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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.

项目总结/摘要被诊断患有晚期癌症的患者通常需要全身治疗，包括化疗，靶向治疗和免疫治疗。该提案将解决影响临床结果的主要问题; 哪些患者将对哪种治疗作出反应的问题，以及与哪些因素相关的问题，内在的或获得的抵抗力。虽然内在耐药性有时可以明确地分配给肿瘤特异性由于一些因素，如特定的体细胞突变，在许多情况下，耐药性的根本基础是模糊的。这一项提案将解决一个新的假设，即大麻二酚（CBD）的使用提供了一个未被充分认识的来源，对临床上重要的癌症治疗的反应的变化。越来越多的人使用CBD 癌症治疗，以减轻癌症疼痛，甚至是因为治疗癌症的好处。在过去，由于问题，对CBD和其他大麻衍生植物化学物质的研究相对有限社会耻辱和法律的限制;然而，越来越多的研究已经产生了令人信服的证据表明CBD影响某些类型肿瘤的生长，并与细胞毒性化疗相互作用，调节它们的活动。一些研究已经证明CBD细胞受体与 EGFR、SRC和其他信号蛋白是重要的治疗靶点，这意味着CBD可能影响针对这些蛋白质的药物的反应。然而，在任何癌症类型中，系统地探讨了CBD与癌症治疗中通常靶向的信号通路的相互作用。在初步研究中，我们一直在研究CBD与175种激酶靶向抑制剂的相互作用，另外的控制化合物限制癌细胞的生长。这就提出了几个具体的CBD-- 抑制剂相互作用，这在两个测试的细胞模型之间不同，但在EGFR- 依赖细胞模型考虑到检测到CBD和EGFR信号传导之间的多种联系，本提案的目的是评估《生物多样性公约》对以路径为目标的活动的影响程度两种EGFR依赖性肿瘤类型（头颈部鳞状细胞癌（HNSCC））中的抑制剂，以及结直肠癌（CRC）），并表征CBD-抑制剂相互作用的潜在机制。在目标1中，我们将在另外的HNSCC和CRC细胞模型中筛选靶向抑制剂文库，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测定。积极的点击率将是使用克隆形成和3D球状体生长分析进一步探索，并定义相互作用的剂量范围。反相蛋白质阵列（RPPA）分析将用于建立信号通路的具体影响通过CBD-抑制剂相互作用。在目标2中，对于选定的特定蛋白质靶向抑制剂，我们将定义 CBD-抑制剂在体内异种移植物和患者来源的异种移植物（PDX）模型中的相互作用证实了CBD- 体外定义的依赖性信号变化适用于体内，并使用大量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。