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.

这个协作式VA优点应用程序（CMA）利用了有成就的研究人员的专业知识，他们形成了一个