Pro-peptide gene delivery for treating prostate cancer bone metastases

用于治疗前列腺癌骨转移的前肽基因递送

基本信息

项目摘要

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.
描述(由申请人提供):骨是前列腺癌转移的最常见部位;约65-75%的转移性前列腺癌患者会发生骨转移,诊断后中位总生存期为2-3年。转移破坏破骨细胞(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。肿瘤与骨发生恶性相互作用,促进肿瘤生长并使骨病理学恶化。我们的长期目标是开发一种成功的干预方法,用于治疗前列腺肿瘤和受影响的组织,消除肿瘤转移,同时使骨恢复到正常的功能状态。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细胞介素(IL)-6和IL-11的信号传导,并且与更晚期的疾病和不良预后相关。我们的实验室已经开发了通过使用靶向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,表达这些肽在体内基因传递后,有针对性的和多功能的“前肽”。这些前肽将靶向骨转移,并且还含有由IL 6 R和IL 11 R拮抗剂肽和骨生成促进肽osteostatin组成的双重治疗域。前肽将被前列腺肿瘤骨转移中高水平存在的明胶酶(MMP 2/9)加工,在转移部位特异性释放治疗肽,在转移部位它们将拮抗IL-6和IL-11信号传导并促进骨恢复。前肽递送的方法将使用超声增强或声致穿孔基因递送或“声致递送”。我们将测试的假设,优化分泌和靶向治疗前肽将消除前列腺肿瘤转移和恢复正常的骨。该提案的主要目标是优化肌肉超声递送后这些靶向治疗性前肽的表达和分泌,并增强骨转移处的积累和特异性肽释放,以消除肿瘤转移并恢复骨。为实现这一目标,我们提出以下具体目标:目标1。优化治疗性前肽向前列腺肿瘤骨转移的递送,目的2。确定前肽在体内的治疗效果的机制。对于这两个目的,前肽肿瘤递送和治疗功效的检测将使用microCT和光学成像。我们预计该项目的完成将为多功能,靶向,基于前肽的治疗前列腺癌骨转移提供基础。该项目的创新之处在于,它将建立一种新型的治疗性前肽剂,其具有简单的声传递系统,该系统将靶向和治疗肿瘤转移和骨。具有临床意义,预计这种方法将 能够改善骨转移性前列腺癌患者的发病率和生活质量,并可应用于以骨/肿瘤病理学为特征的其它疾病。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Marxa L Figueiredo其他文献

Marxa L Figueiredo的其他文献

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{{ truncateString('Marxa L Figueiredo', 18)}}的其他基金

Facilitating Endogenous Bone Repair in Arthritis with Targeted IL-27 Sonodelivery
通过靶向 IL-27 声波传递促进关节炎的内源性骨修复
  • 批准号:
    10352199
  • 财政年份:
    2018
  • 资助金额:
    $ 16.06万
  • 项目类别:
Facilitating Endogenous Bone Repair in Arthritis with Targeted IL-27 Sonodelivery
通过靶向 IL-27 声波传递促进关节炎的内源性骨修复
  • 批准号:
    10088413
  • 财政年份:
    2018
  • 资助金额:
    $ 16.06万
  • 项目类别:
Disrupting tumor/bone malignant interactions with multifunctional cytokine sonodelivery
通过多功能细胞因子超声传递破坏肿瘤/骨恶性相互作用
  • 批准号:
    9894745
  • 财政年份:
    2016
  • 资助金额:
    $ 16.06万
  • 项目类别:
Disrupting tumor/bone malignant interactions with multifunctional cytokine sonodelivery
通过多功能细胞因子超声传递破坏肿瘤/骨恶性相互作用
  • 批准号:
    9262887
  • 财政年份:
    2016
  • 资助金额:
    $ 16.06万
  • 项目类别:
Pro-peptide gene delivery for treating prostate cancer bone metastases
用于治疗前列腺癌骨转移的前肽基因递送
  • 批准号:
    8585630
  • 财政年份:
    2013
  • 资助金额:
    $ 16.06万
  • 项目类别:
Preventing prostate cancer progression by ASC delivery of PEDF and IFNb
通过 ASC 输送 PEDF 和 IFNb 预防前列腺癌进展
  • 批准号:
    8446315
  • 财政年份:
    2012
  • 资助金额:
    $ 16.06万
  • 项目类别:
Preventing prostate cancer progression by ASC delivery of PEDF and IFNb
通过 ASC 输送 PEDF 和 IFNb 预防前列腺癌进展
  • 批准号:
    8289223
  • 财政年份:
    2012
  • 资助金额:
    $ 16.06万
  • 项目类别:
Preventing prostate cancer progression by ASC delivery of PEDF and IFNb
通过 ASC 输送 PEDF 和 IFNb 预防前列腺癌进展
  • 批准号:
    8700570
  • 财政年份:
    2012
  • 资助金额:
    $ 16.06万
  • 项目类别:
MECHANISMS OF XMRV ONCOGENESIS IN PROSTATE CELLS
XMRV 在前列腺细胞中的致癌机制
  • 批准号:
    8359781
  • 财政年份:
    2011
  • 资助金额:
    $ 16.06万
  • 项目类别:
p12CDK2AP1 Regulation of Normal and Neoplastic Growth
p12CDK2AP1 正常和肿瘤生长的调节
  • 批准号:
    8245987
  • 财政年份:
    2009
  • 资助金额:
    $ 16.06万
  • 项目类别:

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