Reactivation of type I interferon pathway to increase the efficacy of chemotherapy

重新激活 I 型干扰素途径以提高化疗效果

• 批准号: 10333372
• 负责人: Serge Y Fuchs
• 金额: $ 36.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-03 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333372
• 关键词: Affinity; Antihypertensive Agents; Antineoplastic Agents; Benign; Binding; Cell surface; Cells; Chemotherapy-Oncologic Procedure; Colorectal Adenocarcinoma; Colorectal Cancer; Data; Disease; Down-Regulation; Endocytosis; Epithelial Cell Proliferation; Exhibits; Family; Fluorouracil; Genes; Human; IFNAR1 gene; IFNAR2 gene; Interferon Type I; Interferon-alpha; Interferons; Knock-in Mouse; Malignant - descriptor; Malignant Neoplasms; Mediating; Pathway interactions; Persons; Pharmacology; Phosphorylation; Pilot Projects; Play; Production; Proteins; Public Health; Publishing; Radiation therapy; Radio; Recombinants; Regimen; Reserpine; Role; STAT1 gene; Solid Neoplasm; Stress; Sumoylation Pathway; Testing; Treatment Efficacy; Treatment Protocols; Tumor-Derived; Ubiquitination; Vesicle; Work; anti-tumor immune response; anticancer treatment; antitumor effect; base; cell killing; chemotherapy; colon cancer patients; colorectal cancer treatment; cytokine; density; efficacy evaluation; experimental study; extracellular vesicles; inhibitor; intestinal epithelium; mutant; neoplastic cell; novel; preclinical study; prevent; receptor; refractory cancer; response; small molecule; standard of care; targeted cancer therapy; tumor; tumor microenvironment; tumorigenic; type I interferon receptor; uptake

ABSTRACT Type I interferons (IFN1, including IFNα and IFNβ) are critical regulators of intestinal epithelial cells proliferation and of anti-tumor immune responses. Accordingly, pharmacologic IFN1 were used in treatment of colorectal cancer (CRC) alone or combined with the 5-fluorouracil (5FU)- based chemotherapy. However, these approaches yielded underwhelming results indicating that the endogenous pathway mediating IFN1 effects is somehow inactivated in CRC. Importantly, all effects of endogenous or pharmacologic IFN1 require the IFNAR1 receptor chain, which is also essential for the efficacy of the anti-cancer treatment regimens including radio- and chemotherapies. Intriguingly, we recently found that the IFN1-IFNAR1 is indeed inactivated in CRC. Our recently published data demonstrate that (a) IFNAR1 undergoes ubiquitination and rapid degradation in response to tumor microenvironment factors such as tumor-derived vesicles, (b) IFNAR1 is often downregulated in malignant and benign tumor cells in human CRC, and (c) low levels of IFNAR1 correlates with poor survival of CRC patients who received standard chemotherapies. Our additional pilot experiments were then focused on ability to overcome the loss of IFNAR1 to restore the efficacy of chemotherapy. Data from these experiments showed a promise for reactivation of the IFN1-IFNAR1 pathway using several approaches. These include a novel and exciting small molecule sumoylation inhibitor TAK981, as well as reserpine, a hypotensive drug preventing the effects of tumor-derived vesicles. In addition, exciting results are obtained using a novel and unique mutant recombinant IFN1 (sIFN-I) that exhibits an increased affinity to IFNAR1 and can act even at low IFNAR1 density. These recently published and pilot data provide a firm support for an overarching hypothesis that the loss of IFNAR1 in CRC undermines its treatment and, conversely, reactivation of the IFN1 pathway will increase the efficacy of CRC chemotherapy. To test this hypothesis, we propose to (i) determine the importance of IFNAR1 loss in responses of colorectal adenocarcinomas to 5-FU-containing regimen (FOLFOX) with or without novel sIFN-I; (ii) reactivate the IFN1-IFNAR1 pathway using a novel sumoylation inhibitor TAK981 to increase the efficacy of chemotherapy; and (iii) prevent the loss of IFNAR1 by interfering with the effect of tumor-derived vesicles using reserpine to increase the efficacy of FOLFOX. Completion of these studies should reveal a novel role of inactivation of IFNAR1 in the sub-optimal efficacy of CRC therapy and to overcome this problem through using the means to reactivate the IFN1-IFNAR1 pathway.

抽象的 I 型干扰素（IFN1，包括 IFNα 和 IFNβ）是肠上皮细胞的重要调节因子 细胞增殖和抗肿瘤免疫反应因此，药理干扰素1。 单独或与5-氟尿嘧啶（5FU）联合用于治疗结直肠癌（CRC）- 然而，这些方法产生的结果并不理想，表明 重要的是，介导 IFN1 效应的内源性通路在 CRC 中以某种方式失活。 内源性或药理学 IFN1 的作用需要 IFNAR1 受体链​​，这也是 对于抗癌治疗方案（包括放射和治疗）的功效至关重要 有趣的是，我们最近发现 IFN1-IFNAR1 确实在化疗中失活。 CRC。我们最近发表的数据表明 (a) IFNAR1 发生泛素化并且 响应肿瘤微环境因素（例如肿瘤来源的囊泡）而快速降解， (b) IFNAR1 在人类 CRC 的恶性和良性肿瘤细胞中经常下调，以及 (c) 低水平的 IFNAR1 与接受标准治疗的 CRC 患者的不良生存率相关 然后，我们进行了额外的试点实验，重点关注克服这些问题的能力。 这些实验的数据显示，失去 IFNAR1 可以恢复化疗的功效。 有望使用多种方法重新激活 IFN1-IFNAR1 途径。 新颖且令人兴奋的小分子苏酰化抑制剂 TAK981 以及利血平（一种 降血压药物可预防肿瘤来源的囊泡的影响。此外，令人兴奋的结果是。 使用新颖且独特的突变重组 IFN1 (sIFN-I) 获得，该突变体重组 IFN1 (sIFN-I) 表现出增加的 这些药物与 IFNAR1 具有亲和力，甚至可以在低 IFNAR1 密度下发挥作用。 数据为 CRC 中 IFNAR1 丢失的总体假设提供了坚实的支持 破坏其治疗，相反，重新激活 IFN1 途径会增加 为了检验这一假设，我们建议 (i) 确定 IFNAR1 缺失在结直肠腺癌对含 5-FU 反应中的重要性 方案（FOLFOX），有或没有新型 sIFN-I；（ii）使用 IFN1-IFNAR1 途径重新激活 新型苏酰化抑制剂 TAK981 可提高化疗疗效；以及 (iii) 预防 使用利血平干扰肿瘤源性囊泡的作用，从而导致 IFNAR1 的损失 增加 FOLFOX 的功效 完成这些研究应该会揭示 FOLFOX 的新作用。 IFNAR1 失活导致 CRC 治疗效果不佳并克服这一问题 通过使用重新激活IFN1-IFNAR1途径的手段。