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

基本信息

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
项目类别：
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

项目摘要

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）：几十年来，晚期检测和耐药性维持了卵巢癌（OVCA）的严峻统计。假设使用与机械上不同成分的组合疗法的新方法是最有效的。这项研究的长期目标是开发，整合和验证关键平台技术，以筛选基于机制的组合方案与光动力疗法（PDT），以进行残留和复发性OVCA。杂细胞3D印刷肿瘤阵列，其中包含OVCA生物学的关键决定因素（带有巨噬细胞和成纤维细胞的内皮细胞和间皮细胞），以及高光谱显微镜，用于同时对多种生物标志物的定量成像，可为OVCA增长和治疗响应提供高度通过高通过平台的高度洞察力。为了解决导致OVCA相关死亡的艰苦毒性和频繁的复发，我们利用纳米技术计划来制造纳米构造，以用于靶向抑制剂的细胞内递送，并与PDT（PDT）（基于FDA批准的光学治疗方法）对OVCA的临床保证提供了合理的PROPS。 PDT可有效地对化学和抗辐射抗性细胞有效，并与化学治疗和生物学剂协同作用，从而提高功效。在杂细胞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个特定目标中实现：1）开发和表征微量转移OVCA的杂细胞3D印刷肿瘤阵列，以及用于治疗剂的细胞内递送的纳米结构。 2）部署杂细胞肿瘤阵列，以评估对两层治疗方法的细胞毒性和分子反应 - i）残留疾病的一线PDT +化学疗法II）ii）二线治疗PDT + PDT + PDT +靶向生物学治疗。 3）验证体内3D肿瘤阵列的治疗反应，以及在3D培养的活体组织中衍生细胞中的治疗反应。该提案的主要可交付成果将是i）杂细胞3D OVCA肿瘤阵列和纳米构造，用于多代理细胞内递送，ii）最佳组合输送策略和条件，以减轻重新生长，ii）严格验证杂细胞肿瘤数据，以在两种临床上均具有临床上的Murine Myline of and the Clunative Murine Myta of CARIUTE of CARIUTE MURENING MURENIS MURENISTATS of CACA MURTASTATS of CACA，文化。这项研究的发现将影响患有晚期（II-IV期）和耐药性OVCA的患者以及接受打捞疗法的患者的结果。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，这些策略将适应广泛的转移性肿瘤和分子靶标。由于分子表达和反应可能是特殊的，因此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会在将来会产生患者抑制治疗的可能性。公共卫生相关性：2010年，估计有21,880例新的卵巢癌病例（OVCA）和13,850例死亡，这在很大程度上是由于无法治疗转移性疾病的无效治疗方法，这些疾病经常在化学疗法后复发。任何单一药物或治疗方式无法治愈疾病的失败表明需要将多种药物结合起来，以协同作用以产生增强的结果。本文提出的杂细胞3D卵巢肿瘤阵列直接解决了对新研究平台的新需求，以迅速揭示最有希望的组合治疗方法，以改善该疾病的惨淡统计数据。