Role of purine metabolism in chemoresistance

嘌呤代谢在化疗耐药中的作用

• 批准号: 9808414
• 负责人: Atique U. Ahmed
• 金额: $ 34.56万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808414
• 关键词: ADP-Ribosylation Factors; Acids; Aftercare; Alkylating Agents; Alkylation; Amino Acids; Anabolism; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Proliferation; Cell division; Cells; Characteristics; Cilia; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Damage; DNA lesion; Data; Diagnosis; Disease; Effectiveness; Engraftment; Enzymes; Excision; FDA approved; Glioblastoma; Glioma; Goals; Immunoprecipitation; In Vitro; Inosine Monophosphate; Isotopes; Kinetics; Knock-out; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Mammalian Cell; Maps; Mass Spectrum Analysis; Metabolic; Mycophenolate; Nerve; Normal Cell; Nucleotides; Operative Surgical Procedures; Oxidoreductase; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Physiological; Process; Protein Family; Protein Isoforms; Proteins; Protocols documentation; Purine Nucleotides; Purines; RNA; Radiation therapy; Radio; Recurrence; Recycling; Regulation; Relapse; Reporting; Resistance; Role; Sampling; Stem cells; Surface Plasmon Resonance; System; Testing; Therapeutic Intervention; Time; Treatment Efficacy; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; chemotherapy; clinically significant; conventional therapy; cytotoxic; effective therapy; falls; improved; in vivo; insight; knock-down; member; mycophenolate mofetil; novel; novel strategies; outcome forecast; prevent; protein protein interaction; purine metabolism; response; small molecule; stable isotope; standard care; stem cell biology; temozolomide; therapy resistant; treatment response; tumor

PROJECT SUMMARY Glioblastoma (GBM), a grade IV tumor, is one of the most aggressive and infiltrative forms of brain cancer. Patients that are currently diagnosed with Glioblastoma (GBM) have a very poor prognosis. Median survival is around 8-10 months even after the standard care protocol of surgical resection followed by alkylating chemotherapy (typically temozolomide or TMZ) and radiotherapy. This is because in nearly all patients the tumor recurs after treatment since GBM cell can become resistant to therapy. Our goal is to develop a treatment for GBM that will reduce recurrence rate and thereby improve the prognosis for patients. One of the distinguishing characteristics of cancer is its uncontrolled cell division. Since cancer cells divide more rapidly than normal cells, they require more purines, the building blocks of DNA and RNA. (The purine biosynthesis pathway has previously been implicated in resistance to chemotherapy). Purines are either synthesized from amino acids and other small molecules through the de novo biosynthesis pathway or are recycled from the microenvironment through the salvage pathway. Cancer cells typically use the de novo biosynthesis pathway, whereas the central nerves system usually rely more on the salvage pathway. Through initial analysis, we have identified ARL13B as a novel regulator of the purine biosynthesis pathway during chemotherapy. ARL13B, a member of the ADP-ribosylation factor-like family protein accountable for cilia maintenance, directly interacts with inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme purine biosynthesis. In our initial studies knocking-down ARL13B inhibited GBM cells’ utilization of the de novo pathway after TMZ treatment and increased utilization of the salvage biosynthesis pathway. The effectiveness of TMZ treatment was also elevated in vitro and in vivo following ARL13B knockdown. We therefore hypothesize that the ARL13B-IMPDH2 regulated switch from the salvage pathway to the de novo purine biosynthesis pathway is necessary for GBM cells’ adaptation to alkylating- based chemotherapy. The goal of this study is to further investigate this hypothesis through the following aims: 1) examine the role of ARL13B in regulating purine metabolism; 2) elucidate the role of purine metabolism in promoting resistance to TMZ; 3) modulate the purine biosynthesis pathway to overcome the resistance against the alkylating-based chemotherapy. Overall, we hope to gain novel insight into the role of purine metabolism in GBM in the context of therapeutic resistance with the end goal of developing a translational therapy to prevent GBM recurrence.!

项目摘要 胶质母细胞瘤（GBM）是IV级肿瘤，是脑癌最具侵略性和浸润形式之一。 目前被诊断为胶质母细胞瘤（GBM）的患者预后较差。中位生存是 即使在手术切除的标准护理方案之后，大约8-10个月，然后进行烷基化 化学疗法（通常是替莫唑胺或TMZ）和放射疗法。这是因为几乎所有患者肿瘤 治疗后复发，因为GBM细胞可以抗治疗。我们的目标是为 GBM将降低复发率，从而改善患者的预后。杰出之一 癌症的特征是其不受控制的细胞分裂。由于癌细胞比正常细胞更快地分裂，所以 他们需要更多的嘌呤，即DNA和RNA的组成部分。 （嘌呤生物合成途径以前具有 与对化学疗法的抗性有关）。嘌呤要么是由氨基酸和其他小的合成的 通过从头生物合成途径或从微环境中回收的分子。 打捞路径。癌细胞通常使用从头生物合成途径，而中枢神经系统 系统通常更多地依靠打捞途径。通过初步分析，我们将ARL13B确定为新颖 ARL13B，ADP-核糖基化的成员 因子样的家族蛋白对纤毛维持责任，直接与单磷酸盐相互作用 脱氢酶2（IMPDH2），限速酶嘌呤生物合成。在我们最初的研究中敲门 ARL13B抑制了TMZ处理后的GBM细胞对从头途径的利用，并增加了对 打捞生物合成途径。 TMZ处理的有效性也升高了体外和体内 在ARL13B敲低之后。因此，我们假设ARL13B-IMPDH2从 从头嘌呤生物合成途径的打捞途径对于GBM细胞适应烷基化是必要的 基于化学疗法。这项研究的目的是通过以下目的进一步研究这一假设： 1）检查ARL13B在调节紫代谢中的作用； 2）阐明紫代谢在 促进对TMZ的抵抗力； 3）调节嘌呤生物合成途径以克服对抗 基于烷基化的化学疗法。总体而言，我们希望对纯代谢在 在理论抵抗的背景下，GBM的最终目标是开发转化疗法以防止 GBM复发。！