Unique Non-Saccharide Mimetics of Sulfated Glycosaminoglycan Target Colon Cancer Stem Cells

硫酸糖胺聚糖靶向结肠癌干细胞的独特非糖模拟物

• 批准号: 10514595
• 负责人: Bhaumik B Patel
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514595
• 关键词: Address; Animal Model; Baltimore; Biological; Biological Assay; Biological Markers; Blood; Cancer Cluster; Cancer Relapse; Carcinoma; Cell Surface Receptors; Cells; Chemoresistance; Clinic; Clinical; Collaborations; Colon; Colon Carcinoma; Colonic Neoplasms; Colony-Forming Units Assay; Colorectal; Colorectal Cancer; Development; Disease remission; Distal; Drug Kinetics; Epidermal Growth Factor Receptor; Exhibits; FGF2 gene; FGFR1 gene; Fiber; Fibroblast Growth Factor Receptors; Fluorouracil; Genomics; Glycobiology; Glycosaminoglycans; Goals; Growth Factor; HT29 Cells; Human; Immunotherapy; In Vitro; Insulin-Like-Growth Factor I Receptor; Intestines; Invaded; Knowledge; Malignant Neoplasms; Mediator; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Nature; Neoplasm Metastasis; Organ; Organoids; Outcome; Pathology; Pharmaceutical Preparations; Phenotype; Play; Polysaccharides; Process; Property; Receptor Signaling; Recurrent Malignant Neoplasm; Regulation; Reproducibility; Reproducibility of Results; Research; Research Personnel; Resources; Role; Sampling; Serum; Signal Transduction; Site; Specificity; System; Testing; Therapeutic; Tissue Sample; Toxic effect; Validation; Xenograft Model; Xenograft procedure; adult stem cell; analog; anti-cancer; cancer cell; cancer immunotherapy; cancer recurrence; cancer stem cell; cancer therapy; carcinogenesis; chemotherapy; colon cancer patients; colorectal cancer treatment; efficacy evaluation; efficacy testing; genetic variant; improved; in silico; in vivo; in vivo Model; inhibitor; innovation; metabolomics; migration; mimetics; mortality; mutant; novel; oxaliplatin; p38 Mitogen Activated Protein Kinase; patient derived xenograft model; personalized medicine; pleiotropism; polysulfated glycosaminoglycan; predictive marker; prototype; receptor; response; scaffold; self-renewal; stem cell biology; stem cell biomarkers; stem cell growth; stem cell self renewal; stem cells; transcriptomics; treatment strategy; tumor growth

