Identification and therapeutic application of miRNA-drivers in lung cancer

肺癌中 miRNA 驱动因子的鉴定和治疗应用

基本信息

批准号：
8566534
负责人：
Andrea L Kasinski
金额：
$ 9.96万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-13 至 2013-11-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8566534
关键词：
14-3-3 Family Accounting Address Adenocarcinoma Agar Animal Model Animals Antineoplastic Agents Area Award BCL2 gene Binding Biochemical Biological Assay Biology Cancer Biology Cancer Patient Cancer cell line Cancerous Carcinoma in Situ Cell Culture Techniques Cell Line Cell Survival Cells Cellular biology Cessation of life Chemicals Clinical Trials Code Collaborations Complement Critiques Curcumin Data Development Plans Developmental Biology Disease Disease Progression Epithelial Cells Faculty Gene Targeting Genes Genetic Goals Government Growth Health Human Hyperplasia Individual Instruction Investigation KRAS2 gene Kinetics Knowledge Lead Life Expectancy Lobular Neoplasia Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mentors MicroRNAs Molecular Biology Molecular Conformation Molecular Genetics Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenic Operative Surgical Procedures Pathway interactions Patients Permeability Pharmacology Postdoctoral Fellow Preclinical Drug Evaluation Principal Investigator Process Proteins Public Health RNA-Binding Proteins RNA-Protein Interaction Radiation Reporting Repression Research Research Personnel Resistance Series Signal Transduction Survival Rate TP53 gene Techniques Testing Therapeutic Toxic effect Training Transcriptional Regulation Universities Woman Work Writing Xenograft procedure analog base cancer initiation cancer therapy carcinogenesis career development chemotherapy clinical application combinatorial design high throughput screening in vivo in vivo Model inhibitor/antagonist innovation lung tumorigenesis meetings member men metaplastic cell transformation molecular marker molecular pathology mouse model mutant nanoparticle neoplastic cell novel novel therapeutics overexpression prevent public health relevance research study response screening small molecule therapeutic development therapeutic target tumor tumor progression tumorigenic unpublished works

项目摘要

DESCRIPTION (provided by applicant): The proposed work focuses on identifying novel miRNA drivers in cancer and utilizes this and other knowledge to develop miRNA-based therapeutics. This "Pathway to Independence" award application includes a mentored career development plan for the transition of the candidate, Dr. Andrea Kasinski, into an independent investigator, as well an accompanying research plan describing the proposed experiments on discovering miRNAs that can potentiate KRAS-driven lung adenocarcinoma and exploring novel therapeutic strategies for re-expressing tumor-suppressive miRNAs, which includes a high-throughput screen to identify a small molecule that can restore miRNA processing and combinatorial miRNA therapies for sensitizing tumors to conventional chemotherapies. The candidate, Dr. Kasinski, is a postdoctoral fellow at Yale, in the lab of Dr. Frank Slack in the Department of Molecular, Cellular, and Developmental Biology. The work leading to her graduate degree in Genetics and Molecular Biology at Emory University was conducted in the lab of Dr. Haian Fu in the Department of Pharmacology and focused on targeting cell survival signaling for therapeutic development. In the Fu lab, Dr. Kasinski performed two very distinct projects that were interrelated based on the ultimate goal of developing targeted therapeutics: in one project Dr. Kasinski utilized biochemical assays to identified IKK-¿ as a direct target of EF24, an analogue of curcumin that ultimately made its way into clinical trials. For the second project a series of genetic and molecular techniques were used to evaluate the transcriptional regulation of an oncogenic 14-3-3 family member, with the hope that this knowledge might spearhead subsequent studies to block 14-3-3 expression. The mentoring and career development plan will supplement her background, which is evenly split between genetic, molecular biology, whole animal studies and small molecule screening, with training and instruction in each, and in the particular areas that this project involves: murine biology, cancer biology, cell culture technique and high-throughput drug screening. Dr. Kasinski's goal is to become a faculty member in an interdisciplinary biosciences, cancer biology, or similar department at an academic, private, or government facility, in which she can research the biology of miRNAs in cancer and work to advance miRNA-based therapies. This research on miRNAs involvement in cancer requires that an innovative and selective screen be performed which Dr. Kasinski is actively pursuing first in cell culture and will advance into animal models. This assay in soft agar is selecting for miRNAs that can specifically cause normal human lung bronchial epithelial cells to become transformed. MiRNAs identified from this assay will be evaluated further in cell culture and ultimately in vivo. The proposed study involving miRNA therapeutics is two fold. The first takes into account the interaction of let-7 and LIN-28. Dr. Kasinski is in an active collaboration with Dr. Haian Fu, Co-Director of the Chemical Biology and Drug Screening Center at Emory University, to perform a high throughput screen (HTS) to identify inhibitors of this protein-RNA interaction. Hits from this HTS will be evaluated for cell permeability, kinetics and in vivo therapeutic potential, by several independent avenues of investigation. Finally building on Dr. Kasinski's current findings that miR-34 and let-7 represent valid therapeutic options for non-small cell lung cancer, she will evaluate these miRNA therapies in combination with currently used chemotherapies and targeted-therapeutics in cell culture, xenografts and in the Kras;p53 double mutant. This work is novel, timely and has clear and significant implications for human health and survival. The identification of miRNAs and targeted-therapies to perturb miRNA imbalance that occurs in cancer is invaluable to the fields of cancer and miRNA biology, and has direct clinical application.

