Systems Modeling of Tumor Heterogeneity and Therapy Response in Colorectal Cancer

结直肠癌肿瘤异质性和治疗反应的系统建模

• 批准号: 10174854
• 负责人: Fiona Ginty
• 金额: $ 64.58万
• 依托单位: GENERAL ELECTRIC GLOBAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174854
• 关键词: Algorithms; Alternative Therapies; Ants; Apoptosis; Area; BRAF gene; Biological Markers; Biological Models; Cell Line; Cell model; Cells; Cessation of life; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Clinical Markers; Clinical Trials; Collaborations; Colorectal Cancer; Competence; Complex; Data; Diagnostic; Disease; Disease Resistance; Distal; Drug resistance; Endothelial Cells; Epithelial Cells; Fluorouracil; Funding; Funding Agency; Heterogeneity; Image; Imaging technology; Immune; Immunocompetence; In Vitro; Incidence; International; Intervention; Investigation; Ireland; KRAS2 gene; Letters; Location; Measurement; Measures; Memorial Sloan-Kettering Cancer Center; Metabolism; Methods; Modeling; Molecular Genetics; Monitor; Multi-Drug Resistance; Northern Ireland; Oncologist; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern Recognition; Performance; Prognosis; Prognostic Marker; Proteins; Randomized Clinical Trials; Randomized Controlled Trials; Recommendation; Recurrence; Research; Resistance profile; Resolution; Risk; Sampling; Spatial Distribution; Surgeon; Systems Biology; TP53 gene; Tissues; United States; United States National Institutes of Health; Universities; Validation; Vision; Work; base; cancer diagnosis; cancer recurrence; cancer stem cell; cell stroma; cellular imaging; chemotherapy; cohort; college; colon cancer patients; cytotoxicity; determinants of treatment resistance; drug testing; endothelial stem cell; genotoxicity; improved; insight; lymph nodes; molecular subtypes; mortality; multiplexed imaging; negative affect; neoplastic cell; novel; novel therapeutics; patient subsets; predictive marker; predictive modeling; predictive signature; prognostic; programs; rectal; response; single cell analysis; stem; stem cells; targeted treatment; tumor; tumor heterogeneity; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) has one of the highest worldwide incidence (>1.3 million new cases) and mortality rates (~610,000 deaths annually). Genotoxic chemotherapy in stage II and III confers minimal treatment benefit (im- proved survival in 3-4% stage II patients and 15-20% patients in stage III), and predictive markers for therapy response are lacking. CRC patients would strongly benefit from novel prognostic and predictive biomarkers that identify patients who will not benefit from 5-FU-based chemotherapy, redirecting them towards targeted or novel interventions and intensified disease monitoring. One of the challenges in implementing such a biomarker approach is that CRC is a highly heterogeneous disease, with evidence for multiple subtypes emerging. The pur- ported causes of chemotherapy resistance are complex and multi-factorial, including dysfunctional apoptosis pathways, immune cell cytotoxicity (in turn, negatively affecting apoptosis and reducing immune-competency) and presence of cancer stem cells (and expression of multi-drug resistance proteins). The numbers, spatial dis- tribution and pathway status of these cells in the tumor and stromal area (and their heterogeneity) is an import- ant consideration, but the significance is not understood. The central hypothesis under investigation in this pro- posal is that modeling of apoptosis pathways at a cellular level and integration with tumor heterogeneity mark- ers in stage II and III CRC patient samples will better predict chemotherapy response, compared to standard biomarkers and treatment algorithms. While the immediate application would be for stage II patients, the re- sults will provide much needed new mechanistic insights into stage III outcomes and diagnostic opportunities for new therapies. We will use a novel single cell imaging technology to profile up to 50 proteins in a single tis- sue micro array (TMA) sections and quantify cellular and spatial distribution in tumor and stromal regions. in >1500 stage II and III CRC patients. These proteins will represent the apoptosis pathway, tumor microenviron- ment, stem cells, stroma and epithelial cells and be quantified at single cell level. Established models will be used to convert single cell apoptosis data into apoptosis competency scores. Heterogeneity in cellular apoptosis will be correlated with recurrence risk in treated and untreated patients. Tumor microenviroment measures (stroma, immune, endothelial), stem cells and available molecular subtype data will be combined with apoptosis scores to further elucidate therapy response. We will validate significant predictive biomarkers in a randomized controlled trial with chemotherapy treated and untreated patients. Finally, in a subset of patients with available cell lines, we will experimentally investigate mechanisms of drug resistance and test whether novel apoptosis- inducing therapies could potentially provide an alternative to chemotherapy. Predictive biomarkers in CRC could potentially save hundreds of thousands of patients per year from treatments with limited benefit and pro- vide oncologists with greater ability to direct patients towards other therapies.