This Collaborative VA Merit Application (CMA) leverages expertise of accomplished researchers who formed a VA Colorectal Cancer (CRC) Cell-Genomics Consortium (VA4C) in May 2017. Cancer stem cells (CSCs) are critical mediators of carcinogenesis and induce cancer relapse resulting in poor outcomes. Glycosaminoglycans (GAGs), linear polysaccharides, that play a critical role in regulation of several hallmarks of cancer, engage various cell surface receptor targets, especially on CSCs. Yet, their biological potential in cancer has not been realized. Based on our highly intriguing recent observations that G2.2, a non-saccharide glycosaminoglycan mimetic (NSGM) of a natural GAG, selectively inhibits CSCs through an oppositely-directed mechanism involving growth factors, we propose that G2.2 is a novel, selective inhibitor of human CSCs. We hypothesize that unique NSGMs can selectively and potently inhibit colorectal CSC growth through a novel mechanism of antipodal pleiotropicity with respect to activation of growth factors. We propose three aims. We will test the efficacy of G2.2 in 50 well characterized CSCs enriched primary human colorectal spheroids/tumoroids as well as normal intestinal organoids, examine comprehensive CSC phenotype (self- renewal, migration, invasion, and chemotherapy resistance), and determine pharmacokinetic profile of the most promising NSGMs (Aim 1). In Aim 2, we will determine molecular mechanism of G2.2 (and analogs). We will determine how antipodal pleiotropic effects arise, e.g., activation of fibroblast growth factor receptor (FGFRs) and inhibition of insulin-like growth factor 1 receptor (IGF1R), and alter pp38/pERK signaling ratio, which contributes to the CSC phenotype. Finally, in Aim 3, we will determine therapeutic utility of NSGMs in vivo by examining efficacy (specifically on CSCs) and toxicity (effect on normal stem cells) in advanced in vivo models of patient-derived xenografts (PDXs) or HT29 orthotopic xenografts either alone or in combination with chemotherapy (5-fluorouracil & oxaliplatin). The proposed studies will be greatly enhanced by collaborative merit process. Specifically, our collaboration with Drs. Mohapatra (Subhra)(Tampa), Raufman (Baltimore) Pisegna (Greater LA) within our cluster of Cancer Stem Cells in Pathology and Treatment of CRCs (CSCPT), as well as other VA4C collaborators including Mohapatra/Kelly (Tampa/Durham), and Dr. Bouvet (San Diego) will allow – a) testing of NSGMs in novel tumoroid models for independent validation (Aim 1); b) decipher predictive biomarkers for NSGM effect through correlation of effect with muti-omics studies; and c) testing of NSGMs in novel animal models such as PDXs and distal colon orthotopic xenografts in Aim 3. Similarly, our expertise and knowledge gained through the proposal will be shared with Drs. Mohapatra and Raufman (CSC assays e.g. comprehensive analyses of CSC markers. CSC selectivity etc.), We will also assist other VA4C investigators in collecting blood, serum and tissue samples. The proposed studies are expected to help decipher novel CSCs signaling and develop unique GAG mimetics as prototypic agents for clinical use.

此协作VA功绩应用程序（CMA）利用成就研究人员的经验 VA结直肠癌（CRC）细胞基因组学联盟（VA4C）于2017年5月。癌症干细胞（CSC）为 癌变的关键介体和诱导癌症复发，导致结果不佳。 糖胺聚糖（插科打），线性多糖，在规则性标志中起着至关重要的作用 在癌症中，有各种细胞表面受体靶标，尤其是在CSC上。 癌症尚未实现，我们的最新观察值G2.2是一种非含糖 天然GAG的糖胺聚糖模拟物（NSGM），通过相反指导有选择地抑制CSC 涉及生长因子的机制，我们提出G2.2是人类CSC的新型遗传 假设独特的NSGM可以通过新颖 对生长因子的激活的抗叶效性机制 将测试G2.2在50个表征富含原代的人类结直肠的50个良好特征的CSC中的功效 球体/肿瘤作为焊接肠道器官，检查全面的CSC表型（自我） 更新，迁移，发明和化学疗法抗性），并确定 最有前途的NSGM（AIM 1） 将确定抗杀菌性多效性效应如何产生，例如激活成纤维细胞gro胶gr virblast gro virblast gro groblast gro virblast gro vorblast groblast Groblars groiblar ector驱动器 （FGFR）和抑制胰岛素样生长因子1受体（IGF1R），并改变Pp38/PP38/PERK信号传导比 最终有助于CSC表型。 通过检查疗效（特别是在CSC上）和毒性（对正常干细胞的毒性）在体内的体内 患者衍生的定克图的模型 化学疗法（5-氟尿嘧啶和奥沙利普蛋白）将通过协作大大增强 优点流程。 我们的癌症干细胞簇中的Pisegna（大LA）在病理学和CRC的治疗（CSCPT）中， 以及其他VA4C合作者，包括Mohapatra/Kelly（Tampa/Durham）和Bouven博士（圣地亚哥） 将允许 - a）在新型肿瘤模型中测试NSGM，以进行独立验证（AIM 1）； NSGM效应的预测性生物标志物与Muti-Omics研究的效应； 新型动物模型中的NSGM，例如PDXS和AIM 3中的远端结肠骨to仪。同样，我们的。 提出的专业知识和知识将与Drs共享。 CSC选择性的综合分析。 调查人员收集血液，预计支撑研究将有助于 解密新颖的CSC信号传导并发展开发独特的插科打胶作为临床用途的原型药物。