Project 1: How tumor ensemble models with two experimental models predict tumor dormancy & reactivation in cancers with gender and/or ethnic disparities

项目1：具有两个实验模型的肿瘤集成模型如何预测肿瘤休眠

• 批准号: 10021575
• 负责人: Richard Mark White
• 金额: $ 10.02万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021575
• 关键词: 4T1; Affect; Agreement; American; Animal Cancer Model; Animals; Behavior; Biopsy; Breast Cancer Cell; Breast Cancer Model; Breast Melanoma; Cancer Model; Cancer Science; Cell Death; Cell Line; Cell division; Cells; Cessation of life; Community Outreach; Cutaneous Melanoma; Data; Dependence; Diffusion; Disease Progression; Distant Metastasis; Doxorubicin; Drug Delivery Systems; Education and Outreach; Epigenetic Process; Equilibrium; Ethnic Origin; Exhibits; Experimental Models; Female; Fishes; Fluorouracil; Funding; Gender; Generations; Genetic; Genome; Health; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunosuppression; Immunotherapy; Inbred BALB C Mice; Luciferases; Malignant Neoplasms; Mathematics; Melanoma Cell; Memorial Sloan-Kettering Cancer Center; Micrometastasis; Mitosis; Modeling; Monitor; Mus; Mutation; Necrosis; Neoplasm Metastasis; Operative Surgical Procedures; Paclitaxel; Patients; Periodicity; Phenotype; Population; Primary Neoplasm; Primary carcinoma of the liver cells; Probability; Process; Proteomics; Recurrence; Sample Size; Shapes; Specificity; Steroids; System; Testing; Theoretical model; Time; Translations; Transplantation; Tumor Cell Line; Variant; Virulent; Woman; Zebrafish; anticancer research; chemotherapy; ethnic disparity; experimental study; gender difference; gender disparity; in vitro Model; insight; male; malignant breast neoplasm; mathematical model; melanoma; neoplastic cell; non-invasive monitor; predictive modeling; predictive test; response; trait; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment

Cancer is one of the world's major health problems. After chemotherapy or surgery, some cancers, e.g., breast cancer and melanoma, by a still mysterious mechanism persist, apparently dormant, for years before distant metastases appear and tumors reactivate and grow. Latent tumor cells may survive by their microenvi- ronment partially excluding T-cells that would attack them. Transplant studies indicate that, rather than static quiescence, these cells and the immune system are in dynamic equilibrium and periodic bursts of cell division and elimination sometimes transform unobservable micrometastases that accumulate genetic, epigenetic and proteomic changes into macrometastases. Details and a complete mechanism are lacking. There is a paucity of experimental or theoretical models that recapitulate latency or its reactivation. One mouse breast cancer model exhibits short-term latency & recurrence. Mathematical cancer models typically describe single tumor growth and/or metastasis generation or the probability of several mutations, but not dor- mancy. We posit a new mathematical population model for the dynamics of a large ensemble (from one or many patients) of tumors of all sizes subject to mitosis, cell death (immunity, chemo or immunotherapy, necro- sis, etc.) and metastasis. Ensembles naturally incorporate response variations of similar tumors. Predictions are probabilistic, proportional to the expected tumor number of each size and time from any initial size distribu- tion. Smaller tumors often respond better to chemotherapy than larger ones, likely due to the latter's more ac- cumulated mutations; tumor-size-dependent parameters model this most simply. Our model finds a surprising interaction among these size-dependent processes in an ensemble that generates intriguing new unexpected qualitative behavior, e.g., diffusion in tumor size space that for the first time predicts dormancy & recurrence. This proposal intimately integrates this new mathematical model with the BALB/c murine breast cancer and the clear, stripeless zebrafish melanoma systems; both allow live non-invasive monitoring of tumor numbers and sizes vs time without animal sacrifice. Our model fits existing human hepatocellular carcinoma and im- mune-suppressed & competent fish melanoma histograms at many times extremely well with only 3 parame- ters. We plan new fish experiments to control/tune the level of immunity so as to access and test parameters predicted to yield dormancy & recurrence. We shall carry out detailed experiments on the mouse breast cancer system, which may exhibit dormancy & recurrence naturally, and use it to test our model. We shall also attempt to modulate its immunity to access and test parameters predicted to yield dormancy & recurrence. Since both these cancers show both ethnic and gender disparities, we shall use melanoma cell with snps that recapitulate ethnicity-specific genetics and segregate (fish) data by gender so as to see if parameters show ethnic and/or gender specificity; this would carry over to dormancy & recurrence. Time and funds permitting, we shall also begin to look at the effect of tumor shape on its parameters' tumor size dependences.

癌症是世界主要健康问题之一。化疗或手术后，某些癌症，例如， 乳腺癌和黑色素瘤，通过一种仍然神秘的机制，在几年前就持续存在，显然处于休眠状态。 出现远处转移，肿瘤重新激活并生长。潜伏的肿瘤细胞可能通过其微环境存活 环境部分排除了会攻击它们的T细胞。移植研究表明，不是静态的 静止时，这些细胞和免疫系统处于动态平衡和细胞分裂的周期性爆发 和消除有时会改变不可观察的微转移，这些微转移会积累遗传、表观遗传和 蛋白质组改变为大转移。缺乏细节和完整的机制。 缺乏概括潜伏期或其重新激活的实验或理论模型。一 小鼠乳腺癌模型表现出短期潜伏期和复发。数学癌症模型通常 描述单个肿瘤的生长和/或转移的产生或几种突变的概率，但不描述 曼西。我们为大型系综的动态提出了一种新的数学总体模型（来自一个或 许多患者）各种大小的肿瘤都经历有丝分裂、细胞死亡（免疫、化疗或免疫治疗、坏死） sis等）和转移。集成自然地包含了类似肿瘤的反应变化。预测 是概率性的，与任何初始大小分布的每个大小和时间的预期肿瘤数量成正比 。较小的肿瘤通常比较大的肿瘤对化疗的反应更好，这可能是因为后者更有效。 累积突变；肿瘤大小相关参数对此进行了最简单的建模。我们的模型发现了一个令人惊讶的 这些依赖于尺寸的过程之间的相互作用在一个整体中产生了有趣的新的意想不到的结果 定性行为，例如，首次预测休眠和复发的肿瘤大小空间中的扩散。 该提案将这种新的数学模型与 BALB/c 小鼠乳腺癌紧密结合， 清晰、无条纹的斑马鱼黑色素瘤系统；两者都允许实时无创监测肿瘤数量 以及大小与时间的关系，无需牺牲动物。我们的模型适合现有的人类肝细胞癌和im- mune 抑制和有效的鱼黑色素瘤直方图在很多时候都非常好，只有 3 个参数 之三。我们计划新的鱼类实验来控制/调整免疫水平，以便访问和测试参数 预计会产生休眠和复发。我们将对小鼠乳腺癌进行详细的实验 系统，它可能会自然地表现出休眠和复发，并用它来测试我们的模型。我们也将尝试 调节其对访问和测试预计产生休眠和复发的参数的免疫力。既然两者 这些癌症表现出种族和性别差异，我们将使用带有 SNP 的黑色素瘤细胞来概括 特定种族的遗传学并按性别分离（鱼）数据，以便查看参数是否显示种族和/或 性别特异性；这将延续到休眠和复发。如果时间和资金允许，我们还将 开始研究肿瘤形状对其参数肿瘤大小依赖性的影响。