项目总结/摘要 结直肠癌（CRC）是世界范围内发病率和死亡率最高的疾病之一（> 130万新发病例） （每年约61万人死亡）。II期和III期的遗传毒性化疗带来的治疗获益最小（IM-100）。 3-4%的II期患者和15-20%的III期患者证实存活），以及治疗的预测标志物 缺乏回应。CRC患者将从新的预后和预测生物标志物中获益， 识别不会从基于5-FU的化疗中获益的患者，将他们重新定向到靶向或 新的干预措施和强化的疾病监测。实施这种生物标志物的挑战之一是， 目前的研究方法是，CRC是一种高度异质性的疾病，有证据表明出现了多种亚型。那只- 化疗耐药的原因是复杂和多因素的，包括功能失调的细胞凋亡 途径，免疫细胞的细胞毒性（反过来，负面影响细胞凋亡和降低免疫能力） 以及癌症干细胞的存在（以及多药耐药蛋白的表达）。数字，空间分布- 这些细胞在肿瘤和间质区域的增殖和通路状态（及其异质性）是重要的， 但它的意义却不被理解。在这个亲调查的中心假设- 最重要的是在细胞水平上对凋亡途径进行建模，并与肿瘤异质性标志物整合， II期和III期CRC患者样本中的患者与标准样本相比， 生物标志物和治疗算法。虽然立即适用于第二阶段的病人，重新- 结果将为III期结局和诊断机会提供急需的新机制见解 新的治疗方法。我们将使用一种新的单细胞成像技术，在单个组织中分析多达50种蛋白质， 扫描微阵列（TMA）切片并定量肿瘤和间质区域中细胞和空间分布。在 >1500例II期和III期CRC患者。这些蛋白质将代表细胞凋亡途径，肿瘤微环境， 间质细胞、干细胞、基质细胞和上皮细胞，并在单细胞水平上定量。已建立的模型将 用于将单细胞凋亡数据转换为凋亡能力评分。细胞凋亡中的异质性 将与治疗和未治疗患者的复发风险相关。肿瘤微环境测量 （间质、免疫、内皮）、干细胞和可用的分子亚型数据将与细胞凋亡相结合 评分以进一步阐明治疗反应。我们将在一个随机的 化疗治疗和未治疗患者的对照试验。最后，在一个可用的患者子集中， 细胞系，我们将实验研究耐药性的机制，并测试是否新的凋亡- 诱导疗法可能提供化疗的替代方案。CRC中的预测性生物标志物 每年可能使数十万患者免于接受疗效有限的治疗， 使肿瘤学家更有能力指导病人接受其他治疗。

项目成果

FLINO: a new method for immunofluorescence bioimage normalization.

• DOI: 10.1093/bioinformatics/btab686
• 发表时间: 2022-01-03
• 期刊: Bioinformatics (Oxford, England)
• 作者: Graf J;Cho S;McDonough E;Corwin A;Sood A;Lindner A;Salvucci M;Stachtea X;Van Schaeybroeck S;Dunne PD;Laurent-Puig P;Longley D;Prehn JHM;Ginty F
• 通讯作者: Ginty F

Prolyl 4-hydroxylase alpha 1 protein expression risk-stratifies early stage colorectal cancer.

• DOI: 10.18632/oncotarget.27491
• 发表时间: 2020-02-25
• 期刊: Oncotarget
• 作者: Tanaka, Atsushi;Zhou, Yihua;Roehrl, Michael H
• 通讯作者: Roehrl, Michael H

An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution.

• DOI: 10.1038/s41418-021-00895-9
• 发表时间: 2022-04
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Lindner AU;Salvucci M;McDonough E;Cho S;Stachtea X;O'Connell EP;Corwin AD;Santamaria-Pang A;Carberry S;Fichtner M;Van Schaeybroeck S;Laurent-Puig P;Burke JP;McNamara DA;Lawler M;Sood A;Graf JF;Rehm M;Dunne PD;Longley DB;Ginty F;Prehn JHM
• 通讯作者: Prehn JHM

Stratification of chemotherapy-treated stage III colorectal cancer patients using multiplexed imaging and single-cell analysis of T-cell populations.

• DOI: 10.1038/s41379-021-00953-0
• 发表时间: 2022-04
• 期刊: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
• 作者: Stachtea X;Loughrey MB;Salvucci M;Lindner AU;Cho S;McDonough E;Sood A;Graf J;Santamaria-Pang A;Corwin A;Laurent-Puig P;Dasgupta S;Shia J;Owens JR;Abate S;Van Schaeybroeck S;Lawler M;Prehn JHM;Ginty F;Longley DB
• 通讯作者: Longley DB

surviveR: a flexible shiny application for patient survival analysis.

• DOI: 10.1038/s41598-023-48894-9
• 发表时间: 2023-12-13
• 期刊: Scientific reports
• 影响因子: 4.6