Heterocellular 3D ovarian tumor arrays for imaging and mechanistic combinations

用于成像和机械组合的异细胞 3D 卵巢肿瘤阵列

• 批准号: 8238894
• 负责人: Tayyaba Hasan
• 金额: $ 39.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-12 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238894
• 关键词: Acute; Address; Animal Model; Biological; Biological Markers; Biological Response Modifier Therapy; Cadherins; Cancer Biology; Cancer Model; Cancer Patient; Carboplatin; Cell Line; Cell Proliferation; Cells; Cessation of life; Cetuximab; Clinical; Clinical Research; Combination Drug Therapy; Combined Modality Therapy; Custom; Data; Detection; Disease; Disease Resistance; Dose; Drug resistance; Endothelial Cells; Epidermal Growth Factor Receptor; Evaluation; Extracellular Matrix; FDA approved; Failure; Feedback; Fibroblasts; Fibronectins; Future; Genetic Heterogeneity; Goals; Grant; Growth; Hypoxia; Image; Imaging Device; Intervention; Kinetics; Laboratories; Libraries; Malignant neoplasm of ovary; Mesothelial Cell; Methods; Microscope; Microscopy; Modality; Modeling; Molecular; Molecular Target; Monitor; Mus; Nanotechnology; Neoplasm Metastasis; Nodule; Outcome; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Photochemistry; Photochemotherapy; Photosensitizing Agents; Play; Printing; Protocols documentation; Radiation; Recurrence; Recurrent disease; Regimen; Reporter; Research; Research Infrastructure; Residual Tumors; Residual state; Residual volume; Resistance; Role; Salvage Therapy; Scanning; Screening procedure; Signal Transduction; Solid Neoplasm; Staging; Survival Rate; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Tumor Burden; Tumor Volume; United States; Validation; Vascular Endothelial Growth Factors; arm; base; bevacizumab; cancer cell; chemotherapy; clinically relevant; cytotoxic; design; flexibility; fluorescence imaging; high throughput screening; improved; in vivo; inhibitor/antagonist; insight; intraperitoneal; macrophage; meetings; mouse model; nanofiber; neoplastic cell; novel strategies; novel therapeutics; ovarian neoplasm; programs; response; scaffold; statistics; targeted delivery; three-dimensional modeling; treatment response; treatment strategy; tumor

DESCRIPTION (provided by applicant): Late detection and drug resistance have maintained the grim statistics for ovarian cancer (OvCa) steady over decades. New approaches using combination therapies with mechanistically distinct components are hypothesized to be most effective. The long term goal of this research is to develop, integrate and validate key platform technologies to screen mechanism-based combination regimens with photodynamic therapy (PDT) for residual and recurrent OvCa. Heterocellular 3D printed tumor arrays that incorporate critical determinants of OvCa biology (endothelial and mesothelial cells with macrophages and fibroblasts) along with hyperspectral microscopy for simultaneous quantitative imaging of multiple biomarkers will provide exceptional insight into OvCa growth and treatment response on a high throughput platform. To address the grueling toxicities and frequent recurrence that cause OvCa-related deaths, we leverage our nanotechnology program to fabricate nanoconstructs for intracellular delivery of targeted inhibitors, and deliver rational combination regimens with PDT, an FDA approved photochemistry-based treatment that has shown clinical promise for OvCa. PDT is effective on chemo and radiation resistant cells and synergizes with chemotherapeutic and biologic agents resulting in improved efficacy. Treatment results optimized in the heterocellular 3D arrays will be rigorously validated in vivo and in ex vivo patient tissue-derived 3D cultures to demonstrate the predictive capabilities of the bio- and imaging-based screening platform. The goals will be realized in 3 specific aims: 1) Develop and characterize heterocellular 3D printed tumor arrays for micrometastatic OvCa, and nanoconstructs for intracellular delivery of therapeutic agents. 2) Deploy heterocellular tumor arrays for assessment of cytotoxic and molecular responses to a two-tiered therapeutic approach- i) first-line PDT + chemotherapy of residual disease followed by ii) second-line treatment of chemoresistant recurrent disease with PDT + targeted biological therapies. 3) Validate treatment response of 3D tumor arrays in vivo, and in ex-vivo tissue derived cells in 3D culture. Major deliverables of this proposal will be i) Heterocellular 3D OvCa tumor arrays and nanoconstructs for multi-agent intracellular delivery, ii) Optimal combination delivery strategies and conditions to mitigate regrowth, and iii) Rigorous validation of the heterocellular tumor array data in the context of both a clinically-relevant murine model for metastatic OvCa, and in patient tissue-derived 3D cultures. The findings from this study will impact outcomes for patients with advanced (stage II-IV) and resistant OvCa and those receiving salvage therapy. The infrastructure developed through this highly integrated approach will create a new framework to rapidly evaluate and optimize new therapeutic strategies that will be adaptable to a broad array of metastatic tumors and molecular targets. Because molecular expressions and responses can be idiosyncratic, the proposed rapid monitoring of biomarkers expression and treatment-induced biomarkers changes creates the possibility of patient-customized treatments in the future. PUBLIC HEALTH RELEVANCE: In 2010 there were an estimated 21,880 new cases of ovarian cancer (OvCa) and 13,850 deaths in the United States, due largely to ineffective treatments for metastatic disease which frequently recurs after chemotherapy. The failure of any single drug or therapeutic modality to cure disease points to the need for treatment strategies combining multiple agents that act synergistically to produce enhanced outcomes. The heterocellular 3D ovarian tumor arrays proposed herein directly address the un-met need for a new research platform to rapidly reveal the most promising combination treatments to improve the dismal statistics for this disease.

