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: 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
• 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

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.

项目总结