Interaction of cannabidiol (CBD) with targeted inhibitors of essential cancer signaling pathways

大麻二酚 (CBD) 与重要癌症信号通路靶向抑制剂的相互作用

基本信息

批准号：
10651045
负责人：
ERICA A. GOLEMIS
金额：
$ 25.51万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651045
关键词：
3-Dimensional Address Advanced Malignant Neoplasm Affect Aftercare Area Bioinformatics Biological Assay Breast Cancer Cell Cancer Cell Growth Cancer Model Cancer cell line Cannabidiol Cannabinoids Cannabis Cell Death Cell Line Cell Survival Cell model Cisplatin Clinical Clinical Research Clinical Trials Colorectal Cancer Combined Modality Therapy Communities Complement Cytotoxic Chemotherapy Data Diagnosis Disease Dose Drug Interactions Drug Targeting Drug usage Epidermal Growth Factor Receptor Growth Growth Factor Receptors Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Immune response Immunotherapy In Vitro Individual Investigation Laws Legal Libraries Malignant Neoplasms Marijuana Measurement Mediator Modeling Nuclear Outcome Outcome Assessment Paclitaxel Pathway interactions Patients Pattern Perception Performance Pharmaceutical Preparations Phase Phosphotransferases Phytochemical Pilot Projects Prognosis Protein Analysis Protein Array Analysis Proteins Proteomics Publishing Recording of previous events Recurrent disease Relaxation Research Resistance Signal Pathway Signal Transduction Signaling Protein Solid Neoplasm Somatic Mutation Source Stigmatization Systemic Therapy Testing Therapeutic United States Variant Work Xenograft procedure antagonist cancer care cancer pain cancer therapy cancer type chemotherapy clinically relevant data resource disease prognosis in vivo in vivo Model inhibitor innovation interest marijuana use novel novel therapeutic intervention patient derived xenograft model preclinical study receptor receptor expression response screening social stigma synergism targeted cancer therapy targeted treatment therapeutic target therapy outcome treatment response tumor tumor growth

项目摘要

PROJECT SUMMARY/ABSTRACT Patients diagnosed with advanced cancers typically required systemic therapies, which include chemotherapy, targeted therapy, and immunotherapy. This proposal will address major issues affecting clinical outcomes; the question of which patient will respond to which therapy, and the question of what factors are associated with intrinsic or acquired resistance. Although intrinsic resistance can sometimes be clearly assigned to tumor-specific factors, such as specific somatic mutations, in many cases the underlying basis for resistance is obscure. This proposal will address the novel hypothesis that use of cannabidiol (CBD) provides an under-appreciated source of variation in response to clinically important cancer therapies. A growing number of individuals use CBD during cancer treatment to alleviate cancer pain, or even because of perceived benefits for treating their cancers. In the past, there has been relatively limited study of CBD and other cannabis-derived phytochemicals due to issues of social stigma and legal restrictions; however, a growing number of studies have generated convincing evidence that CBD affects the growth of some types of tumors and interacts with cytotoxic chemotherapies to modulate their activity. Some studies have demonstrated interaction between CBD cellular receptors and signaling by EGFR, SRC, and other signaling proteins that are important therapeutic targets, implying CBD might affect response to drugs targeting those proteins. However, no published studies in any cancer type have systematically probed the interaction of CBD with the signaling pathways commonly targeted in cancer therapy. In pilot studies, we have been investigating the interaction of CBD with 175 kinase-targeted inhibitors and additional control compounds in restricting the growth of cancer cells. This has identified several specific CBD- inhibitor interactions, which differed between two cell models tested, but were more notable in an EGFR- dependent cell model. Given multiple connections identified between CBD and EGFR signaling detected, the objective of this proposal is to evaluate the degree to which CBD influences the activity of pathway-targeted inhibitors in two EGFR-dependent tumor types (head and neck squamous cell carcinoma (HNSCC), and colorectal cancer (CRC)), and to characterize the underlying mechanisms of CBD-inhibitor interaction. In Aim 1, we will screen the targeted inhibitor library in additional HNSCC and CRC cell models to establish consistent patterns of interaction, using CellTiterBlue and nuclear count as initial screening assays. Positive hits will be further explored using clonogenic and 3D spheroid growth analysis, and dose range of interaction defined. Reverse-phase protein array (RPPA) analysis will be used to establish signaling pathways specifically affected by CBD-inhibitor interaction. In Aim 2, for selected specific protein-targeted inhibitors of interest, we will define the CBD-inhibitor interaction in xenograft and patient-derived xenograft (PDX) models in vivo, confirm CBD- dependent signaling changes defined in vitro pertain in vivo, and use bioinformatic analysis of large data resources to understand the relationship between CBD receptor expression, prognosis, and drug response.

项目摘要/摘要被诊断为晚期癌症的患者通常需要进行全身治疗，包括化学疗法，靶向治疗和免疫疗法。该提案将解决影响临床结果的主要问题；这哪个患者将回答哪种疗法的问题以及与哪些因素有关的问题固有或获得的阻力。尽管有时可以清楚地分配给肿瘤特异性的固有阻力在许多情况下，诸如特定体细胞突变之类的因素是耐药性的基础是晦涩的。这提案将解决使用大麻二酚（CBD）的新假设。响应临床上重要的癌症疗法的变异。越来越多的人在癌症治疗以减轻癌症的疼痛，甚至是由于治疗癌症的感知益处。在过去，由于问题而对CBD和其他大麻衍生的植物化学物质进行了相对有限的研究社会污名和法律限制；但是，越来越多的研究产生了令人信服的 CBD影响某些类型肿瘤的生长并与细胞毒性化学疗法相互作用的证据调节他们的活动。一些研究表明CBD细胞受体与 EGFR，SRC和其他是重要治疗靶标的信号传导，这意味着CBD可能影响对靶向这些蛋白质的药物的反应。但是，在任何癌症类型的研究中均未发表研究系统地探测了CBD与癌症治疗中通常针对的信号通路的相互作用。在试点研究中，我们一直在研究CBD与175个激酶靶向抑制剂的相互作用限制癌细胞生长的其他控制化合物。这已经确定了几个特定的CBD- 抑制剂相互作用，两种测试的细胞模型之间有所不同，但在EGFR-中更为明显依赖性细胞模型。鉴于检测到的CBD和EGFR信号之间的多个连接，该提案的目的是评估CBD影响涉及途径的活动的程度两种EGFR依赖性肿瘤类型（头颈鳞状细胞癌（HNSCC）和结直肠癌（CRC）），以表征CBD抑制剂相互作用的潜在机制。在AIM 1中，我们将在其他HNSCC和CRC细胞模型中筛选目标抑制剂库以建立一致的相互作用的模式，使用CellTiterBlue和核计数作为初始筛选分析。积极的命中将是使用克隆原性和3D球体生长分析以及定义的相互作用剂量范围进一步探索。逆相蛋白阵列（RPPA）分析将用于建立特异性影响的信号通路通过CBD抑制剂相互作用。在AIM 2中，对于选定的特定蛋白质靶向感兴趣的抑制剂，我们将定义异种移植物和患者衍生的异种移植（PDX）模型中的CBD抑制剂相互作用在体内确认CBD- 依赖信号传导变化在体内定义的体内相关，并使用大数据的生物信息学分析了解CBD受体表达，预后和药物反应之间的关系。