描述（由申请人提供）：晚期检测和耐药性使卵巢癌（OvCa）的严峻统计数据保持了数十年的稳定。新的方法，使用联合治疗与机械不同的组件被假设为是最有效的。本研究的长期目标是开发、整合和验证关键平台技术，以筛选基于机制的联合方案与光动力疗法（PDT），用于治疗残留和复发性OvCa。异质细胞3D打印肿瘤阵列结合了OvCa生物学的关键决定因素（内皮细胞和间皮细胞以及巨噬细胞和成纤维细胞），沿着高光谱显微镜，用于多种生物标志物的同时定量成像，将在高通量平台上提供对OvCa生长和治疗反应的特殊见解。为了解决导致OvCa相关死亡的剧烈毒性和频繁复发，我们利用我们的纳米技术计划来制造用于细胞内递送靶向抑制剂的纳米结构，并提供与PDT的合理组合方案，PDT是FDA批准的基于光化学的治疗，已显示出OvCa的临床前景。PDT对化疗和放射抗性细胞有效，并与化疗剂和生物制剂协同作用，从而提高疗效。在异质细胞3D阵列中优化的治疗结果将在体内和离体患者组织衍生的3D培养物中进行严格验证，以证明基于生物和成像的筛选平台的预测能力。这些目标将在3个具体目标中实现：1）开发和表征用于微转移OvCa的异细胞3D打印肿瘤阵列，以及用于治疗剂细胞内递送的纳米结构。2)部署异质细胞肿瘤阵列，以评估对两层治疗方法的细胞毒性和分子反应- i）一线PDT +残留疾病化疗，然后ii）PDT +靶向生物治疗对化疗耐药复发性疾病的二线治疗。3)在3D培养物中观察体内3D肿瘤阵列和离体组织衍生细胞的治疗反应。该提案的主要可交付成果将是i）用于多药剂细胞内递送的异细胞3D OvCa肿瘤阵列和纳米结构，ii）减轻再生长的最佳组合递送策略和条件，以及iii）在转移性OvCa的临床相关小鼠模型和患者组织衍生的3D培养物中对异细胞肿瘤阵列数据进行严格验证。这项研究的结果将影响晚期（II-IV期）和耐药OvCa患者以及接受挽救治疗的患者的结局。通过这种高度集成的方法开发的基础设施将创建一个新的框架，以快速评估和优化新的治疗策略，这些策略将适用于广泛的转移性肿瘤和分子靶点。由于分子表达和反应可能是特异质的，因此所提出的对生物标志物表达和治疗诱导的生物标志物变化的快速监测创造了未来患者定制治疗的可能性。 公共卫生相关性：2010年，美国估计有21，880例卵巢癌（OvCa）新发病例和13，850例死亡，主要是由于化疗后经常复发的转移性疾病治疗无效。任何单一药物或治疗方式治愈疾病的失败都表明需要结合多种药物的治疗策略，这些药物协同作用以产生增强的结果。本文提出的异细胞3D卵巢肿瘤阵列直接解决了对新研究平台的未满足需求，以快速揭示最有希望的组合治疗，以改善这种疾病的令人沮丧的统计数据。