Characterizing cytotoxic therapy induced shifts in the cost-to-benefit ratio of high ploidy

细胞毒疗法引起高倍性成本效益比变化的特征

• 批准号: 10688196
• 负责人: Noemi Andor
• 金额: $ 53.26万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688196
• 关键词: Affect; Apoptosis; Brain Neoplasms; Cancer cell line; Cell Death; Cell Energetics; Cell Line; Cell Proliferation; Cell Survival; Cells; Chromosome Segregation; Chromosomes; Clinical; Coin; Computing Methodologies; Cytotoxic Chemotherapy; DNA; DNA Damage; DNA sequencing; Data; Diploidy; Disease; Dose; Drug Monitoring; Drug Targeting; Endowment; Environment; Event; Evolution; Fluorescence Microscopy; Gastric Tissue; Generations; Genetic Materials; Genome; Genomic Segment; Genomics; Glioblastoma; Glucose; Growth; Haploidy; Human Genome Project; Image; In Vitro; Joints; Knowledge; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Medicine; Microtubules; Mitotic; Modeling; Outcome; Oxygen; Parents; Patients; Pharmaceutical Preparations; Phase; Phenotype; Ploidies; Population; Population Heterogeneity; Process; Prognosis; Proliferating; Research; Resistance; Resources; Risk; Role; S phase; Somatic Cell; Spatial Distribution; Stomach; Stomach Neoplasms; Testing; Time; Tissues; Validation; Vinblastine; brain tissue; cancer cell; cancer type; chromosome missegregation; cost; expectation; experimental study; fitness; gastric cancer cell; imaging platform; in silico; in vivo; inorganic phosphate; malignant stomach neoplasm; mathematical methods; mathematical model; migration; neoplastic cell; prevent; programs; replication stress; response; segregation; single cell sequencing; single-cell RNA sequencing; transcriptome; translational potential; tumor; tumor DNA; tumor heterogeneity; tumor metabolism

SUMMARY Traditional phase I dose-finding strategies monitor drug response only for two weeks, based on the assumption that it will suffice to observe how therapy affects doubling time of a homogeneous population over 2-4 generations. But with the paradigm shift that most cancers are heterogeneous comes an urgent need to consider that therapy-induced shifts in population composition manifest over longer time frames. We previously coined the “tip-over hypothesis of DNA damage therapy sensitivity”, proposing that cytotoxic therapy is effective if it pushes a cell’s somatic copy number alteration (SCNA) load above a tipping point. Variable proximity of co-existing tumor cells to this tipping point imply that dose-response relations need not be monotonic. Cytotoxic therapy can drive one cell into apoptosis, while skyrocketing another cell into malignant proliferation. As the developers of widely used computational and mathematical methods, with established research programs in tumor metabolism, and with a broad record of modeling dynamic processes and integrating various omics- and imaging platforms, our team brings complementary expertise to develop a personalized cytotoxic therapy strategy that confines therapy-induced selection of resistant clones. We will test the potential of tumor cell DNA content and dNTP substrate availability to predict a tumor’s vulnerability to increasing SCNA rate. Hereby, the aforementioned tipping point is accounted for not by elevated SCNA load alone, but by an inability of the tissue micro-environment (TME) to provide the necessary resources. Experiments are proposed in stomach and brain tumors—two cancer types whose TME can “afford” vastly different amounts of DNA. Our preliminary studies show that energetic costs of DNA content levels required for >75% SCNA load do not, in the absence of cytotoxic therapy, justify the masking benefits they bring. In particular, we showed that limiting dNTP concentrations amplify divergence in S-phase duration between high- and low-ploidy cells. Our hypothesis is that cytotoxic therapy causes a net-increase in fitness of tumors that exceed the SCNA tipping point. This hypothesis is founded on two unexpected recent findings: (i) integrated single-cell RNA- and DNA-sequencing analyses of stomach cancer cells suggests that the risk of cell death immediately after an SCNA event, rather than just SCNA rate, impacts clonal diversity. Aim 1 will integrate single cell sequencing with imaging and mathematical modeling of heterogeneous populations that evolve through chromosome missegregations, to examine observed SCNA landscapes and missegregation tolerances, and to predict effective cytotoxic therapy doses. (ii) Even minimal changes in DNA content among co-existing clones within the same Glioblastoma can result in significantly longer S-phases. Aim 2 will evaluate Oxygen, Phosphate and Glucose as rate-limiting substrates of dNTP synthesis of co-evolving subpopulations in stomach and brain tissue environments. This is the first study to investigate if and how clinical decisions can benefit from integrating a tumor environment’s energetic provision with the energetic demands of cancer cells’ genomic makeup.

