Targeting regenerative reprogramming in colorectal cancer

靶向结直肠癌的再生重编程

• 批准号: 10644262
• 负责人: Salvador Alonso Martinez
• 金额: $ 29.26万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644262
• 关键词: ATAC-seq; Advisory Committees; Antineoplastic Agents; Automobile Driving; Award; Bar Codes; Carcinoma; Cells; Cellular Stress; Chemotherapy and/or radiation; Chromatin; Clinical; Clinical Trials; Colorectal Cancer; Computational Biology; Consensus; Data; Development; Diagnosis; Drug resistance; Epigenetic Process; Event; Exposure to; Fluorouracil; Genetic; Genetic Engineering; Genetic Transcription; Genotype; Goals; Growth; Immune response; Inflammatory; KRAS2 gene; Knowledge; Laboratories; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Medicine; Mentors; Mentorship; Mesenchymal; Mutation; Neoadjuvant Therapy; Organoids; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Phenotype; Population; Pre-Clinical Model; Rectal Neoplasms; Refractory; Refractory Disease; Research; Research Personnel; Residual Neoplasm; Resistance; Risk; Role; Sampling; Technology; Testing; Therapeutic; Treatment Failure; Tumor Escape; Validation; anticancer research; cancer cell; cancer therapy; career; career development; clinical translation; combinatorial; cytotoxic; design; effective therapy; environmental stressor; epigenetic therapy; exome; exome sequencing; exosome; experimental study; fitness; improved outcome; inhibitor; innovation; innovative technologies; knock-down; metastatic colorectal; molecular dynamics; molecular subtypes; mouse model; neoplastic cell; non-genetic; participant enrollment; pressure; prevent; programs; regenerative; regenerative cell; research and development; resistance mechanism; response; response biomarker; restraint; single cell technology; single-cell RNA sequencing; small hairpin RNA; small molecule inhibitor; stem cells; targeted treatment; tissue regeneration; tool; transcriptome sequencing; treatment response; treatment strategy; tumor

ABSTRACT Poorly defined fitness features enable a subset of cancer cells to survive therapy, ultimately giving rise to treatment-refractory tumors. The expanded use of sequencing tools have led to the recognition that refractory tumors often lack a genetic mechanism of resistance, and instead co-opt a regenerative program characterized by activation of developmental, inflammatory, mesenchymal and stem cell features. Importantly, these regenerative states are conserved across diverse cancers of epithelial origin, and are potentially reversible. Our preliminary data indicate that therapy resistance in colorectal cancer (CRC) is fueled by preexisting cells via a YAP-driven regenerative program that is strikingly similar to the consensus molecular subtype 4 of CRC, a poor risk phenotype often observed in treatment-refractory tumors. Our central hypothesis is that a preexisting population drives regenerative reprogramming and tumor escape through epigenetic adaptations that can be targeted therapeutically. First we propose characterizing the preexisting (pre-resistant) state using barcode lineage tracing and single-cell technologies. Using patient-derived organoids (PDOs) to isolate the founding clones of resistance, we will study the contribution of preexisting versus actively gained fitness features through whole-exome (WES) and RNA sequencing (RNA-seq). Using pre-clinical models of resistance to KRAS-inhibition (KRASi), we will define the role of genetic and non-genetic drivers of tumor escape. To develop approaches that abrogate regenerative reprogramming, we will perform a focused shRNA screen targeting 50 chromatin regulators. To expedite clinical translation, we will test readily available compounds targeting the top hits of the screen, in combination with standard therapies. We believe that our innovative tools will maximize our opportunity to develop treatment approaches with immediate clinical impact. During the award period, the candidate will conduct research at Weill Cornell Medicine (WCM) and Memorial Sloan Kettering (MSK) under the mentorship of Dr. Lukas Dow and an advisory committee. The candidate will commit at least 9 person-months of his professional effort to the research and career development activities outlined here. With his mentor and advisory committee, the candidate has designed a 5-year plan aimed at expanding his knowledge and expertise in cancer research, including single cell technologies, computational biology, genetic engineering, and functional screens. The goal of the career plan is to launch an independent career as a laboratory investigator focused on therapy resistance and biomarkers of response in CRC.

抽象的 定义较差的健身特征使癌细胞的一部分能够在治疗中生存，最终导致 治疗 - 饮食肿瘤。扩展的测序工具的使用导致了耐火材料的认识 肿瘤通常缺乏抗药性的遗传机制，而是选择了再生程序的特征 通过激活发育，炎症，间充质和干细胞特征。重要的是，这些 再生状态在上皮来源的各种癌症中保守，并且可能可逆。我们的 初步数据表明，结直肠癌（CRC）的治疗抗性是通过A的细胞通过A促进的 YAP驱动的再生程序与CRC的共有分子亚型4非常相似，CRC很差 在治疗症状肿瘤中经常观察到风险表型。 我们的中心假设是，先前存在的人口驱动再生重编程和肿瘤逃生 通过可以针对治疗的表观遗传适应。首先，我们提出表征 使用条形码谱系跟踪和单细胞技术，预先存在（耐药性）状态。使用患者来源 器官（PDOS）为了隔离抗药性的创建克隆，我们将研究先前存在的贡献 积极通过全外视（WES）和RNA测序（RNA-Seq）获得健身特征。使用临床前 对KRAS抑制（KRASI）的抗性模型，我们将定义遗传和非遗传驱动因素的作用 肿瘤逃脱。为了开发废除再生重编程的方法，我们将执行重点 shRNA筛选靶向50个染色质调节剂。为了加快临床翻译，我们将随时测试 与标准疗法结合使用的化合物，靶向屏幕的顶部命中率。我们相信我们的 创新的工具将最大程度地利用我们开发具有直接临床影响的治疗方法的机会。 在奖励期间，候选人将在Weill Cornell Medicine（WCM）和纪念馆进行研究 在Lukas Dow博士和咨询委员会的指导下，Sloan Kettering（MSK）。候选人会 将他的专业努力的至少9个人数投入研究和职业发展活动 在这里概述。候选人与他的导师和咨询委员会一起设计了一项针对的5年计划 扩大他在癌症研究方面的知识和专业知识，包括单细胞技术，计算 生物学，基因工程和功能筛选。职业计划的目标是启动独立 作为实验室研究者的职业专注于CRC中的耐药性和反应的生物标志物。