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.

癌症是世界上主要的健康问题之一。化学疗法或手术后，一些癌症，例如 乳腺癌和黑色素瘤，通过一种仍然神秘的机制持续存在，显然是休眠的多年 远处转移出现，肿瘤重新激活并生长。潜在的肿瘤细胞可以通过其微膜生存 Ronment部分排除了会攻击它们的T细胞。移植研究表明，而不是静态 静止，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状态 消除有时会转化不可观察的微转移，从而积累遗传，表观遗传和 蛋白质组学变成大量变体。缺乏细节和完整的机制。 实验或理论模型很少概括潜伏期或其重新激活。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 描述单个肿瘤生长和/或转移产生或几种突变的概率，但不存在 Mancy。我们为一个大型合奏的动态设置了一个新的数学人口模型（来自一个或 许多患者）各种大小的肿瘤，受到有丝分裂，细胞死亡（免疫，化学疗法或免疫疗法，死灵）的肿瘤 sis等）和转移。合奏自然融合了相似肿瘤的反应变化。预测 具有概率，与任何初始尺寸分布的每个大小的预期肿瘤数和时间成正比 tion。较小的肿瘤通常比较大的肿瘤对化疗反应更好，这可能是由于后者的AC- 累积突变；肿瘤尺寸依赖性参数最简单地模拟了这一点。我们的模型发现一个令人惊讶的 在合奏中，这些尺寸依赖性过程之间的相互作用会产生有趣的新意外事件 定性行为，例如，首次预测休眠与复发的肿瘤大小空间的扩散。 该建议将这种新的数学模型与BALB/C鼠乳腺癌和 透明，无脱剥离的斑马鱼黑色素瘤系统；两者都允许对肿瘤数量的无创监测 大小与没有动物牺牲的时间。我们的模型适合现有的人类肝细胞癌和IM- Mune抑制和称职的鱼类黑色素瘤直方图非常好，只有3个参数 Ters。我们计划进行新的鱼实验，以控制/调整免疫水平，以访问和测试参数 预测会产生休眠和复发。我们将对小鼠乳腺癌进行详细的实验 系统可能自然表现出休眠和复发，并使用它来测试我们的模型。我们还将尝试 调节其访问和测试参数的免疫力，预测会产生休眠和复发。两者既是 这些癌症同时显示种族和性别差异，我们将使用概括的SNP使用黑色素瘤细胞 通过性别，特定于种族的遗传学和隔离（鱼）数据，以查看参数是否显示种族和/或 性别特异性；这将导致休眠与复发。时间和资金允许，我们也将 开始查看肿瘤形状对其参数的肿瘤大小依赖性的影响。