概括 基于假设 它将供应观察治疗如何影响2-4岁以上同质人群的两倍时间 几代人。但是，随着大多数癌症是异质的范式转变，迫切需要考虑 治疗引起的人口组成的转变在较长的时间范围内表现出来。我们以前创造了 “ DNA损伤疗法敏感性的小费假设”，提出细胞毒性疗法是有效的 单元格在临界点上方的躯体拷贝数变化（SCNA）负载。共存的可变接近度 肿瘤细胞到这个临界点意味着剂量反应关系不必单调。细胞毒性疗法可以 将一个细胞驱动到凋亡中，同时将另一个细胞飞向恶性增殖。作为开发商 广泛使用的计算和数学方法，肿瘤中建立的研究计划 新陈代谢，并具有建模动态过程并整合各种OMICS - 和 成像平台，我们的团队带来了完善的专业知识来制定个性化的细胞毒性疗法策略 这限制了治疗引起的抗性克隆的选择。我们将测试肿瘤细胞DNA含量和 DNTP底物的可用性可预测肿瘤易于增加SCNA速率。特此， 仅凭SCNA负载升高，而是由于组织的无力而不是升高的临界点。 微环境（TME）提供必要的资源。实验是在摊位和大脑中提出的 肿瘤 - 两种癌症类型的TME可以“ A a o od”大量不同的DNA。我们的初步研究 在没有细胞毒性的情况下，表明> 75％SCNA负载所需的DNA含量水平的能量成本不会 治疗，证明他们带来的掩盖益处。特别是，我们表明限制DNTP浓度 在高倍和低倍细胞之间的S相持续时间扩增差异。我们的假设是细胞毒性 治疗会导致超过SCNA临界点的肿瘤适应性的净炎症。这个假设是 建立在两个出乎意料的发现上：（i）集成的单细胞RNA和DNA-seter-seter-sewers分析 胃癌细胞表明，SCNA事件后立即发生细胞死亡的风险，而不仅仅是SCNA 速率，影响克隆多样性。 AIM 1将将单细胞测序与成像和数学集成 通过染色体错误分析演化的异质种群的建模，检查观察到的 SCNA景观和错误分析公差，并预测有效的细胞毒性疗法剂量。 （ii）甚至 同一胶质母细胞瘤内共存克隆中DNA含量的最小变化可能导致 明显更长的s量。 AIM 2将评估氧气，磷酸盐和葡萄糖作为限制速率底物 DNTP合成了stallch和脑组织环境中共同群的共同群。这是第一个研究 调查临床决策是否可以从整合肿瘤环境的能源中受益 提供癌细胞基因组构成的能量需求。

项目成果

Mathematical Modeling of Clonal Interference by Density-Dependent Selection in Heterogeneous Cancer Cell Lines.

• DOI: 10.3390/cells12141849
• 发表时间: 2023-07-14
• 期刊: CELLS
• 影响因子: 6
• 作者: Veith, Thomas;Schultz, Andrew;Alahmari, Saeed;Beck, Richard;Johnson, Joseph;Andor, Noemi
• 通讯作者: Andor, Noemi