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
• 负责人: Marxa L Figueiredo
• 金额: $ 35.06万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262887
• 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; 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; Recruitment Activity; Relapse; STAT1 gene; Seeds; Serum; Signal Transduction; Site; Skeletal Muscle; Skeleton; Soil; T-Lymphocyte; Therapeutic; Time; Toxic effect; Transforming Growth Factors; Treatment Efficacy; Tumor Burden; Tumor Pathology; Ultrasonography; advanced disease; base; bone; bone cell; bone loss; chemotherapy; cytokine; gene delivery system; gene product; immune activation; immunogenic; immunoregulation; improved; in vivo; mortality; neoplastic cell; novel; osteogenic; outcome forecast; plasmid DNA; prevent; public health relevance; release factor; skeletal-related events; synergism; tumor; tumor growth

 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（由申请人提供）：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，以增强肿瘤生长并促进泌尿系统相关事件（SRE），即严重疼痛和骨折。大多数晚期前列腺癌患者的肿瘤转移到骨，一半在30-35个月内达到死亡率。尽管取得了相当大的进展，但目前的治疗方法仅通过降低肿瘤生长速率和/或将SRE的时间延迟几个月来延长总生存期。目前仍然严重缺乏可以在减少肿瘤负荷的同时恢复骨骼的治疗方法。肿瘤-骨串扰的中心生长促进途径涉及白细胞介素（IL-6和IL-11）和转化生长因子β（TGFβ）信号传导，两者均与晚期疾病和不良预后相关。我们的实验室最近开发了一种基因递送策略，以表达细胞因子基因产物，从而在远处肿瘤转移处破坏IL-6/11和TGFβ信号。我们使用由核定位聚合物和质粒DNA组成的纳米复合物，并通过超声（sonodelivery）增强递送。使用超声递送，我们已经表明白细胞介素-27（IL-27），一种IL-6/11的天然拮抗剂，降低肿瘤负荷并改善骨稳态。我们已经表明，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。我们最近的数据表明，尽管IL-27单药治疗前景广阔，但仍可以通过添加第二种可减弱TGFβ信号传导的治疗剂来改善。我们已经观察到成骨蛋白-1（OP-1），一种天然的TGFβ拮抗剂，显著增强IL-27的功效。我们的假设是，优化多功能细胞因子IL-27和OP-1向肿瘤/骨微环境的递送和靶向，将破坏关键的恶性串扰，同时诱导免疫激活，以减少肿瘤负荷，恢复骨，并增加存活率。(Aim 1）为了实现血清中细胞因子的治疗有效水平，我们将优化基因递送和骨骼肌的细胞因子分泌。(Aim 2）为了提高细胞因子的治疗效果和降低潜在的毒性，我们将通过配体介导的靶向作用促进细胞因子在肿瘤骨转移中的滞留。(Aim 3）为了检查IL-27+OP-1（27 OP 1）超声递送的功效并确定治疗应用，我们将在当前化疗的背景下检查27 OP 1。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和罗利）和配体介导的靶向（Pasqualini）方面的优势。我们预计该项目将为一种简单有效的基于超声传递的干预提供基础，该干预在恢复骨的同时减少肿瘤负荷，并可与当前的免疫调节化疗协同作用。这种方法有望改善骨转移性前列腺癌患者的发病率和生活质量，并适用于其他涉及骨/肿瘤病理学的疾病。