Ligand-Directed Targeting in Prostate Cancer Metastasis

我们的实验室已经使用体内噬菌体展示（1）来证明器官的血管内皮是如何被激活的。 以组织特异性方式修饰，以及（2）证明癌症的发展伴随着 形成肿瘤相关血管的细胞中的特定异常。从以前在机构审查委员会的工作- 批准的方案涉及用随机文库静脉内注射到 在不可逆损伤的患者中，从注射后前列腺活组织检查中分离归巢肽。所选 序列模拟了白细胞介素11（IL-11）的基序，实际上它与IL-11受体α（IL-11）结合。 11 R）。随后的研究，包括广泛的免疫组化分析原发性和转移性 前列腺癌样本显示在疾病进展期间IL-1 IR表达增加，特别是在前列腺癌患者中。 骨转移人类前列腺癌血管系统选择性结合前列腺素A的开创性观察 小肽基序通过IL-11 R的表达为基础和转化研究提供了许多潜在的方向。在 特别是，它产生了一种新的假设，即IL-11 R介导的信号传导在肿瘤发生中具有生物学重要性。 前列腺癌向致死表型的进展;并且，了解这种表达是如何 调节-特别是与进展到去势抵抗状态有关-将提供新的和相关的 对人类前列腺癌生物学的深入了解。这种前列腺归巢肽的发现也 提出了基于选择性结合的新型成像剂和治疗剂的用途。我们选择 为了积极地追求治疗应用：我们已经生产了一种试剂，BMTP-11（骨转移 靶向肽-11），其中所选择的肽基序与线粒体破坏剂组合，和 因此是诱导骨化的部分。在此背景下，最重要的翻译研究问题是：1） BMTP-11是否选择性分布于人类前列腺癌患者，2）IL-11 R表达如何 因为这些信息对于选择患者和调节有效的治疗方法非常重要。 BMTP-11治疗，以及3）这种药物的毒性是什么，以及它们如何在机械上 理解，从而减轻。以下具体目标说明了我们与这些目标相关的优先事项 问题.我们将（i）研究肿瘤内IL-11和IL-11 Ra的诱导和活性 （ii）确定介导上调的刺激， IL-11 Ra的激活。将IL-11、IL-11 R和去势抵抗性肿瘤生长联系起来的潜在相互作用将被研究。 研究;和（iii）开发临床前和临床试验，以评估BMTP-11在患者中的活性。 相关性（参见说明）： 转移性、去势抵抗性前列腺癌仍然是一种致命的疾病表型，中位数 存活时间约为18个月，在美国每年有超过28，000人死亡。那里 迫切需要新的方法。靶向骨隔室可以改变 疾病BMTP-11是特别有吸引力的，因为它可能能够选择性地递送细胞凋亡， 通过配体定向靶向骨转移的诱导剂。

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.