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.!

项目概要 胶质母细胞瘤 (GBM) 是一种 IV 级肿瘤，是最具侵袭性和浸润性的脑癌之一。 目前被诊断患有胶质母细胞瘤（GBM）的患者的中位生存期很差。 即使在手术切除和烷化的标准护理方案之后，也需要大约 8-10 个月 化疗（通常是替莫唑胺或 TMZ）和放疗 这是因为几乎所有患者都患有肿瘤。 由于 GBM 细胞会对治疗产生耐药性，因此治疗后会复发。我们的目标是开发一种治疗方法。 GBM 将降低复发率并改善患者的预后之一。 癌症的特征是不受控制的细胞分裂，因为癌细胞比正常细胞分裂得更快， 它们需要更多的嘌呤，即 DNA 和 RNA 的组成部分。 嘌呤是由氨基酸和其他小分子合成的 分子通过从头生物合成途径或通过 挽救途径。癌细胞通常使用从头生物合成途径，而中枢神经则使用这种途径。 系统通常更依赖于抢救途径，通过初步分析，我们已将 ARL13B 确定为一种新颖的系统。 化疗期间嘌呤生物合成途径的调节剂 ARL13B，ADP-核糖基化的成员。 负责纤毛维持的类因子家族蛋白，直接与单磷酸肌苷相互作用 在我们的初步研究中，脱氢酶 2 (IMPDH2) 是嘌呤生物合成的限速酶。 ARL13B 抑制 GBM 细胞在 TMZ 治疗后对 de novo 途径的利用，并增加对 补救生物合成途径的TMZ治疗效果在体外和体内也得到了提高。 因此，我们保留了 ARL13B-IMPDH2 调节开关。 从头嘌呤生物合成途径的挽救途径对于GBM细胞适应烷基化是必要的 本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在调节嘌呤代谢中的作用；2）阐明嘌呤代谢在 促进TMZ耐药；3）调节嘌呤生物合成途径，克服耐药性 总的来说，我们希望对嘌呤代谢的作用有新的认识。 GBM 在治疗耐药的背景下，最终目标是开发一种转化疗法来预防 GBM复发！