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: 10573175
• 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/10573175
• 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; Epithelial Cells; 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; Phosphorylation; Pilot Projects; Play; Production; Proliferating; Proteins; Public Health; Publishing; Radiation therapy; Recombinants; Regimen; Reserpine; Role; STAT1 gene; Solid Neoplasm; Stress; Sumoylation Pathway; Testing; Therapeutic; Treatment Efficacy; Treatment Protocols; Tumor-Derived; Ubiquitination; Vesicle; Work; anti-tumor immune response; anticancer treatment; antitumor effect; chemotherapy; colon cancer patients; colorectal cancer treatment; cytokine; density; efficacy evaluation; experimental study; extracellular vesicles; inhibitor; intestinal epithelium; mutant; neoplastic cell; novel; pharmacologic; 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）是肠上皮的关键调节剂 细胞增殖和抗肿瘤免疫反应。根据药理学IFN1 单独用于结直肠癌（CRC）或与5-氟尿嘧啶（5FU） - 基于化学疗法。但是，这些方法产生了巨大的结果，表明 CRC中介导IFN1效应的内源性途径在某种程度上灭活。重要的是，一切 内源性或药理学IFN1的影响需要IFNAR1受体链，这也是 对于抗癌治疗方案的效率至关重要 化学疗法。有趣的是，我们最近发现IFN1-IFNAR1确实在 CRC。我们最近发布的数据表明，（a）IFNAR1经历了泛素化和 响应肿瘤微环境因素（例如肿瘤衍生蔬菜）的快速降解， （b）在人CRC中的恶性和良性肿瘤细胞中，IFNAR1通常被下调，并且（c） 低水平的IFNAR1与接受标准的CRC患者的存活率差有关 化学疗法。然后，我们的其他试点实验专注于克服的能力 IFNAR1损失以恢复化学疗法的效率。这些实验的数据显示了 使用几种方法对IFN1-IFNAR1途径进行重新激活的承诺。这些包括 新颖而令人兴奋的小分子sumoylation抑制剂tak981以及储备金 降压药阻止了肿瘤衍生的蔬菜的作用。此外，令人兴奋的结果是 使用新颖且独特的突变体重组IFN1（SIFN-I）获得的，该突变体显示出增加 对IFNAR1的亲和力甚至可以在低IFNAR1密度下起作用。这些最近出版和飞行员 数据为CRC中IFNAR1丢失的总体假设提供了坚定的支持 破坏其治疗方法，相反，IFN1途径的重新激活将增加 CRC化疗的功效。为了检验这一假设，我们建议（i）确定 IFNAR1在结直肠腺癌对5-FU的反应中的重要性 有或没有新型SIFN-I的疗法（FOLFOX）； （ii）使用A重新激活IFN1-IFNAR1途径 新型Sumoylation抑制剂TAK981提高化学疗法的效率； （iii）预防 通过干扰使用储备金的肿瘤衍生蔬菜的影响而损失IFNAR1 提高FOLFOX的效率。这些研究的完成应揭示 在CRC治疗的亚最佳效率中失活IFNAR1并克服了这个问题 通过使用手段重新激活IFN1-IFNAR1途径。