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.

项目摘要 恶性黑色素瘤是产生色素的黑素细胞的肿瘤，是导致大多数的 与皮肤癌有关的死亡。皮肤黑色素瘤可以通过手术惊喜成功治疗； 但是，一旦疾病转移，生存率将大大降低。最近的一些研究 已经提出，在某些情况下，肿瘤微环境的线索可以表观遗传编程 黑色素瘤细胞进入恶性黑色素瘤起始细胞（MIC），该细胞具有耐药性，并引发了浸润和浸润和 转移。在Kilian实验室中，我们发现了肿瘤拓扑与激活之间的关系 肿瘤性麦克风可能证明转移之前的早期转化步骤。在科普兰实验室， 我们已经开发了新型的组合疗法来治疗黑色素瘤，几名患者衍生的肿瘤异种移植物 （PDTX）准确模仿患者对护理标准的反应的模型。我们将采用我们的套房 设计的细胞外矩阵可以解读拓扑，力学和矩阵之间的相互作用 组成，指导在患者衍生细胞中激活MIC状态，这些细胞显示不同程度的药物 灵敏度。我们将这些矩阵参数转换为新的3D几何结构组织工程 微肿块模型。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 - 基于格式并评估对护理标准和前瞻性新疗法的微量反应。我们将使用 无胸腺裸鼠的原位异种移植物研究细胞的生长，侵袭和传播，并使用 信息以告知我们的3D肿瘤模拟型的设计。为了利用我们的微量阵列 治疗性开发，我们将使用我们的肿瘤模仿者进行一项小型试点研究 - 体外和作为一种新型体内微肿瘤异种移植物，以辨别我们的仿生系统概括程度如何 与细胞系和异种移植物相比，肿瘤发生和药物敏感性。该项目旨在建立一个 完全甚至什至替代患者衍生Xenographotic（PDX）模型的替代方法，其中患者的细胞 源自活检或惊喜的人可能被整合到个性化医学的肿瘤模拟中。