Ligand-Directed Targeting in Prostate Cancer Metastasis

我们实验室已经使用活体噬菌体展示(1)来展示器官的血管内皮细胞是如何 以组织特异性的方式进行修饰，以及(2)证明癌症的发展伴随着 形成肿瘤相关血管的细胞的特殊异常。根据以前在IRB的工作- 批准的方案涉及通过静脉注射随机文库到 一名不可逆性损伤患者，从注射后的前列腺活检组织中分离出一种归巢多肽。选定的 该序列模拟白细胞介素11(IL-11)的基序，实际上与IL-11受体α(IL-11)结合。 11 R)。随后的研究，包括对原发和转移的广泛免疫组织化学分析 前列腺癌样本在疾病进展过程中IL-1IR的表达增加，尤其是在 骨转移。人类前列腺癌的血管系统选择性地结合一种 通过IL-11R的小肽基序为基础研究和翻译研究提供了许多潜在的方向。在……里面 特别是，它产生了一个新的假设，即IL-11R介导的信号在 前列腺癌的进展到致命的表型；以及，理解这种表达是如何 受监管的--与进化到去势抵抗状态有关的特殊性--将提供新颖和相关的 对人类前列腺癌生物学的洞察。这种前列腺肽的发现也 建议使用基于选择性结合的新型成像和治疗剂。我们已经选择了 为了积极寻求治疗应用：我们生产了一种制剂BMTP-11(骨转移 靶向肽-11)，其中所选择的肽基序与线粒体破坏相结合，以及 因此，诱导细胞凋亡的部分。在这种背景下，最重要的翻译研究问题是：1) BMTP-11是否选择性地分布于人类前列腺癌，2)IL-11R是如何表达的 监管，因为这些信息对于患者的选择和有效的调制是很重要的 BMTP-11治疗，以及3)这种制剂的毒性是什么，它们是如何机械地 理解，并因此减轻。以下具体目标表明了我们与这些相关的优先事项 问题。我们将(I)研究IL-11和IL-11ra在肿瘤内的诱导和活性 前列腺癌进展过程中的微环境；(Ii)确定介导上调的刺激和 激活IL-11ra。将IL-11、IL-11R与去势抵抗肿瘤生长联系起来的潜在相互作用 研究；以及(Iii)开发临床前和临床检测以评估患者的BMTP-11活性。 相关性(请参阅说明)： 转移性、耐去势前列腺癌仍然是一种致命的疾病表型，中位数为 存活时间约为18个月，每年在美国造成超过28,000人死亡。那里 迫切需要新的方法。以骨间室为靶点可以改变 疾病。BMTP-11特别有吸引力，因为它可能能够选择性地传递细胞凋亡- 通过配体定向靶向治疗骨转移的诱导剂。

Our laboratory has used in vivo phage display (1) to demonstrate how the vascular endothelium of organs is modified in a tissue-specific manner, and (2) to prove that the development of cancer is accompanied by specific abnormalities in the cells that form tumor-associated blood vessels. From previous work in an IRB- approved protocol involving phage-display screening with a random library injected intravenously into an irreversibly injured patient, a homing peptide was isolated from post-injection prostate biopsies. The selected sequence mimicked a motif of interleukin 11 (IL-11), and it in fact was bound to IL-11 receptor alpha (IL- 11 R). Subsequent studies, including an extensive immunohistochemical analysis of primary and metastatic prostate cancer samples, showed increased expression of IL-1 IR during disease progression, particularly in bone metastases. The seminal observation that the vasculature of human prostate cancer selectively binds a small peptide motif via IL-11R raises many potential directions for both basic and translational research. In particular, it engenders the novel hypothesis that IL-11R-mediated signaling is biologically important in the progression of prostate cancer to a lethal phenotype; and, that understanding how this expression is regulated-particularty in relation to progression to a castrate-resistant state-will provide novel and relevant insights into the biology of human prostate cancer. The discovery of this prostate-homing peptide also suggests the use of novel imaging and therapeutic agents based on the selective binding. We have chosen to pursue aggressively a therapeutic application: we have produced an agent, BMTP-11 (Bone Metastasis Targeting Peptide-11), in which the selected peptide motif is combined with the mitochondrial disrupting, and therefore apoptosis-inducing moiety. The most important translational research issues in this context are: 1) Does BMTP-11 selectively distribute to prostate cancer in human patients, 2) How is IL-11R expression regulated, because this information is important for the selection of patients and the modulation of effective BMTP-11 treatment, and 3) What are the toxicities of this agent, and how can they be mechanistically understood and thereby mitigated. The following Specific Aimis state our priorities relevant to these questions. We will (i) Study the induction and activity of IL-11 and the IL-11Ra within the tumor microenvironment during prostate cancer progression; (ii) Determine the stimuli mediating up-regulation and activation ofthe IL-11Ra. Potential interplay linking IL-11, IL-11R and castrate-resistant tumor growth will be investigated; and (iii) Develop pre-clinical and clinical assays to evaluate BMTP-11 activity in patients. RELEVANCE (See instructions): Metastatic, castration-resistant prostate cancer continues to be a lethal disease phenotype, with median survival time of about 18 months and accounting for over 28,000 deaths annually in the United States. There is a pressing need for new approaches. Targeting the bone compartment can alter the natural history of the disease. BMTP-11 is especially attractive because it may be capable of selectively delivering an apoptosis- inducing agent by means of ligand-directed targeting of bone metastases.