Pro-peptide gene delivery for treating prostate cancer bone metastases

描述（申请人提供）：骨是前列腺癌最常见的转移部位；约65-75%的转移性前列腺癌患者会发生骨转移，诊断后的中位总生存期为2-3年。转移瘤破坏破骨细胞（骨吸收）和成骨细胞（骨形成）之间的正常稳态，削弱骨骼，导致骨折和严重疼痛的风险增加。肿瘤与骨以恶性串扰的方式相互作用，促进肿瘤生长，加重骨病理。我们的长期目标是开发一种成功的干预方法来治疗前列腺肿瘤和受影响的组织，消除肿瘤转移，同时恢复骨骼的正常功能状态。促进前列腺肿瘤和骨之间恶性串扰的途径涉及细胞因子白介素(IL)-6和IL-11的信号传导，并与更晚期的疾病和不良预后相关。我们的实验室已经开发出通过使用靶向IL-6和IL-11受体的抑制肽来破坏这些恶性细胞因子信号的策略。我们提出了一种新的策略，在基因传递后，在体内表达这些肽作为靶向和多功能的“前肽”。这些前肽将靶向骨转移瘤，并含有由IL6R和IL11R拮抗剂肽和促骨生成肽（osteostatin）组成的双重治疗结构域。前列腺肿瘤骨转移中存在高水平的明胶酶（MMP2/9）会处理这些前肽，在转移部位特异性释放治疗肽，在那里它们会拮抗IL-6和IL-11信号并促进骨修复。前肽递送的方法将使用超声增强或超声穿孔基因递送或“超声递送”。我们将验证优化分泌和靶向治疗性前肽将消除前列腺肿瘤转移和恢复正常骨骼的假设。本研究的主要目的是优化这些靶向治疗性前肽在肌肉超声传递后的表达和分泌，增强骨转移处的积累和特异性肽释放，以消除肿瘤转移，恢复骨骼。为实现这一目标，我们提出以下具体目标：优化治疗性前肽输送到前列腺肿瘤骨转移，和Aim 2。确定前肽在体内的治疗作用机制。对于这两个目标，检测前肽肿瘤传递和治疗效果将使用微ct和光学成像。我们期待这个项目的完成将为多功能、靶向、基于前肽的前列腺癌骨转移治疗提供基础。这个项目的创新之处在于，它将建立一种新的治疗前肽剂，它具有简单的超声传递系统，可以同时靶向和治疗肿瘤转移和骨骼。具有临床意义，预计该方法将

DESCRIPTION (provided by applicant): Bone is the most common site for prostate cancer metastasis; ~65-75% of patients with metastatic prostate cancer will develop bone metastases, with a median overall survival of 2-3 years following diagnosis. Metastases disrupt normal homeostasis between osteoclasts (bone resorption) and osteoblasts (bone formation), weakening the skeleton, causing an increased risk of bone fractures and severe pain. The tumor interacts with bone in a malignant crosstalk which acts to enhance tumor growth and worsen bone pathology. Our long-term objective is to develop a successful intervention for treating both the prostate tumor and the affected one tissue, eliminating the tumor metastases while restoring the bone to a normal functional state. The pathways promoting the malignant crosstalk between prostate tumors and bone involve signaling by cytokines interleukin (IL)-6 and IL-11 and are associated with more advanced disease and a poor prognosis. Our laboratory has developed strategies for disrupting these malignant cytokine signals by using inhibitory peptides targeting the IL-6 and IL-11 receptors. We propose a novel strategy to express these peptides in vivo following gene delivery as targeted and multifunctional 'propeptides'. These propeptides will target bone metastases and also contain dual therapeutic domains composed of IL6R and IL11R antagonist peptides and an osteogenesis-promoting peptide, osteostatin. The propeptides will be processed by gelatinases (MMP2/9) present at high levels in prostate tumor bone metastases, specifically releasing therapeutic peptides at the site of metastasis, where they will antagonize IL-6 and IL-11 signaling and promote bone restoration. The method of propeptide delivery will use ultrasound-enhanced or sonoporation gene delivery or 'sonodelivery'. We will test the hypothesis that optimized secretion and targeting of therapeutic propeptides will eliminate prostate tumor metastases and restore normal bone. The main goal of this proposal is to optimize expression and secretion of these targeted therapeutic propeptides following muscle sonodelivery, and enhance accumulation and specific peptide release at bone metastases to eliminate tumor metastases and restore bone. We propose the following specific aims to accomplish this goal: Aim 1. Optimize delivery of therapeutic propeptides to prostate tumor bone metastases, and Aim 2. Determine mechanisms of therapeutic efficacy of propeptides in vivo. For both Aims, detection of propeptide tumor delivery and efficacy of therapy will use microCT and optical imaging. We anticipate completion of this project will provide the foundations for a multifunctional, targeted, propeptide-based therapeutic for treating prostate cancer bone metastases. This project is innovative in that it will establish a novel therapeutic propeptide agent with a simple sonodelivery system that will target and treat both the tumor metastases and the bone. Of clinical significance, it is expected that this approach will enable improvement of bone-metastatic prostate cancer patient morbidity and quality of life and could be applicable to other diseases characterized by bone/tumor pathology.