Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers

开发 CDK12 抑制剂以克服 HER2 和 KRAS 驱动的乳腺癌和肺癌的治疗耐药性

基本信息

批准号：
10279337
负责人：
Derek Ronald Duckett
金额：
$ 67.92万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-12 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10279337
关键词：
Affect Apoptosis Biochemical Biological Biological Assay Biological Models Brain Breast Cancer Treatment Bypass Cancer Patient Cells Chemicals Cisplatin Cyclin-Dependent Kinases Data Development Disease Disseminated Malignant Neoplasm Dose Drug Kinetics Drug Targeting Drug Tolerance Drug resistance ERBB2 gene Enhancers Enzymes Epigenetic Process Epithelial Evaluation FRAP1 gene Fatty acid glycerol esters Future Genes Genetic Transcription Goals Growth Factor Receptors Image Immune system Immunocompetent Investigational Drugs KRAS2 gene Lead Ligands Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Mediating Mesenchymal Metabolism Mission Modeling Molecular Molecular Probes Mutation Neoplasm Metastasis New Agents Non-Small-Cell Lung Carcinoma Oncogenes Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacotherapy Play Property Proteomics Receptor Signaling Reporter Reporting Research Resistance Resistance development Role Signal Transduction Solubility Stress Structure Testing Transcription Alteration Transcription Process Transcriptional Regulation Trastuzumab United States National Institutes of Health Work Xenograft Model acquired drug resistance analog anti-cancer anti-cancer therapeutic anticancer activity base cancer cell chemotherapy clinical development combat design disability epigenetic regulation first-in-human fluorescence imaging immune resistance immunoregulation improved in vivo ineffective therapies inhibitor/antagonist innovation insight kinase inhibitor lung cancer cell malignant breast neoplasm mammary neoplastic cell novel novel strategies novel therapeutics overexpression patient derived xenograft model phosphoproteomics pre-clinical prevent programs research clinical testing resistance mechanism response safety assessment single-cell RNA sequencing small molecule stressor success targeted agent targeted treatment therapy resistant three-dimensional modeling transcriptome sequencing translational approach treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor progression

项目摘要

Project Summary Although the development of targeted therapies has improved overall cancer patient survival, adaptive responses by tumor cells can render these treatments ineffective. The development of agents that block adaptive responses, thereby increasing treatment durability is desperately needed. We and others have demonstrated that inhibitors of the transcriptional cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) are strong candidates to combat acquired drug resistance. The long-term goal of this proposal is to develop a highly effective CDK12/13 inhibitor with an aggregate set of properties suitable to advance as a safety assessment candidate to overcome therapy resistance in both TNBC and HER2+ breast cancers and KRAS inhibitor-resistant NSCLCs. The overall objective in this application is to identify targets and pathways altered by treatment-directed CDK12/13 rewiring and develop new therapeutics that render this rewiring - an exploitable vulnerability. The central hypothesis is that CDK12/13 acts as a driver of transcriptional and post-transcriptional adaptation and that targeting CDK12/13 will block drug-induced escape and improve treatment response in breast and lung cancer. The rationale for this project posits that: (i) multiple malignancies hijack CDK12/13 to provoke transcriptional and signaling plasticity as an adaptive stress resistance mechanism, and (ii) elucidation of mechanisms underpinning compound action will offer a strong scientific framework that will facilitate future clinical development of these new agents for improved patient outcome. The central hypothesis will be tested by pursuing three Specific Aims: (1) Optimize the drug-like properties of in-house CDK12/13 specific inhibitors; (2) Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses treatment resistance in TNBC and HER2+ breast cancers (3) Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses KRASG12C inhibitor resistance in NSCLC. Accordingly, using a battery of approaches, we will: a) optimize key CDK12/13 inhibitor parameters to deliver a safety assessment candidate; b) define and validate the transcriptional and translational mechanisms, whereby SR-4835 provokes resensitization to chemotherapy, and c) validate cell-based observations in pre-clinical xenograft models. The research approach of our Multi-PI application is innovative, as our team has developed exceptionally selective and novel small molecule CDK12/13 in vivo active molecular probes that will enable (i) interrogation of the roles of CDK12/13 during adaptation to treatment resistance (ii) evaluation that disrupting transcriptional control will counter-resistance mechanisms providing lasting, more durable anti-cancer responses or even cures; and (iii) understanding of the critical signaling nodes that drive drug resistance. The proposed research is highly significant and provides a strong scientific rationale for the continued development of novel CDK12/13 inhibitors. We submit that insight into the molecular underpinnings of the master effectors of CDK12 and CDK13-driven signaling, together with an optimized CDK12/13 inhibitor will offer new opportunities for improved combination treatments for breast and lung cancer.

项目概要尽管靶向治疗的发展提高了癌症患者的总体生存率，但适应性肿瘤细胞的反应会使这些治疗无效。阻止自适应代理的开发反应，从而提高治疗的持久性是迫切需要的。我们和其他人已经证明转录细胞周期蛋白依赖性激酶 12 (CDK12) 和 13 (CDK13) 的抑制剂是强有力的候选者对抗获得性耐药性。该提案的长期目标是开发高效的CDK12/13 具有一系列特性的抑制剂，适合作为安全评估候选者来克服 TNBC 和 HER2+ 乳腺癌以及 KRAS 抑制剂耐药 NSCLC 的治疗耐药性。整体本申请的目的是确定治疗导向的 CDK12/13 重连改变的靶点和途径并开发新的疗法，使这种重新布线成为可利用的漏洞。中心假设是 CDK12/13 充当转录和转录后适应的驱动因素，并且靶向 CDK12/13 将阻止药物引起的逃逸并改善乳腺癌和肺癌的治疗反应。这样做的理由该项目假设：(i) 多种恶性肿瘤劫持 CDK12/13 以激发转录和信号可塑性作为一种适应性应激抵抗机制，以及（ii）阐明支撑复合作用的机制将提供一个强大的科学框架，促进这些新药未来的临床开发改善患者的治疗效果。中心假设将通过追求三个具体目标来检验：（1）优化内部 CDK12/13 特异性抑制剂的类似药物特性； (2) 定义和验证机制 CDK12/13 抑制可预防或逆转 TNBC 和 HER2+ 乳腺癌的治疗耐药性 (3) 定义并验证 CDK12/13 抑制可预防或逆转 KRASG12C 抑制剂的机制 NSCLC 中的耐药性。因此，使用一系列方法，我们将： a) 优化关键的 CDK12/13 抑制剂提供候选安全评估的参数； b) 定义并验证转录和翻译 SR-4835 引起对化疗重新敏感的机制，以及 c) 验证基于细胞的临床前异种移植模型中的观察结果。我们的 Multi-PI 应用程序的研究方法是创新的，因为我们的团队开发了具有特殊选择性的新型小分子CDK12/13体内活性分子探针将能够 (i) 探究 CDK12/13 在适应治疗耐药过程中的作用 (ii) 评估破坏转录控制将对抗耐药机制，提供持久的、更多的持久的抗癌反应甚至治愈； (iii) 了解驱动的关键信号节点耐药性。拟议的研究非常重要，并为该研究提供了强有力的科学依据。持续开发新型CDK12/13抑制剂。我们提出对分子基础的洞察 CDK12 和 CDK13 驱动信号传导的主效应器以及优化的 CDK12/13 抑制剂将为改进乳腺癌和肺癌的联合治疗提供新的机会。