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

基本信息

批准号：
10573138
负责人：
Samuel H Kim
金额：
$ 4.02万
依托单位：
STANFORD UNIVERSITY
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：
2022-06-21 至 2025-06-20
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573138
关键词：
Address Apoptosis Apoptotic BCL1 Oncogene Binding Bioinformatics Biological Assay Biology Breast Cancer Cell Breast Cancer cell line Bypass CASP3 gene Cancer Biology Cell Death Cell Death Induction Cell Survival Cells ChIP-seq Chemicals Consensus Development Disease Progression Doxycycline Enhancers Epigenetic Process Equilibrium Estrogen Receptors Estrogen receptor positive Family member Feedback 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 cancer cell cancer therapy cancer type candidate identification candidate validation carcinogenesis efficacy evaluation 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

项目摘要

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.

抽象的个性化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就会出现这种情况。这些疗法直接抑制癌症驱动因素的催化和/或配体诱导功能，通过突变逃逸或导致耐药性表观遗传/转录旁路。为了解决突变逃逸问题，最近的治疗方法利用化学诱导接近（CiP）：双功能分子，招募两种蛋白质接近紧急治疗效果。然而，当前基于 CiP 的疗法仅限于降解，这会受到影响来自与直接抑制癌症驱动因素类似的抵抗反馈机制。然后，我们认出了 45% 的癌症基因是直接转录调节因子。因此，该提案概述了一种新颖的 CiP- 启用治疗范式来劫持癌症驱动因素，以放大治疗转录程序直接杀死癌细胞。具体来说，该提案的目标是劫持乳腺癌中的雌激素受体以驱动过度表达促凋亡因子诱导癌细胞死亡。首先，我将系统地定义最有效的亲转录上调的凋亡因子诱导多个雌激素受体阳性细胞死亡乳腺癌细胞系。其次，我将识别并验证调节这些亲的转录因子通过将生物信息分析与高通量反式激活因子诱导相结合来检测细胞凋亡因子招聘屏幕。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招募到内源标记的转录因子调节因子来靶向转录上调有效的促凋亡因子和靶向 dCas9。我将一起确定并证明雌激素受体可以被 CiP 诱导招募到促凋亡因子的转录因子调节因子中，以诱导乳腺癌细胞死亡。成功完成所描述的目标不仅将建立一种新的治疗方法雌激素受体阳性乳腺癌，也是跨多种癌症的通用治疗范例具有反式激活癌症驱动因素的类型。此外，我将为后续确定强有力的候选人治疗性异双功能分子的开发。提出的建议也反映了我的培训目标成为桥接化学生物学工具和表观遗传基因的跨学科医师科学家解决癌症生物学和治疗中的关键问题和需求的监管。