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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：
10703529
负责人：
Derek Ronald Duckett
金额：
$ 7.41万
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/10703529
关键词：
Affect Apoptosis Biochemical 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 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.

项目总结