Redox modulation - Impact on Tumor Growth and Therapeutic Anticancer Efficacy

项目摘要 尽管癌症生物学取得了进展，但耐药性仍然是患者和临床医生的主要障碍。许多癌症 治疗剂提高活性氧（ROS）的产生，通常导致退化，随后是 复发和治疗抗性。该项目继续Kelkka等人发表的工作， 在Nox 2复合物的Ncf 1分子中携带功能缺失突变的小鼠中的肿瘤生长抑制 （Kelkka，T.等，2013年）。鉴于Ncf 1突变小鼠更容易受到人类的动物模型的影响， 自身免疫性疾病（Zhong，J.等人，2018），免疫细胞可能对转移更有效， 当白细胞中的ROS产生被抑制时，肿瘤进展。然而，他们的研究并没有确定 白细胞在Nox 2介导的肿瘤生长中起主要作用，为癌症治疗提供了可能的靶点。 目前有五项临床试验正在评估Auranofin，一种FDA批准的硫氧还蛋白还原酶1（TrxR）抑制剂， 作为恶性肿瘤如胶质母细胞瘤、卵巢癌、肺癌和白血病的可能治疗。 早期的研究表明，抑制肿瘤中的TrxR抑制体内肿瘤进展（斯塔福德，W. C. et al. 2018，Yoo，M. H.等人，2006）。然而，这些研究，以及迄今为止的绝大多数研究， 金诺芬对免疫受损动物模型的有限测试。我们有强有力的证据表明TrxR 在免疫活性动物中抑制显著促进实体鼠同源肿瘤的肿瘤生长 如B16 F10黑素瘤和刘易斯肺癌（LLC）模型。我们的研究得到了 被忽视的，但令人信服的研究，在文学（Hiramoto，K。et al. 2014，Mirabelli，C. K.等人，1985）。 因此，我们的目的还在于显示树突状细胞或B细胞中TrxR的抑制可以促进肿瘤进展。 这个重组的博士项目，由于依赖多种育种，受到COVID的严重影响， 将完成两个高影响力手稿的实验，以发表在《细胞》或《生物医学杂志》等期刊上。 免疫：1）建立靶向同基因树突状细胞中Ncf 1-Nox 2的治疗潜力的手稿 用于对抗B16 F10和LLC癌症模型的细胞; 2）建立TrxR 1抑制作用的手稿 在树突状细胞和机制，促进B16 F10和LLC肿瘤生长，及其意义的抗癌 疗法我们将使用六种小鼠品系来帮助我们理解宿主氧化还原生物学在癌症中的意义 免疫监视具体而言，我们将使用具有关键表型的小鼠模型：BQ.Txnrd1Flox、BQ.Ncf1m1J (Ncf1突变小鼠）、BQ. CD 11 c-cre、BQ.MB1-cre、BQ.CD4-cre和BQ.TN3条件性Ncf 1野生型敲除- 对小鼠如果成功，这将具有治疗意义。

PROJECT SUMMARY Despite advances in cancer biology, drug resistance is a major obstacle to patients and clinicians. Many cancer therapeutics elevate reactive oxygen species (ROS) production, often leading to regression followed by reoccurrence and therapeutic resistance. This project continues work published by Kelkka et al. which observed tumor growth inhibition in mice carrying a loss of function mutation in the Ncf1 molecule of the Nox2 complex (Kelkka, T. et al. 2013). Given that Ncf1 mutant mice are more susceptible to animal models of human autoimmune diseases (Zhong, J. et al. 2018), immune cells may be more efficacious against metastasis and tumor progression when ROS production in leukocytes is inhibited. However, their studies did not identify which leukocyte plays the major role in the Nox2-mediated tumor growth, presenting possible targets for cancer therapy. Currently five clinical trials are evaluating Auranofin, an FDA approved thioredoxin reductase 1 (TrxR) inhibitor, as a possible treatment for malignancies such as glioblastoma, ovarian cancer, lung carcinoma, and leukemia. Earlier studies have shown that inhibition of TrxR in tumors suppresses, in vivo tumor progression (Stafford, W. C. et al. 2018, Yoo, M. H. et al. 2006). However, these studies, and a vast majority of studies to-date, have limited testing of Auranofin to immuno-compromised animal models. We have strong evidence that TrxR inhibition in immune-competent animals significantly promote tumor growth of solid murine syngeneic tumors such as the B16F10 melanoma and the Lewis Lung Carcinoma (LLC) models. Our studies are supported by overlooked, yet convincing studies in the literature (Hiramoto, K. et al. 2014, Mirabelli, C. K. et al. 1985). Therefore, we also aim to show that inhibition of TrxR in dendritic cells or B cells may promote tumor progression. This reorganized PhD project, having been heavily affected by COVID due to dependence on multiple breeding, will finalize experiments for two high-impact manuscripts for publication aimed at journals such as Cell or Immunity: 1) A manuscript establishing the therapeutic potential of targeting Ncf1-Nox2 in syngeneic dendritic cells for use against B16F10 and LLC cancer models; 2) a manuscript establishing the effects of TrxR1 inhibition in dendritic cells and mechanism for promoting B16F10 and LLC tumor growth, and its implication for anticancer therapy. We will use six mouse strains to help us understand the significance of host Redox biology in cancer immune surveillance. Specifically, we will use mouse models with key phenotypes: BQ.Txnrd1Flox, BQ.Ncf1m1J (Ncf1 mutant mice), BQ.CD11c-cre, BQ.MB1-cre, BQ.CD4-cre, and BQ.TN3 conditional Ncf1 wildtype knock- in mice. If successful, this will be of therapeutic significance.