Engineered microtumor arrays for development of combination therapies

用于开发联合疗法的工程微肿瘤阵列

• 批准号: 10442587
• 负责人: John A. Copland
• 金额: $ 26.01万
• 依托单位: UNIVERSITY OF NEW SOUTH WALES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442587
• 关键词: 3-Dimensional; BRAF gene; Biology; Biomedical Engineering; Biomimetics; Biopsy; Cell Fraction; Cell Line; Cells; Cessation of life; Characteristics; Clinical Trials; Combinatorics; Combined Modality Therapy; Cues; Cutaneous Melanoma; Dangerousness; Data; Development; Disease; Disease Progression; Drug resistance; Engineering; Epigenetic Process; Excision; Extracellular Matrix; Geometry; Growth; Harvest; Heterogeneity; Human; Implant; In Vitro; International; Laboratories; Lead; MEK inhibition; MEKs; Malignant Neoplasms; Mechanics; Melanoma Cell; Metastatic Melanoma; Modeling; Monitor; Mus; Mutation; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Phenotype; Pigments; Pilot Projects; Pre-Clinical Model; Primary Neoplasm; Process; Prognosis; Proteins; RNA Interference; Reproducibility; Resistance; Role; Signal Transduction; Skin Cancer; Somatic Mutation; Structure-Activity Relationship; Survival Rate; Suspensions; System; Techniques; Therapeutic; Tissue Engineering; Tissues; Translating; Tumor Tissue; Tumor-Derived; Xenograft Model; Xenograft procedure; base; cell type; chemotherapy; design; drug development; drug sensitivity; epigenetic regulation; geometric structure; high throughput analysis; in vivo; individualized medicine; inhibitor; intravital imaging; knock-down; mechanotransduction; melanocyte; melanoma; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; patient response; pluripotency; prospective; response; screening; standard of care; stem cells; success; targeted treatment; therapeutic development; three-dimensional modeling; tool; treatment response; tumor; tumor heterogeneity; tumor microenvironment; tumor progression; tumor xenograft; tumorigenesis; tumorigenic

PROJECT SUMMARY Malignant melanoma is a tumor of the pigment-producing melanocytes, and is responsible for the majority of skin cancer related deaths. Cutaneous melanoma can be successfully treated through surgical excision; however, once the disease has metastasized, the survival rate is significantly reduced. Some recent studies have suggested that in certain contexts, cues from the tumor microenvironment can epigenetically reprogram melanoma cells into a malignant melanoma initiating cell (MIC) that is drug resistant and primed for invasion and metastasis. In the Kilian laboratory we have discovered a relationship between tumor topology and activation of a tumorigenic MIC that may prove an early transformation step preceding metastasis. In the Copland laboratory, we have developed novel combination therapies to treat melanoma, and several patient derived tumor xenograft (PDTX) models that accurately mimic patient response to standard of care. We will employ our suite of engineered extracellular matrices to decipher the interplay between topology, mechanics and matrix composition, in guiding activation of the MIC state in patient derived cells that display varying degrees of drug sensitivity. We will translate these matrix parameters into a novel 3D geometrically structured tissue engineered microtumor model. To evaluate the potential as a tool for drug development we will fabricate a 96-well plate- based format and evaluate microtumor response to standard of care and prospective new therapies. We will use orthotopic xenografts in athymic nude mice to study growth, invasion and dissemination of our cells, and use this information to inform the design of our model 3D tumor-mimics. Towards leveraging our microtumor array for therapeutic development, we will perform a small pilot study of combination therapies using our tumor-mimics— in vitro and as a novel in vivo microtumor xenograft—to discern how closely our biomimetic system recapitulates oncogenesis and drug sensitivity compared to cell lines and xenografts. This project aims to establish a complementary or even alternative approach to patient derived xenograft (PDX) models, where a patient’s cells derived from biopsy or excision may be integrated into a tumor-mimic for individualized medicine.

项目概要 恶性黑色素瘤是产生色素的黑色素细胞的肿瘤，是造成大多数黑色素瘤的原因。 皮肤癌相关的死亡可以通过手术切除成功治疗； 然而，最近的一些研究表明，一旦疾病发生转移，生存率就会显着降低。 研究表明，在某些情况下，来自肿瘤微环境的线索可以进行表观遗传重编程 黑色素瘤细胞转化为恶性黑色素瘤起始细胞（MIC），该细胞具有耐药性并准备好侵袭和 在 Kilian 实验室，我们发现了肿瘤拓扑结构与激活之间的关系。 致瘤性 MIC 可能证明转移前的早期转化步骤。 我们开发了新的联合疗法来治疗黑色素瘤和几种患者来源的肿瘤异种移植物 （PDTX）模型可以准确模拟患者对标准护理的反应，我们将采用我们的套件。 设计细胞外基质来破译拓扑、力学和基质之间的相互作用 组合物，引导显示不同程度药物的患者来源细胞中 MIC 状态的激活 我们将把这些矩阵参数转化为一种新颖的 3D 几何结构组织工程。 为了评估作为药物开发工具的潜力，我们将制造一个 96 孔板 - 我们将使用基于格式并评估微肿瘤对护理标准和前瞻性新疗法的反应。 无胸腺裸鼠的原位异种移植物研究我们细胞的生长、侵袭和传播，并使用此 为我们的 3D 肿瘤模拟模型的设计提供信息，以利用我们的微肿瘤阵列。 治疗开发，我们将使用我们的肿瘤模拟物进行联合疗法的小型试点研究—— 体外和作为一种新型体内微肿瘤异种移植物——以了解我们的仿生系统的重现程度 与细胞系和异种移植物相比，肿瘤发生和药物敏感性。 患者来源的异种移植（PDX）模型的补充甚至替代方法，其中患者的细胞 来自活检或切除的肿瘤可以整合到肿瘤模拟物中以用于个体化医疗。