Elucidating Critical Dependencies Underlying Therapeutic Evasion in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

阐明费城染色体样急性淋巴细胞白血病治疗逃避背后的关键依赖性

基本信息

批准号：
10507298
负责人：
Yang-Yang Ding
金额：
$ 18.45万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-08 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10507298
关键词：
ATAC-seq Acute Lymphocytic Leukemia Acute leukemia Adolescent Adult Acute Lymphocytic Leukemia Advisory Committees Apoptosis Apoptotic Automobile Driving BCL2 gene Big Data Bioinformatics Biological Biology Cancer Etiology Cell Cycle Cell Cycle Arrest Cell Line Cell Proliferation Cells Cellular biology Cessation of life ChIP-seq Chemoresistance Child Childhood Chronic Clinical Clinical Trials Clinical Trials Design Combined Modality Therapy Complex Computational Biology DNA sequencing Dasatinib Data Data Set Dependence Diagnosis Drug Targeting Environment Epigenetic Process Evolution Future Gene Expression Profile Genes Genetic Genetic Transcription Genomics Goals Growth Harvest Heterogeneity Human In Vitro International K-Series Research Career Programs Knock-out Lead Malignant Childhood Neoplasm Malignant Neoplasms Mediating Mentors Mentorship Methodology Modeling Mutation Oncogenic Outcome Pathway interactions Patients Pharmacology Pharmacotherapy Phenotype Philadelphia Chromosome Phosphotransferases Population Recurrence Regulator Genes Relapse Research Research Personnel Research Training Resistance Resources Role Scientist Signal Transduction System Systems Biology Techniques Therapeutic Time Training Transcriptional Regulation Translating Tyrosine Kinase Inhibitor Validation Yang acute lymphoblastic leukemia cell base c-myc Genes career childhood cancer mortality clinical translation clinically relevant design early phase clinical trial experience experimental study gene regulatory network genetic signature high risk improved in vivo in vivo Model inhibitor inhibitor therapy insight knock-down leukemia molecular targeted therapies multidisciplinary multiple omics non-genetic oncogene addiction overexpression patient derived xenograft model pre-clinical precision medicine precision medicine clinical trials resistance mechanism risky driving single cell analysis skills synergism targeted agent targeted treatment therapy resistant transcription factor transcription regulatory network transcriptome transcriptome sequencing transcriptomics translational physician translational scientist treatment response

项目摘要

PROJECT SUMMARY/ABSTRACT This mentored career development award proposal will facilitate my career goal to become an independent translational researcher using advances in experimental genomics and bioinformatics to develop improved precision medicine therapies for children with difficult-to-cure cancers. During the 5-year training period I plan to acquire critical skills in computational biology and pursue additional didactic training in transcriptional regulation, death pathways, single cell analyses, and early-phase clinical trial design. The proposed studies and training will be completed under the co-mentorship of Dr. Kai Tan and Dr. Sarah Tasian, both internationally recognized leaders with complementary expertise in systems and single cell biology and in translational leukemia research, respectively. My multi-disciplinary Advisory Committee is composed of world-renowned scientists who have extensive mentoring experience and diverse expertise, including Drs. Chi Dang, Nancy Speck, John Maris, and Xiaolu Yang. The scientific proposal is aimed at elucidating critical dependencies that synergize with kinase pathway oncogene addiction in Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL), a kinase-driven leukemia with dismal outcomes. Ph-like ALL comprises 15-40% of childhood and adult ALL cases and is associated with extremely high relapse rates and very poor overall survival. We observed in preclinical Ph-like ALL models that treatment with the JAK inhibitor ruxolitinib has incomplete efficacy and also resulted in global gene expression changes. Thus, combination therapy approaches that effectively target key therapeutic escape mechanisms are needed. Additionally, single-cell variability in Ph-like ALL that may drive targeted therapy resistance is unknown. I hypothesize that ruxolitinib treatment in JAK/STAT pathway-altered Ph-like ALL cells leads to rewiring of the gene regulatory network at transcriptional and epigenetic levels (likely mediated by c-MYC), resulting in cell cycle arrest and apoptotic priming amenable to co-targeting. I propose in Aim 1 to model patient leukemia reponse to kinase inhibition in vivo and to identify transcriptional regulatory network changes during chronic ruxolitinib treatment with subsequent functional validation. This represents an unbiased approach to identifying unknown oncogenic dependencies. In Aim 2, I will use single-cell techniques to examine genetic and non-genetic sub-populational changes during targeted drug perturbation over time, then to characterize and target resistant cell states. These studies will form the basis for developing rational combinations of molecularly targeted therapies to improve cure rates for patients with Ph-like ALL. In summary, I will benefit from the exceptional interdisciplinary expertise and track-record of my mentors and Advisory Committee, as well as the rich intellectual environment and scientific resources available at CHOP and Penn, which provide an ideal setting in which to conduct cutting-edge omics analyses for eventual clinical translation. These research and training efforts will help me realize my ultimate goal to translate “big data” into clinically relevant cures for children with cancer.

项目摘要/摘要这项修订的职业发展奖提案将有助于我的职业目标成为独立翻译研究人员使用实验基因组学和生物信息学方面的进步来发展改善了难以治愈癌症儿童的精确药物疗法。在5年的培训期间我计划获得计算生物学的关键技能，并在转录中接受其他教学培训调节，死亡途径，单细胞分析和早期临床试验设计。拟议的研究和培训将在凯·坦博士和莎拉·塔西安博士的合法下完成公认的领导者具有完善的系统和单细胞生物学以及翻译白血病的领导者研究分别。我的多学科咨询委员会由世界知名的科学家组成拥有丰富的心理经验和包括Drs在内的潜水专业知识。 Chi Dang，Nancy Speck，John Maris，和小杨。该科学建议旨在阐明与激酶协同作用的关键依赖性费城染色体样（pH）急性淋巴细胞白血病（ALL）的途径癌基因成瘾激酶驱动的白血病患有令人沮丧的结果。所有pH值都占童年和成人的15-40％并与极高的继电器率和总体生存率非常差有关。我们在临床前观察到类似于用JAK抑制剂鲁辛尼治疗的所有模型的效率不完整，也导致全球基因表达变化。这是有效靶向关键疗法的组合疗法。需要逃生机制。此外，类似于pH的单细胞变异性可能会驱动针对目标治疗抗性尚不清楚。我假设在jak/stat途径改变的pH样本中，ruxolitinib治疗全部细胞导致基因调节网络在转录和表观遗传水平上的重新布线（可能是由 c-myc），导致细胞周期停滞和凋亡的启动，可与靶向。我在AIM 1中建议建模患者白血病对体内激酶抑制的反应并确定转录调节网络变化在慢性鲁唑替尼治疗期间，随后的功能验证。这代表了一种公正的方法确定未知的致癌依赖性。在AIM 2中，我将使用单细胞技术检查遗传随着时间的推移，靶向药物扰动期间的非遗传亚孔子变化，然后表征和表征靶标细胞状态。这些研究将构成开发分子合理组合的基础针对类似pH的患者的靶向疗法可提高治疗率。总而言之，我将从我的导师和咨询委员会的卓越跨学科专业知识和田径记录以及 Chop and Penn提供丰富的智力环境和科学资源，可提供理想的环境在其中进行最终临床翻译的最先进的OMICS分析。这些研究和培训努力将帮助我实现我的最终目标，将“大数据”转化为临床相关的治疗方法癌症。