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

基本信息

批准号：
10669704
负责人：
Diana S-L. Chow
金额：
$ 61.49万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/10669704
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 Packaging Drug resistance Endotoxins Extracellular Matrix Fibrosis Formulation Future Gastrointestinal Neoplasms Genes Goals Hemolysis Liquid Chromatography Liver Liver Cirrhosis 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 Plasma Platelet aggregation Play Polymers Pre-Clinical Model Preparation Prevalence Prevention 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 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 manufacture neglect neoplastic cell novel novel therapeutics patient derived xenograft model pharmacokinetics and pharmacodynamics pharmacologic response scale up self-renewal smoothened signaling pathway stem cell biomarkers stemness success systemic toxicity tumor tumor initiation zeta potential

项目摘要

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.

项目概要肝细胞癌（HCC）的患病率正在增加，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部位的复发是主要问题 HCC 中的问题。创新的联合疗法是治疗 HCC 的一种有吸引力的策略。癌症干细胞 (CSC) 是自我更新、多能、缓慢增殖的恶性细胞的一小部分，在各种癌症类型（包括 HCC）的肿瘤发生、转移、复发和多药耐药性。针对 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 是不够的，因为新的 CSC 可以通过以下方式不断地从非 CSC 肿瘤细胞中衍生出来：上皮间质转化（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在很大程度上仍然不满意。该提案旨在开发一种基于聚合物胶束的 HCC 耐药性解决方案。聚合物胶束输送系统与环杷明 (CPA)（一种天然存在的刺猬蛋白）共同配制 (Hh) 能够消除 CSC 的信号抑制剂，以及细胞毒性化疗药物紫杉醇 (PTX) 阻止有丝分裂的进展并引发细胞凋亡。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）可显着延长中位生存期转基因小鼠在预防和治疗环境中患有自发性 c-Myc 驱动的 HCC。而且， M-CPA/PTX 明显比单独的 PTX、单独的 CPA 或 CPA + PTX 的物理混合物更有效。 M-CPA/PTX 下调 c-Myc，抑制肿瘤球体形成，抑制 EMT，并降低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，我们的初步保证 M-CPA/PTX 技术的 IND 前进一步开发。有两个主要目标对于该项目：降低 M-CPA/PTX 临床转化的风险并获得强大的 IND 包。为了实现我们的目标，我们将追求 3 个具体目标：1）扩大高质量 M-CPA/PTX 的合成并充分表征由此产生的产品； 2）确定抗肿瘤功效、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 发挥其抗 HCC 活性的机制。我们的最终目标是将 M-CPA/PTX 转化为该诊所将其视为一种安全有效的疗法，可提高 HCC 患者的生存率。该项目将有非凡的影响，因为它将为潜在有效的全身疗法的临床转化铺平道路为 HCC 患者提供帮助，并深入了解 CSC 和肿瘤基质在抗 HCC 治疗耐药中的作用。