Towards Translation of MU-CN29: New Therapeutic Nanoparticle for Drug-Resistant NSCLC

摘要 非小细胞肺癌(NSCLC)是男性和女性癌症死亡的主要原因。尽管 快速的治疗进展，EGFR突变的NSCLC的5年存活率仍然是令人沮丧的16% 过去几十年。特别是，对广泛使用的治疗方法迅速产生抗药性，如 酪氨酸激酶抑制物(TKI)是非小细胞肺癌患者长期生存的关键障碍。此外， 患有EGFR突变肿瘤的患者对免疫检查点抑制剂(ICIS)没有反应，留下了 长期缓解的希望很小，甚至没有希望。因此，确定抗性和分子决定因素 开发一种针对化疗和免疫耐受途径的疗法是最好的机会 提高带有EGFR突变的非小细胞肺癌患者的存活率。我们假设MU-CN29，领头羊 靶向siRNA纳米结合物，恢复耐药非小细胞肺癌患者对酪氨酸激酶抑制剂的敏感性。我们进一步 假设MU-CN29将诱导全身免疫反应，启动肿瘤微环境 通过ICIS进行免疫治疗。因此，该TTNCI提案的中心目标是开发、评估和 验证MU-CN29作为治疗耐药非小细胞肺癌的有效药物。我们在体外和体内的前景 实验结果证实了抗性驱动受体酪氨酸激酶Ax1和AX1之间的串扰 Fn14通路在耐药非小细胞肺癌中的作用此外，我们发现Ax1和FN14的共敲除， 利用MU-CN29与双siRNAs共价连接，使耐药肿瘤对酪氨酸激酶增敏 抑制剂(TKI)，体内外。为了使MU-CN29能够转化为人体试验，在本提案中，我们将 根据FDA指南制造纳米颗粒，在小鼠和狗身上进行详细的毒理学研究 受试者，并在临床相关动物模型中评价其治疗效果。这样做的具体目的是 应用：(1)确定MU-CN29临床级生产方案；(2)确定安全性和安全性 MU-CN29对小鼠非小细胞肺癌模型的疗效；(3)建立MU-CN29对犬癌患者的安全性。 这些数据将验证MU-CN29纳米颗粒平台是一种有前途的抗药性策略 NSCLC和催化未来的临床试验。

ABSTRACT Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in both men and women. Despite rapid therapeutic advances, the 5-year survival rate of EGFR-mutant NSCLC remains a dismal 16% for the past several decades. In particular, the rapid emergence of resistance to widely used treatments, such as the tyrosine kinase inhibitor (TKI), is the key obstacle to achieving long-term NSCLC patient survival. Further, patients with EGFR mutated tumors fail to respond to immune checkpoint inhibitors (ICIs), leaving them with little to no hope of a long-term remission. Therefore, identifying the molecular determinants of resistance and developing a therapeutic that targets the chemo- and immune-resistant pathways, is the best chance to improve survival rates in NSCLC patients with an EGFR mutation. We hypothesize that MU-CN29, the lead targeted siRNA nanoconjugate, restores sensitivity to tyrosine kinase inhibitors in resistant NSCLC. We further postulate that MU-CN29 will induce a systemic immune response, priming the tumor microenvironment for immunotherapy via ICIs. Therefore, the central objective of this TTNCI proposal is to develop, evaluate, and validate MU-CN29 as an effective therapeutic agent for resistant NSCLC. Our promising in vitro and in vivo experimental results confirmed the crosstalk between the resistance-driving receptor tyrosine kinase AXL and FN14 pathways in drug resistant NSCLC. Additionally, we found that the co-knockdown of both AXL and FN14, using MU-CN29, covalently attached with the dual siRNAs, sensitized the resistant tumors to tyrosine kinase inhibitor (TKI), in vitro and in vivo. To enable translation of MU-CN29 to human trials, in this proposal, we will manufacture the nanoparticles as per FDA guidelines, perform detailed toxicology studies in murine and canine subjects, and evaluate the therapeutic efficacy in clinically relevant animal models. The specific aims of this applications are: (1) Determine MU-CN29 clinical-grade production protocols; (2) Determine the safety and efficacy of MU-CN29 in murine NSCLC models; (3) Establish safety of MU-CN29 in canine cancer patients. The data will validate MU-CN29 nanoparticle platform as a promising strategy to combat drug resistance in NSCLC and catalyze clinical trials in the future.