Pre-IND Development of Polymeric Micelles with Dual Drug Payloads for HCC Therapy

项目总结 肝细胞癌的发病率正在增加，但化疗选择仍然非常有限。 对全身治疗的抵抗以及全身治疗后局部和远处的复发是主要原因。 肝细胞癌的问题。创新的联合疗法是治疗肝癌的一种有吸引力的策略。肿瘤干细胞 (CSC)是一小部分自我更新、多潜能、缓慢增殖的恶性细胞，在 包括肝细胞癌在内的各种癌症类型的肿瘤发生、转移、复发和多药耐药。 靶向CSCs可能为有效的抗肝癌治疗提供一条很有前途的途径。然而，只针对CSC 将是不够的，因为新的CSCs可以不断地从非CSC肿瘤细胞通过 上皮向间充质转化(EMT)的激活。因此，同时消除CSC是至关重要的 和增殖的非CSC肿瘤细胞。迄今为止，实现这一目标的药理学方法在很大程度上仍然存在。 不能令人满意。这项提议寻求开发一种基于聚合物胶束的解决方案，以解决肝细胞癌的耐药性。 聚合物胶束递送系统是与环丙胺(CPA)共同配制的，环胺是一种自然产生的刺猬 (HH)能够清除CSCs的信号转导抑制剂和细胞毒性化疗药物紫杉醇(PTX) 这阻止了有丝分裂的进程，并触发了细胞凋亡。在初步研究中，我们已经证明 同时含有CPA和PTX的聚合物胶束，称为M-CPA/PTX，显著延长了中位生存期 在预防和治疗环境中对自发c-Myc驱动的肝癌转基因小鼠的研究。此外， M-CPA/PTX明显优于单独使用PTX、单独使用CPA或CPA/PTX的物理混合物。 M-CPA/PTX下调c-Myc，抑制肿瘤球体形成，抑制EMT，减少 细胞外基质成分有利于极大地改善两种药物的肿瘤处置。加在一起， 我们初步保证了M-CPA/PTX技术的进一步前期开发。有两个主要目标 对于本项目：降低M-CPA/PTX临床翻译的风险，并获得可靠的IND包。为了实现我们的目标 目标，我们将追求3个具体目标：1)放大合成高质量的M-CPA/PTX并充分表征 2)测定其抗肿瘤效果、生物分布、药代动力学(PK)、毒性、 临床前肝细胞癌模型中M-CPA/PTX的药效学(PD)及PK/PD相关性； M-CPA/PTX抗肝癌作用机制的研究我们的最终目标是将M-CPA/PTX转化为 临床认为是一种安全有效的治疗方法，可提高肝细胞癌患者的存活率。这个项目将会有 特殊的影响，因为它将为潜在有效的系统疗法的临床翻译铺平道路 并深入了解肿瘤干细胞和肿瘤间质在抗肝癌治疗抵抗中的作用。

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is increasing in prevalence, yet chemotherapy options remain very limited. Resistance to systemic therapy and recurrence at local and distant sites following systemic therapy are major problems in HCC. Innovative combination therapy is an appealing strategy for treating HCC. Cancer stem cells (CSC) are a small subset of self-renewing, pluripotent, slowly proliferating malignant cells that play key roles in tumor initiation, metastasis, recurrence, and multidrug resistance in various cancer types, including HCC. Targeting CSCs may offer a promising avenue for effective anti-HCC therapy. However, targeting CSC alone would be insufficient because new CSCs could be constantly derived from non-CSC tumor cells through activation of epithelial-to-mesenchymal transition (EMT). It is therefore critical to simultaneously eliminate CSCs and proliferating non-CSC tumor cells. To date, pharmacologic approaches toward this goal remain largely unsatisfactory. This proposal seeks to develop a polymeric micelle-based solution to drug resistance in HCC. The polymeric micellar delivery system is co-formulated with cyclopamine (CPA), a naturally occurring hedgehog (Hh) signaling inhibitor capable of eliminating CSCs, and paclitaxel (PTX), a cytotoxic chemotherapeutic agent that blocks the progression of mitosis and triggers apoptosis. In preliminary studies, we have demonstrated that polymeric micelles containing both CPA and PTX, termed M-CPA/PTX, significantly prolonged median survival of transgenic mice with spontaneous c-Myc-driven HCC in both preventive and therapeutic settings. Moreover, M-CPA/PTX was significantly more efficacious than PTX alone, CPA alone, or a physical mixture of CPA + PTX. M-CPA/PTX downregulated c-Myc, suppressed tumor spheroid formation, inhibited EMT, and decreased components of extracellular matrix in favor of vastly improved tumor disposition of both drugs. Taken together, our preliminary warrant further pre-IND development of the M-CPA/PTX technology. There are two primary goals for this project: to de-risk clinical translation of M-CPA/PTX and to obtain a robust IND package. To achieve our goals, we will pursue 3 specific aims: 1) to scale up synthesis of high-quality M-CPA/PTX and fully characterize the resulting products; 2) to determine the antitumor efficacy, biodistribution, pharmacokinetics (PK), toxicity, pharmacodynamics (PD), and PK/PD correlation of M-CPA/PTX in preclinical models of HCC; 3) to evaluate the mechanism by which M-CPA/PTX exerts its anti-HCC activity. Our ultimate goal is to translate M-CPA/PTX into the clinic as a safe and effective therapy that improves survival of patients with HCC. This project will have exceptional impact because it will pave the path for clinical translation of a potentially effective systemic therapy for HCC patients and provide insight into the role of CSCs and tumor stroma in resistance to anti-HCC therapy.