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）的患病率正在增加，但是化学疗法的选择仍然非常有限。 在全身治疗后，在本地和遥远部位的全身疗法和复发性的抵抗力是主要的 HCC中的问题。创新的组合疗法是治疗HCC的有吸引力的策略。癌干细胞 （CSC）是一小部分自我更新，多能，缓慢增殖的恶性细胞，它们在 包括HCC在内的各种癌症类型的肿瘤起始，转移，复发和多药耐药性。 针对CSC可以为有效的抗HCC治疗提供有前途的途径。但是，仅针对CSC 将不够的，因为新的CSC可以通过 上皮到间质转变（EMT）的激活。因此，同时消除CSC至关重要 并增殖的非CSC肿瘤细胞。迄今为止，实现此目标的药理方法仍然很大程度上仍然 不令人满意。该提案旨在开发基于聚合物的胶束在HCC中耐药性的方法。 聚合物胶束递送系统与天然存在的刺猬cyclopamine（CPA）共建立 （HH）能够消除CSC的信号抑制剂和紫杉醇（PTX），一种细胞毒性化学治疗剂 这阻断了有丝分裂的进展和触发凋亡。在初步研究中，我们已经证明了 含有CPA和PTX的聚合物胶束，称为M-CPA/PTX，显着延长了中位生存期 在预防和治疗环境中具有自发C-MYC驱动的HCC的转基因小鼠的。而且， M-CPA/PTX明显比单独使用PTX，单独使用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并减少 细胞外基质的成分有利于大大改善两种药物的肿瘤处置。在一起， 我们的初步保证M-CPA/PTX技术进一步开发。有两个主要目标 对于这个项目：M-CPA/PTX的临床临床翻译并获得了强大的IND包。实现我们的 目标，我们将追求3个具体目标：1）扩展高质量M-CPA/PTX的合成并完全表征 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，毒性， HCC临床前模型中M-CPA/PTX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转换为 该诊所是一种安全有效的疗法，可改善HCC患者的存活率。这个项目将有 出色的影响，因为它将为潜在有效的全身疗法的临床翻译铺平道路 对于HCC患者，并深入了解了CSC和肿瘤基质在抗HCC治疗中的作用。