Genomic screening to identify novel stress-inducing chemotherapies for carcinoma

基因组筛选以确定新型应激诱导癌症化疗药物

基本信息

批准号：
8403386
负责人：
Andrew Michael Fribley
金额：
$ 23.07万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403386
关键词：
Academia Address Adjuvant Therapy Affect Apoptosis Apoptotic Biological Assay Breathing Carcinoma Caring Cell Death Cell Line Cells Chemicals Cisplatin Development Disease Dose Drug Interactions Drug Kinetics Enzymes Funding Genetic Programming Genomics Glean Growth Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Head and neck structure Human In Vitro Individual Instruction Investigation Laboratories Lead Libraries Luciferases Malignant Epithelial Cell Mediating Metabolic Metabolism Michigan Molecular Target Neoplasm Metastasis Operative Surgical Procedures P-Glycoprotein Pain Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Probability Proteasome Inhibition Proteins Pump Radiation Radiation therapy Reporter Reporting Resistance Sensitivity and Specificity Series Signal Transduction Stress Structure Structure of thyroid parafollicular cell Survival Rate Technology Testing Tumor Burden Universities Work Xenograft Model Xenograft procedure analog arm base cellular targeting chemotherapy cost effective cytotoxic drug clearance drug development drug metabolism high throughput screening improved in vivo insight killings mouth squamous cell carcinoma neoplastic cell new therapeutic target novel protein folding research study response screening small molecule small molecule libraries success therapeutic development treatment strategy tumor

项目摘要

Despite technological advances in surgery and radiotherapy for patients who suffer from oral squamous cell carcinoma (OSCC), the survival rate has remained un-improved during the last two decades indicating our ability to treat patients has reached a plateau. We have reported that proteasome inhibition induced ER stress CHOP-mediated apoptosis in HNSCC cell lines, including several that are cisplatin-resistent. ER stress leads to a physiological response known as the unfolded protein response (UPR) which consists of distinct parallel genetic programs that attempt to restore homeostatic protein folding or lead to apoptosis if the stress is prolonged or robust. We hypothesized that we could use high throughput screening (HTS) with diverse chemical libraries to identify novel small molecule CHOP activators to induce apoptosis in OSCC cells. We have developed a Complementary cell-based assay using stably transfected CMQ-K1 cells that individually report on the PERK/elF2D/CH0P (apoptotic) and the IRE1/XBP1 (adaptive) pathways of the UPR. Identifying compounds that specifically activate only PERK/elF2n/CHOP and not 1RE1/XBP1 has allowed us to aile out many compounds that generally perturb protein folding. 65 hit compounds have been identified that activated the CHOP but not the XBP1 reporter with chemical signatures amenable for synthetic analoging and therapeutic development. We propose to test the ability of these 65 Compounds along with commercially available analog series to induce CHOP expression and apoptosis in a panel of OSCC cells. The hiost promising candidates will be evaluated in vivo in a well-characterized rbd^ht xenograft model. The long-term objectives of the proposed studies are to elucidate the ability of these novel small molecules to induce CHOP and inhibit growth or induce apoptosis in OSCC cells and to further screen very large diverse libraries of chemical probes with our complementary cell-based screen, Small molecule UPR agonisits identified through these studies will pfovide a convenient cost-effective rneans of treating patients suffering from a disease for which therapies are limited to minimally effective chemotherapies, damaging radiation or painful surgeries that often interfere with their ability to speak, chew or even breathe.

尽管对患有口腔鳞状细胞的患者进行了手术和放疗方面的技术进步癌（OSCC），在过去的二十年中，生存率一直未得到改善，表明我们治疗患者的能力已经达到平稳状态。我们报道了蛋白酶体诱导的ER HNSCC细胞系中的应力切碎介导的细胞凋亡，包括几种抗顺铂的。嗯压力导致生理反应称为展开的蛋白质反应（UPR），该反应由不同的平行遗传程序试图恢复稳态蛋白折叠或导致凋亡压力是延长或健壮的。我们假设我们可以使用高通量筛选（HTS）不同的化学文库识别新型的小分子切碎激活剂以诱导OSCC凋亡细胞。我们使用稳定转染的CMQ-K1细胞开发了一种基于互补的细胞测定法单独报告PERK/ELF2D/CH0P（凋亡）和IRE1/XBP1（自适应）途径 UPR。识别专门激活PERK/ELF2N/CHOP而不是1RE1/XBP1的化合物使我们能够消除许多通常会扰动蛋白质折叠的化合物。 65个命中率是鉴定出激活CHOP，但没有使用化学特征的XBP1记者适合合成类似物和治疗性发育。我们建议测试这65种化合物的能力以及可商购的模拟系列，以诱导一系列面板中的斩波表达和凋亡 OSCC细胞。 HIOST有希望的候选人将在体内评估良好的RBD^ht 异种移植模型。提出的研究的长期目标是阐明这些新颖的能力小分子诱导切碎并抑制生长或诱导OSCC细胞中的凋亡，并进一步筛选我们的互补细胞筛选小分子的化学探针的非常大的化学探针库通过这些研究确定的UPR激动剂将使方便的具有成本效益的治疗方法患有疗法的疾病患者仅限于最小有效的化学疗法，损害辐射或痛苦的手术通常会干扰其说话，咀嚼甚至呼吸的能力。