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 尽管治疗进展迅速，EGFR突变型NSCLC的5年生存率仍为16%， 过去几十年。特别是，对广泛使用的治疗方法，如 酪氨酸激酶抑制剂（TKI）是实现NSCLC患者长期生存的关键障碍。此外，本发明还 EGFR突变肿瘤患者对免疫检查点抑制剂（ICI）没有反应， 长期缓解的希望微乎其微因此，确定抗性的分子决定因素， 开发一种针对化疗和免疫抵抗途径的治疗方法，是最好的机会， 提高EGFR突变NSCLC患者的生存率。我们假设MU-CN 29， 靶向siRNA纳米缀合物，恢复耐药NSCLC对酪氨酸激酶抑制剂的敏感性。我们进一步 假设MU-CN 29将诱导全身免疫应答，启动肿瘤微环境， 免疫疗法通过ICIs。因此，本TTNCI提案的中心目标是开发、评估和 验证MU-CN 29作为耐药NSCLC的有效治疗剂。我们有前途的体外和体内 实验结果证实了阻力驱动受体酪氨酸激酶AXL和 耐药NSCLC中的FN 14通路。此外，我们发现AXL和FN 14的共敲除， 使用与双siRNA共价连接的MU-CN 29，使耐药肿瘤对酪氨酸激酶敏感， 抑制剂（TKI），在体外和体内。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指南生产纳米颗粒，在小鼠和犬中进行详细的毒理学研究 受试者，并在临床相关的动物模型中评估治疗功效。具体目标是 应用是：（1）确定MU-CN 29临床级生产方案;（2）确定安全性和 MU-CN 29在鼠NSCLC模型中的功效;（3）确定MU-CN 29在犬癌症患者中的安全性。 这些数据将验证MU-CN29纳米颗粒平台作为对抗耐药性的有前途的策略， 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.