a relatively new approach, the SAR for scaffolds and linkers is not well known. Work by us and others over the past few years has begun to develop a more solid understanding, but more data are needed before de novo engineering of such constructs will become viable. In Aim 3 we will investigate polymer scaffolds and linear linkers as divergent approaches to systematically define the degrees of freedom inherent in engineering such systems. The long-term goal of this work is to develop targeting agents appropriate for in vivo human use, which will carry payloads appropriate for diagnostic imaging and delivery of therapy.