Hijacking cancer driver to activate cell death by chemically induced proximity

劫持癌症驱动因素通过化学诱导接近激活细胞死亡

• 批准号: 10388906
• 负责人: Samuel H Kim
• 金额: $ 3.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2025-06-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388906
• 关键词: Address; Apoptosis; Apoptotic; BCL2 gene; Binding; Bioinformatics; Biological Assay; Biology; Breast Cancer Cell; Breast Cancer cell line; Bypass; CASP3 gene; Cancer Biology; Cell Death; Cell Survival; Cells; ChIP-seq; Chemicals; Consensus; Development; Disease Progression; Doxycycline; Enhancers; Epigenetic Process; Equilibrium; Estrogen Receptors; Estrogen receptor positive; Family member; Feedback; Fibrinogen; Gene Expression Regulation; Genetic Transcription; Goals; Homeostasis; Individual; Induction of Apoptosis; Informatics; Knowledge; Lead; Libraries; Ligands; Literature; MCF7 cell; Malignant Neoplasms; Maps; Measures; Mutation; Oncogenes; Pathway interactions; Patients; Physicians; Proteins; Research Personnel; Resistance; Risk; Scientist; Sirolimus; Specificity; T47D; Tacrolimus Binding Proteins; Testing; Therapeutic; Therapeutic Effect; Time; Training; Trans-Activators; Transactivation; Transcript; Transcription Coactivator; Translating; Up-Regulation; base; cancer cell; cancer therapy; cancer type; experimental study; gain of function; genome-wide; inhibitor; loss of function; malignant breast neoplasm; novel; novel therapeutic intervention; novel therapeutics; overexpression; personalized medicine; programs; promoter; recruit; resazurin; resistance mechanism; resistance mutation; skills; targeted cancer therapy; targeted treatment; therapy resistant; tool; transcription factor; transcriptome sequencing; transcriptomics

Abstract Personalized targeted cancer therapy, while initially effective, leads to resistance and disease progression in >50% of patients in as rapidly as few months after initiating therapy. These therapies directly inhibit the catalytic and/or ligand-induced functions of the cancer driver, leading to resistance via mutational escape or epigenetic/transcriptional bypass. To address mutational escape, recent therapeutic approaches leverage Chemically induced Proximity (CiP): bifunctional molecules that recruit two proteins into proximity for an emergent therapeutic effect. However, current CiP-based therapies are limited to degradation, which suffers from similar feedback mechanisms of resistance as direct inhibition of the cancer driver. Then, we recognized that 45% of all cancer genes are direct transcriptional regulators. Therefore, this proposal outlines a novel CiP- enabled therapeutic paradigm to hijack cancer drivers to amplify a therapeutic transcriptional program to directly kill cancer cells. Specifically, the goal of this proposal is to hijack the estrogen receptor in breast cancer to drive overexpression of pro-apoptotic factors to induce cancer cell death. First, I will systematically define the most potent pro- apoptotic factors for transcriptional upregulation induced cell death across multiple estrogen receptor positive breast cancer cell lines. Second, I will identify and validate transcription factors that regulate these pro- apoptotic factors by integrating bioinformatic analysis with a high throughput transactivator inducible recruitment screen. Finally, I will demonstrate that estrogen receptor in breast cancer can be hijacked for targeted transcriptional upregulation by recruiting it to an endogenously tagged transcription factor regulator of potent pro-apoptotic factors and to a targeted dCas9. Together, I will identify and demonstrate that estrogen receptor can be inducibly recruited by CiP to a transcription factor regulator of pro-apoptotic factors to induce breast cancer cell death. The successful completion of the aims described will establish not only a novel therapeutic approach for estrogen receptor positive breast cancer but also a generalizable therapeutic paradigm across multiple cancer types with transactivating cancer drivers. Furthermore, I will identify robust candidates for subsequent therapeutic heterobifunctional molecule development. The proposal presented also reflects my training goals of becoming an interdisciplinary physician-scientist bridging chemical biology tools and epigenetic gene regulation to address critical problems and needs in cancer biology and therapy.

摘要 个性化的靶向癌症治疗，虽然最初有效，但会导致耐药性和疾病进展， >50%的患者在开始治疗后几个月内迅速恢复。这些疗法直接抑制 癌症驱动因子的催化和/或配体诱导功能，通过突变逃逸导致抗性，或 表观遗传/转录旁路。为了解决突变逃逸，最近的治疗方法利用 化学诱导邻近（CiP）：双功能分子，招募两种蛋白质接近， 紧急治疗效果。然而，目前的基于CIP的疗法限于降解，其遭受 从类似的反馈机制的阻力作为直接抑制癌症的驱动程序。然后我们意识到 45%的癌症基因都是直接转录调节因子因此，该提案概述了一种新的CiP- 使治疗范例能够劫持癌症驱动程序来扩增治疗转录程序， 直接杀死癌细胞。 具体来说，这项提案的目标是劫持乳腺癌中的雌激素受体， 促凋亡因子来诱导癌细胞死亡。首先，我将系统地定义最有效的亲- 转录上调诱导的凋亡因子在多种雌激素受体阳性细胞中的表达 乳腺癌细胞系。其次，我将鉴定和验证调节这些前- 通过整合生物信息学分析和高通量反式激活因子诱导的凋亡因子 招聘屏幕最后，我将证明乳腺癌中的雌激素受体可以被劫持， 通过将其募集到内源性标记的转录因子调节子， 有效的促凋亡因子和靶向的dCas 9。我将一起鉴定并证明雌激素 受体可被CiP诱导性募集至促凋亡因子的转录因子调节物，以诱导 乳腺癌细胞死亡。 所述目标的成功完成不仅将建立一种新的治疗方法， 雌激素受体阳性乳腺癌，也是多种癌症的可推广的治疗范例 具有反式激活癌症驱动因子的类型。此外，我将为以后的工作确定强有力的候选人。 治疗性异型双功能分子的开发。提出的建议也反映了我的培训目标， 成为跨学科的物理学家，科学家桥梁化学生物学工具和表观遗传基因 监管，以解决癌症生物学和治疗中的关键问题和需求。