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的分子结构，使其与正常组织的交叉反应最小。细胞表面受体和表位是这些药物的有吸引力的靶标，因为它们比细胞内靶标更容易接近，在靶向药物的设计中允许更多的自由度。目前的提案旨在开发针对胰腺腺癌（PaAdo）的靶向药物，这是一种具有高死亡率且无有效治疗方法的毁灭性疾病。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能来自使用多聚体药物，同时针对多个受体。多聚体配体是一类含有多拷贝结合部分的新型靶向药物。因此，它们以合作亲和力结合，结合可能是非线性的，与靶蛋白表达水平有关。此外，它们提供了将多个不同的结合配体混合到同一化学结构上的可能性，从而提供了进一步的区分。该项目围绕3个独立的具体目标组织，以解决我们知识中的基本空白：人类癌症的适当靶点尚未充分确定。在过去的一年里，我们分析了28个PaAdos和103个正常组织的RNA表达数据。从这些数据中，我们已经确定了29个基因产物，可以作为单一药物或3-和4-基因组合潜在地区分PaAdo与正常组织。其中三个靶点已通过免疫组化（IHC）验证。Aim 1的重点将是使用组织阵列的免疫组化检测剩余的26个基因产物。小配体是有用的，但不易获得。虽然抗体是有用的靶向剂，但将它们组装成多聚体复合体会使它们过于庞大。因此，我们正在识别和迭代开发更小的靶向配体与可溶性相和固体支持的高通量方法。这些方法将在目标2中应用于最多五个经过验证的目标。多聚体结构的构效关系（SAR）定义不清。由于这是一种相对较新的方法，因此对支架和连接体的SAR还不是很清楚。在过去的几年里，我们和其他人的工作已经开始发展出更扎实的理解，但在这种结构的从头设计成为可行之前，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合人体内使用的靶向药物，它将携带适合诊断成像和治疗递送的有效载荷。

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.