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

摘要 I型干扰素(IFN1，包括干扰素α和干扰素β)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，药理上的IFN1是 用于单独或联合5-氟尿嘧啶(5FU)治疗结直肠癌(CRC)- 以化疗为基础。然而，这些方法产生的结果并不令人印象深刻，表明 介导IFN1效应的内源性途径在结直肠癌中以某种方式失活。重要的是，所有 内源性或药理学的IFN1效应需要IFNAR1受体链，这也是 对抗癌治疗方案的疗效至关重要，包括放射治疗和 化疗。有趣的是，我们最近发现IFN1-IFNAR1确实在 CRC。我们最近公布的数据表明：(A)IFNAR1经历了泛素化和 对肿瘤微环境因素(如肿瘤来源的小泡)的快速降解， (B)IFNAR1在人类结直肠癌的恶性和良性肿瘤细胞中经常下调，以及。(C) 低水平的IFNAR1与接受标准治疗的结直肠癌患者的生存不良相关 化疗。然后，我们的其他试点实验集中在克服 失去IFNAR1以恢复化疗疗效。这些实验的数据显示， 承诺使用几种方法重新激活IFN1-IFNAR1途径。其中包括一个 新的激动型小分子苏莫化抑制剂TAK981以及利血平 降压药物预防肿瘤衍生小泡的作用。此外，令人兴奋的结果是 使用一种新颖而独特的突变型重组IFN1(SIFN-I)获得，该重组IFN1具有更强的 与IFNAR1有亲和力，即使在低浓度的IFNAR1下也能发挥作用。这些是最近发布和试行的 数据有力地支持了一个重要的假设，即结直肠癌中IFNAR1的丢失 破坏其治疗，反之，重新激活IFN1通路将增加 结直肠癌化疗的疗效。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)，加或不加新的SIFN-I；(Ii)用一种 新的苏莫化抑制剂TAK981，以提高化疗的疗效；和(Iii)预防 利血平干预肿瘤源性囊泡的作用导致IFNAR1的丢失 提高FOLFOX的疗效。这些研究的完成应该会揭示一个新的角色 IFNAR1失活在结直肠癌治疗中的次优疗效及克服这一问题 通过使用该手段重新激活IFN1-IFNAR1途径。

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.