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

用于 HCC 治疗的具有双药物有效负载的聚合物胶束的 IND 前开发

• 批准号: 10407228
• 负责人: Diana S-L. Chow
• 金额: $ 64.3万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407228
• 关键词: Adenocarcinoma; Animal Model; Apoptosis; BAY 54-9085; Biodistribution; Biological Assay; Biological Markers; Canis familiaris; Chemistry; Clinic; Clinical; Clinical Paths; Combined Modality Therapy; Complement Activation; Development; Distant; Dose; Drug Kinetics; Drug resistance; Endotoxins; Extracellular Matrix; Fibrosis; Formulation; Future; Gastrointestinal Neoplasms; Genes; Goals; Hemolysis; Liquid Chromatography; Liver Cirrhosis; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Messenger RNA; Micelles; Mitosis; Monitor; Multi-Drug Resistance; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Organ; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Plasma; Platelet aggregation; Play; Polymers; Pre-Clinical Model; Preparation; Prevalence; Prevention therapy; Preventive; Primary carcinoma of the liver cells; Prognosis; Proliferating; Quality of life; Rattus; Recurrence; Reproducibility; Research Contracts; Resistance; Risk; Rodent; Role; Site; System; Systemic Therapy; Technology; Therapeutic; Toxic effect; Transgenic Mice; Translating; Transplantation; Tumor Stem Cells; Tyrosine Kinase Inhibitor; Up-Regulation; Work; base; c-myc Genes; cancer cell; cancer stem cell; cancer type; chemotherapeutic agent; chemotherapy; clinical risk; clinical translation; clinically relevant; cyclopamine; cytotoxic; density; drug development; drug efficacy; drug release profile; effective therapy; epithelial to mesenchymal transition; improved; inhibitor; innovation; insight; liver cancer model; neglect; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; response; scale up; self-renewal; smoothened signaling pathway; stem cell biomarkers; stemness; success; systemic toxicity; tumor; tumor initiation; zeta potential

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.

项目摘要 肝细胞癌（HCC）的发病率正在增加，但化疗的选择仍然非常有限。 对全身治疗的抵抗和全身治疗后局部和远处的复发是主要的 HCC的问题。创新的联合治疗是治疗HCC的一种有吸引力的策略。癌症干细胞 (CSC)是自我更新，多能性，缓慢增殖的恶性细胞的一个小子集，在肿瘤的发生中起关键作用。 包括HCC在内的各种癌症类型中的肿瘤起始、转移、复发和多药耐药性。 靶向CSC可能为有效的抗HCC治疗提供有希望的途径。然而，仅针对CSC 这是不够的，因为新的CSC可以不断地从非CSC肿瘤细胞中衍生出来， 上皮-间充质转化（EMT）的激活。因此，同时消除CSC至关重要 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主要仍然是 不满意。该提案旨在开发一种基于聚合物胶束的解决方案，以解决HCC中的耐药性。 聚合物胶束传递系统与环巴胺（CPA），一种天然存在的刺猬， (Hh)能够消除CSC的信号传导抑制剂和紫杉醇（PTX），细胞毒性化疗剂 阻止有丝分裂并引发细胞凋亡。在初步研究中，我们已经证明， 含有CPA和PTX的聚合物胶束，称为M-CPA/PTX，显著延长中位生存期 的转基因小鼠与自发的c-Myc驱动的肝癌在预防和治疗设置。此外，委员会认为， M-CPA/PTX比单独的PTX、单独的CPA或CPA + PTX的物理混合物显著更有效。 M-CPA/PTX下调c-Myc表达，抑制肿瘤球体形成，抑制EMT，降低肿瘤细胞增殖。 细胞外基质的成分有利于大大改善两种药物的肿瘤处置。综合起来看， 我们初步保证了M-CPA/PTX技术的进一步IND前开发。有两个主要目标 对于本项目：降低M-CPA/PTX临床翻译的风险，并获得稳健的IND包装。实现我们 目标，我们将追求3个具体目标：1）规模合成高质量的M-CPA/PTX，并充分表征 得到的产物; 2）测定抗肿瘤功效、生物分布、药代动力学（PK）、毒性， M-CPA/PTX在HCC临床前模型中的药效学（PD）和PK/PD相关性; 3）评估M-CPA/PTX在HCC临床前模型中的作用， M-CPA/PTX发挥其抗HCC活性的机制。我们的最终目标是将M-CPA/PTX转化为 临床作为一种安全有效的治疗方法，提高肝癌患者的生存率。该项目将有 特殊的影响，因为它将为潜在有效的全身治疗的临床转化铺平道路 并提供了对CSC和肿瘤间质在抗HCC治疗抵抗中的作用的深入了解。