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: 9891323
• 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/9891323
• 关键词: Address; Animal Model; Baltimore; Biological; Biological Assay; Biological Markers; 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; Human; Immunotherapy; In Vitro; Insulin-Like-Growth Factor I Receptor; Intestines; Knowledge; Malignant Neoplasms; Mediator of activation protein; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Nature; Neoplasm Metastasis; Organ; Organoids; Outcome; Pathology; Pharmaceutical Preparations; Phenotype; Play; Polysaccharides; Process; Property; Receptor Inhibition; Receptor Signaling; Regulation; Reproducibility; Reproducibility of Results; Research; Research Personnel; Resources; Role; Sampling; Serum; Signal Transduction; Site; Specificity; Structure; System; Testing; Therapeutic; Tissue Sample; Toxic effect; Validation; Xenograft Model; Xenograft procedure; adult stem cell; analog; anti-cancer; base; 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/antagonist; innovation; metabolomics; migration; mimetics; model development; mortality; mutant; novel; oxaliplatin; p38 Mitogen Activated Protein Kinase; patient derived xenograft model; personalized medicine; pleiotropism; polysulfated glycosaminoglycan; predictive marker; receptor; response; scaffold; self-renewal; stem; 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 优异申请 (CMA) 利用了成就卓著的研究人员的专业知识，这些研究人员组成了 VA 结直肠癌 (CRC) 细胞基因组学联盟 (VA4C)，2017 年 5 月。癌症干细胞 (CSC) 致癌的关键介质并诱导癌症复发，导致不良结果。 糖胺聚糖 (GAG) 是一种线性多糖，在多种标志的调节中发挥着关键作用 在癌症中，多种细胞表面受体靶标，特别是 CSC，然而，它们的生物学潜力。 根据我们最近非常有趣的观察，G2.2（一种非糖）尚未被认识到。 天然 GAG 的糖胺聚糖模拟物 (NSGM)，通过相反方向选择性抑制 CSC 通过涉及生长因子的机制，我们提出 G2.2 是一种新型的、选择性的人类 CSC 抑制剂。 认为独特的 NSGM 可以通过一种新颖的机制选择性地、有效地抑制结直肠 CSC 的生长。 我们提出了三个目标。 将测试 G2.2 在 50 个特征明确的富含原代人类结直肠的 CSC 中的功效 球体/肿瘤样体以及正常肠道类器官，检查综合 CSC 表型（自体 更新、迁移、侵袭和化疗耐药性），并确定其药代动力学特征 最有前途的 NSGM（目标 1） 在目标 2 中，我们将确定 G2.2（和类似物）的分子机制。 将决定反足多效性效应如何产生，例如成纤维细胞生长因子受体的激活 (FGFR) 和抑制胰岛素样生长因子 1 受体 (IGF1R)，并改变 pp38/pERK 信号传导比率， 最后，在目标 3 中，我们将确定 NSGM 的治疗效用。 通过在体内先进检查功效（特别是对 CSC）和毒性（对正常干细胞的影响） 患者来源的异种移植物（PDX）或HT29原位异种移植物模型，单独或与 化疗（5-氟尿嘧啶和奥沙利铂）将通过合作大大加强。 具体来说，我们与 Mohapatra（苏布拉）（坦帕）​​、Raufman（巴尔的摩）博士的合作。 Pisegna（大洛杉矶）属于我们的癌症干细胞病理学和结直肠癌治疗 (CSCPT) 集群， 以及其他 VA4C 合作者，包括 Mohapatra/Kelly（坦帕/达勒姆）和 Bouvet 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（目标 1）； 通过效果与多组学研究的相关性来预测 NSGM 效果的生物标志物；以及 c) 测试 新型动物模型中的 NSGM，例如目标 3 中的 PDX 和远端结肠原位异种移植物。同样，我们的 通过该提案获得的专业知识和知识将与 Mohapatra 和 Raufman 博士（CSC）分享。 分析（例如 CSC 标记物的综合分析等），我们还将协助其他 VA4C。 研究人员收集血液、血清和组织样本预计会有所帮助。 破译新型 CSC 信号传导并开发独特的 GAG 模拟物作为临床使用的原型药物。