Development of novel protein-based therapeutics for lung cancer

肺癌是全球癌症死亡的主要原因。肺癌的早期症状有哪些？ 小细胞肺癌（NSCLC）。这个应用程序的目标是实现一个协作工作， 临床前模型，生物工程和功能基因组学，以进一步表征和验证一种新的"首次在 肺癌的治疗策略。我们先前发表的工作和广泛的 初步数据表明，CLCF1-CNTFR信号传导的阻断代表了一种独特的， 肺癌的治疗方法。Sweet-Cordero和Cochran实验室 在过去的几年里，他们进行了广泛的合作，以验证这一信号轴，首先是用shRNA遗传学。 方法，现在通过开发工程CNTFR受体诱饵（eCNTFR）。在目标1中， 我们将通过测量其热稳定性和蛋白水解稳定性来进一步开发eCNTFR作为治疗候选物， 潜在的免疫原性和毒性、可制造性和药代动力学，并将优化这些 所需的属性。我们还将对eCNTFR与CLCF 1的复合物进行结构分析，以确定 高亲和力结合特性。最后，我们将测试eCNTFR在各种各样的治疗效果。 NSCLC的临床前模型，包括人细胞系和患者来源的异种移植物。在目标2中，我们 进行体外生化试验，以充分确定eCNTFR的细胞自主作用机制 封锁为了进一步了解eCNTFR在体内的作用机制，我们将补充异种移植 用一个良好表征的肺癌基因工程小鼠模型。重要的是，这种模式 这将使我们能够研究eCNTFR不仅对肿瘤细胞，而且对微环境的影响， 评估eCNTFR是否具有免疫调节作用。在目标3中，我们将确定最有效的 组合方法来增强eCNTFR治疗。这些努力将以合理和 通过利用CRISPR/CAS9使用专门针对FDA目标的库， 批准的药物。然后将在动物模型中测试候选组合疗法。我们的研究将 阐明这种配体/受体信号传导轴的关键生物学基础，并将提供临床前 验证靶向肺癌的创新策略，以保证其进一步的临床开发。

Lung cancer is the leading cause of cancer deaths worldwide. The most prevalent type of lung cancer is Non- Small Cell Lung Cancer (NSCLC). The goal of this application is to implement a collaborative effort involving preclinical models, bioengineering and functional genomics to further characterize and validate a novel “first in class” therapeutic strategy for the treatment of lung cancer. Our prior published work and extensive preliminary data indicates that blockade of CLCF1-CNTFR signaling represents a unique and previously unexplored approach for lung cancer therapy. The Sweet-Cordero and Cochran laboratories have collaborated extensively over the past several years to validate this signaling axis, first with shRNA genetic approaches, and now through the development of an engineered CNTFR receptor decoy (eCNTFR). In Aim 1, we will further develop eCNTFR as a therapeutic candidate by measuring its thermal and proteolytic stability, potential for immunogenicity and toxicity, manufacturability, and pharmacokinetics, and will optimize these properties as needed. We will also perform structural analysis of eCNTFR in complex with CLCF1 to define high affinity binding characteristics. Lastly, we will test eCNTFR for therapeutic efficacy across a wide array of preclinical models of NSCLC including human cell lines and patient-derived xenografts. In Aim 2, we will perform in vitro biochemical assays to fully define the cell-autonomous mechanism of action of eCNTFR blockade. To further understand the mechanism of action of eCNTFR in vivo, we will complement xenograft models with a well-characterized genetically engineered mouse model of lung cancer. Importantly, this model will allow us to study the effects of eCNTFR not only on tumor cells but also on the microenvironment, and to assess whether eCNTFR has immunomodulatory effects. In Aim 3, we will identify the most effective combination approaches to enhance eCNTFR therapy. These efforts will be carried out in a rational and unbiased manner by leveraging CRISPR/CAS9 using a library directed specifically at the targets of FDA approved drugs. Candidate combination therapies will then be tested in animal models. Our studies will elucidate critical biological underpinnings of this ligand/receptor signaling axis, and will provide preclinical validation of an innovative strategy for targeting lung cancer to warrant its further clinical development.