描述（由申请人提供）：拟议的工作重点是识别癌症中的新型 miRNA 驱动因素，并利用这一知识和其他知识来开发基于 miRNA 的疗法。此“独立之路”奖励申请包括一项针对癌症转型的指导职业发展计划。候选人 Andrea Kasinski 博士成为一名独立研究者，以及一项随附的研究计划，描述了拟议的实验，旨在发现可增强 KRAS 驱动的肺腺癌的 miRNA，并探索新的治疗策略重新表达肿瘤抑制 miRNA，其中包括高通量筛选，以鉴定可以恢复 miRNA 加工的小分子，以及使肿瘤对化疗敏感的组合 miRNA 疗法。该候选人 Kasinski 博士是耶鲁大学的博士后研究员。她在埃默里大学分子、细胞和发育生物学系 Frank Slack 博士的实验室工作，获得遗传学和分子生物学硕士学位。是在药理学系的 Haian Fu 博士的实验室进行的，重点是针对细胞生存信号以进行治疗开发。在 Fu 实验室中，Kasinski 博士进行了两个截然不同的项目，这两个项目基于开发靶向药物的最终目标而相互关联。疗法：在一个项目中，Kasinski 博士利用生化检测来鉴定 IKK-¿作为 EF24 的直接靶标，EF24 是姜黄素的类似物，最终进入临床试验。在第二个项目中，使用了一系列遗传和分子技术来评估致癌 14-3-3 家族成员的转录调控。希望这些知识能够引领后续研究阻止 14-3-3 表达。指导和职业发展计划将补充她的背景，通过培训，她的背景均匀分布在遗传、分子生物学、整体动物研究和小分子筛选之间。以及该项目涉及的每个特定领域的指导：鼠生物学、癌症卡辛斯基博士的目标是成为跨学科生物科学、癌症生物学或学术、私人或政府机构的类似部门的教职人员，在那里她可以研究生物学。这项关于 miRNA 参与癌症的研究需要进行创新和选择性筛选，Kasinski 博士首先在细胞培养中积极追求这一点，并将在动物模型中进行这项试验。软琼脂正在选择能够特异性地导致正常人肺支气管上皮细胞发生转化的 miRNA，该分析中鉴定出的 miRNA 将在细胞培养物中进行进一步评估，并最终在体内进行。考虑到let-7和LIN-28的相互作用，Kasinski博士正在与埃默里大学化学生物学和药物筛选中心联合主任Haian Fu博士积极合作，以进行高水平的研究。最后，基于 Kasinski 博士目前的 miR 发现，将通过几个独立的研究途径来评估该 HTS 的抑制剂的细胞渗透性、动力学和体内治疗潜力。 -34和let-7代表了非小细胞肺癌的有效治疗选择，她将在细胞培养中结合目前使用的化疗和靶向治疗来评估这些miRNA疗法，异种移植物和 Kras;p53 双突变体中的这项工作是新颖的、及时的，并且对人类健康和生存具有明确而重大的影响。 miRNA 的鉴定和扰乱癌症中发生的 miRNA 失衡的靶向治疗对于癌症领域具有无价的价值。癌症和miRNA生物学，并具有直接的临床应用。