权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
9894745
负责人：
Marxa L Figueiredo
金额：
$ 40.99万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894745
关键词：
Attenuated Avidity BMP7 gene Biocompatible Materials Biometry Bone Matrix Bone Resorption Bone Tissue Bone neoplasms Bone remodeling CD8B1 gene Cancer Patient Clinical Complement Factor B Cytokine Gene DNA delivery Data Diagnosis Disease Distant Environment Equilibrium Foundations Fracture Gene Delivery Goals Growth Growth Factor Homeostasis Immune Immunocompetent Immunologic Surveillance Immunotherapy Interferon Type II Interleukin-11 Interleukin-6 Interleukins Intervention Laboratories Lesion Ligands Malignant - descriptor Malignant Bone Neoplasm Malignant neoplasm of prostate Mature Bone Mediating Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Morbidity - disease rate Muscle Myelogenous Neoplasm Metastasis Nuclear Osteoblasts Osteoclasts Osteogenesis Pain Pathology Pathway interactions Patients Peptide Signal Sequences Polymers Positioning Attribute Prostatic Neoplasms Quality of life Relapse STAT1 gene Seeds Serum Signal Transduction Site Skeletal Muscle Skeleton Soil Therapeutic Time Toxic effect Transforming Growth Factors Treatment Efficacy Tumor Burden Tumor Pathology Ultrasonography advanced disease advanced prostate cancer base bone bone cell bone loss chemotherapy cytokine effector T cell gene delivery system gene product immune activation immunogenic immunoregulation improved in vivo mortality neoplastic cell novel osteogenic outcome forecast plasmid DNA prevent prostate cancer metastasis public health relevance recruit release factor skeletal-related events synergism therapeutic cytokines tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer modifies the balance between osteoclasts (bone resorption) and osteoblasts (bone formation) to enhance tumor growth and promote skeletal-related events (SRE), i.e. severe pain and fractures. The majority of advanced prostate cancer patients have tumors metastasize to bone and half reach mortality within 30-35 months. Despite considerable progress, current therapeutics only prolong overall survival by reducing the tumor growth rate and/or delay time to SRE by a few additional months. There remains a critical lack of therapies that can reduce tumor burden while simultaneously restoring the bone. The central growth- promoting pathways for tumor-bone crosstalk involve interleukin (IL-6 and IL-11) and transforming growth factor β (TGFβ) signaling, both of which correlate with advanced disease and poor prognosis. Our laboratory recently developed a gene delivery strategy to express cytokine gene products that can in turn disrupt the IL-6/11 and TGFβ signals at distant tumor metastases. We use a nanoplex composed of nuclear-localizing polymer and plasmid DNA and delivery is enhanced by ultrasound (sonodelivery). Using sonodelivery, we have shown that interleukin-27 (IL-27), a natural antagonist of IL-6/11, reduces tumor burden and improves bone homeostasis. We have shown that IL-27 is a multifunctional cytokine that drives antitumor activity through immune-activation and anti-angiogenic mechanisms. Moreover, our lab has identified that IL-27 is a pro-osteogenic factor. Our most recent data indicates that despite its high promise, IL-27 monotherapy still can be improved by the addition of a second therapeutic that can attenuate TGFβ signaling. We have observed that the osteogenic protein-1 (OP-1), a natural TGFβ antagonist, significantly augments IL-27 efficacy. Our hypothesis is that optimizing delivery and targeting of multifunctional cytokines IL-27 and OP-1 to the tumor/bone microenvironment will disrupt key malignant crosstalk while inducing immune-activation to reduce tumor burden, restore bone, and increase survival. (Aim 1) To achieve therapeutically effective levels of cytokines in serum, we will optimize gene delivery and cytokine secretion from skeletal muscle. (Aim 2) To enhance therapeutic efficacy of cytokines and reduce potential toxicity, we will promote cytokine retention at tumor-bone metastases by ligand-mediated targeting. (Aim 3) To examine the efficacy of IL-27+OP-1 (27OP1) sonodelivery and determine therapeutic applications, we will examine 27OP1 in the context of current chemotherapies. This project leverages the strengths of the team in sonodelivery and biomaterials (Figueiredo, Emrick), tumor/bone microenvironment (Keller and Rowley) and ligand-mediated targeting (Pasqualini). We anticipate this project will provide the foundation for a simple, effective sonodelivery-based intervention that reduces tumor burden while restoring bone and can synergize with current immunomodulatory chemotherapies. This approach is expected to improve bone-metastatic prostate cancer patient morbidity and quality of life and would be applicable to other diseases involving bone/tumor pathology.

描述(申请人提供)：前列腺癌改变破骨细胞(骨吸收)和成骨细胞(骨形成)之间的平衡，以促进肿瘤生长和促进骨骼相关事件(SRE)，即严重疼痛和骨折。大多数晚期前列腺癌患者有肿瘤转移到骨，有一半的人在30-35个月内死亡。尽管取得了长足的进步，但目前的治疗方法只是通过降低肿瘤生长率和/或将SRE的时间推迟几个月来延长总体生存时间。目前仍然严重缺乏在减轻肿瘤负担的同时恢复骨骼的治疗方法。肿瘤-骨串连的中枢促生长途径包括白介素6和白介素11和转化生长因子ββ信号通路，两者均与疾病进展和预后不良有关。我们实验室最近开发了一种基因递送策略来表达细胞因子基因产物，这些基因产物可以反过来干扰远处肿瘤转移中的IL-6/11和转化生长因子β信号。我们使用由核定位聚合物和质粒DNA组成的纳米复合体，并通过超声波(超声波传递)增强传递。通过声学传递，我们已经证明了IL-27(IL-27)，一种IL-6/11的天然拮抗剂，可以减轻肿瘤负担，改善骨骼稳态。我们已经证明，IL-27是一种多功能细胞因子，通过免疫激活和抗血管生成机制来驱动抗肿瘤活性。此外，我们的实验室已经确定IL-27是一种促成骨因子。我们最新的数据表明，尽管IL-27单一疗法前景看好，但通过添加第二种疗法来减弱转化生长因子β信号，仍然可以改善这种疗法。我们观察到，成骨蛋白-1(OP-1)，一种天然的转化生长因子β拮抗剂，显著增强IL-27的疗效。我们的假设是，优化多功能细胞因子IL-27和OP-1的传递和靶向到肿瘤/骨微环境将扰乱关键的恶性串扰，同时诱导免疫激活，以减轻肿瘤负担，恢复骨骼，提高生存率。(目的1)为了达到治疗上有效的血清细胞因子水平，我们将优化骨骼肌的基因传递和细胞因子分泌。(目的2)为了提高细胞因子的治疗效果，减少潜在的毒性，我们将通过配体介导的靶向来促进细胞因子在肿瘤-骨转移瘤中的滞留。(目的3)为了检测IL-27+OP-1(27OP1)的疗效和确定治疗应用，我们将在当前化疗的背景下检测27OP1。该项目利用了该团队在声传递和生物材料(Figueiredo，Emrick)、肿瘤/骨微环境(Keller和Rowley)以及配体介导的靶向(Pasqualini)方面的优势。我们预计该项目将为一种简单、有效的基于声学传递的干预奠定基础，这种干预在恢复骨骼的同时减轻肿瘤负担，并可以与当前的免疫调节性化疗协同作用。这种方法有望改善骨转移前列腺癌患者的发病率和生活质量，并将适用于其他涉及骨/肿瘤病理的疾病。