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Development of liver homing PAR2 pepducins for the treatment of Hepatocellular Carcinoma

开发肝归巢 PAR2 pepducins 用于治疗肝细胞癌

基本信息

批准号：
10547111
负责人：
Athan Kuliopulos
金额：
$ 39.25万
依托单位：
OASIS PHARMACEUTICALS
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：
2022-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547111
关键词：
Address American Cancer Society Apoptotic BAY 54-9085 Biological Assay Blood Vessels Boston CYP2C19 gene CYP2D6 gene CYP3A4 gene Cancer Etiology Cause of Death Cell Surface Receptors Cell Survival Cells Cessation of life Cirrhosis Clinical Clinical Research Clinical Trials Coagulation Process Combined Modality Therapy Complement Coupled Cytochrome P450 Data Development Disease Dose Drug Interactions Drug Kinetics Endothelium Enzymes Epidemic Excision Extracellular Matrix Proteins Fatty Liver Feasibility Studies Fibrosis GTP-Binding Proteins Goals Gold Guidelines Hematology HepG2 Hepatic Hepatitis B Hepatocyte Hepatology Homing Human Immune checkpoint inhibitor Immunosuppression Immunotherapy In Vitro Incidence Inflammation Inflammatory Interstitial Collagenase Investigation Lead Liver Liver Cirrhosis Liver Fibrosis Liver Function Tests Liver diseases MAP Kinase Gene MMP2 gene MMP9 gene Malignant neoplasm of liver Medical Medical center Metabolic Metabolism Modeling Mus Neoplasm Metastasis Obesity Outcome PAR-2 Receptor Pathologic Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Primary carcinoma of the liver cells Production Proto-Oncogene Proteins c-akt Receptor Signaling Regimen Reporting Risk Factors Safety Signal Transduction Small Business Technology Transfer Research Systemic Therapy Technology Testing Therapeutic Time Toxic effect Toxicology Tumor Suppression Tyrosine Kinase Inhibitor angiogenesis biomarker evaluation biomarker panel cancer cell cell motility chronic liver disease clinical development clinical toxicology cyr61 protein effective therapy first-in-human healthy volunteer improved in vitro testing in vivo in vivo Model indexing inhibitor interest liver cancer model liver development liver injury meetings migration mortality mouse model multiplexed imaging nonalcoholic steatohepatitis novel novel strategies phase 1 study pre-clinical preclinical study research clinical testing response safety study side effect standard of care stellate cell therapy outcome tumor tumor growth tumor microenvironment tumor xenograft wound healing

项目摘要

Hepatocellular carcinoma (HCC) has become the second leading cause of cancer-related death in the world, with a 72% mortality rate in the US. The rise in incidence of HCC is due to a steady increase in the major risk factors of liver fibrosis, cirrhosis, and hepatitis B/C, with limited efficacy conferred by existing treatments at advanced stages of the disease. Systemic therapy with tyrosine kinase inhibitors, most notably sorafenib, is now recommended by most guidelines for those patients not eligible for liver resection. The vast majority of HCCs occur with underlying hepatic damage (characterized by pathological vascular, inflammatory and pro- fibrotic responses); and a highly abnormal tumor microenvironment (TME) with exuberant angiogenesis, immunosuppression, and fibrosis. Sorafenib monotherapy does not effectively overcome these abnormalities in the damaged liver and the TME. Accordingly, there remains a high unmet medical need for new approaches for the treatment of HCC. An emerging new target in HCC is the G protein-coupled, protease-activated receptor 2 (PAR2). PAR2 is a signaling receptor for coagulation and tumor-associated proteases that is highly abundant in various liver cells (hepatocytes, endothelium, stellate cells, inflammatory cells) which controls fibrotic, inflammatory and metabolic processes that lead towards severe NASH, liver cirrhosis and HCC. PAR2 expression in HCC tumors is significantly correlated with poor survival, poor differentiation and advanced tumor-node-metastasis stage. We found that hepatic PAR2 expression was greatly enhanced in patients (n=108) with high levels of liver fibrosis and cirrhosis. In addition to being involved in fibrosis and inflammation, PAR2 activates a number of hepatic cancer promoting pathways including Gi-PI3K, TGFb, phospho-AKT and Raf-MAPK signaling to stimulate cancer cell migration/invasion, EMT, metastasis, anti-apoptotic survival, proliferation, angiogenesis, and promotion of a permissive tumor microenvironment. Pilot data indicate that PAR2 pepducin treatment may potentially suppress HCC tumor development that will be validated in detail using in vitro and in vivo hepatocellular mouse models of tumor growth and survival. Aims 1 and 2 outline bridging studies as a collaborative effort between Oasis Pharmaceuticals (Lexington, MA) and Tufts (Boston, MA) that would provide key feasibility milestones to advance the clinical development of PAR2 pepducin into the HCC indication. The major milestones at the end of the 6 months is efficacy in HCC mouse models (significant suppression of tumor growth and improved survival) (Aim 1), and 28-day safety/toxicity assessments (>10-fold therapeutic safety index) of combination therapy with sorafenib (Aim 2). If this Phase I STTR study is successful in accomplishing the outlined efficacy and safety milestones, this would provide the basis for a preIND meeting with the FDA, IND submission, and initiating a Phase 1 clinical trial in HCC patients.

肝细胞癌（HCC）已成为世界上第二大癌症相关死亡原因，在美国有72%的死亡率HCC发病率的上升是由于主要风险的稳步增加，肝纤维化、肝硬化和B/C型肝炎的因素，现有治疗的疗效有限，疾病的晚期。使用酪氨酸激酶抑制剂，最显著的是索拉非尼的全身治疗，现在大多数指南建议那些不适合肝切除的患者。绝大多数 HCC发生时伴有潜在的肝损伤（以病理性血管、炎症和促肝细胞凋亡为特征）。纤维化反应）;和具有旺盛血管生成的高度异常肿瘤微环境（TME），免疫抑制和纤维化。索拉非尼单药治疗不能有效克服这些异常，受损的肝脏和TME因此，对新方法的医疗需求仍然很高，用于治疗HCC。HCC中一个新兴的新靶点是G蛋白偶联的、蛋白酶激活的受体2（PAR 2）。PAR 2是凝血和肿瘤相关蛋白酶的信号受体，其高度依赖于细胞因子。在各种肝细胞（肝细胞、内皮细胞、星状细胞、炎性细胞）中丰富，纤维化、炎症和代谢过程导致严重NASH、肝硬化和HCC。PAR2 在HCC肿瘤中的表达与低生存率、低分化和晚期转移显著相关。肿瘤淋巴结转移期。我们发现，肝PAR 2的表达大大增强，（n=108）具有高水平的肝纤维化和肝硬化。除了参与纤维化和炎症， PAR 2激活许多肝癌促进途径，包括Gi-PI 3 K、TGF β、磷酸化AKT和磷酸化AKT。 Raf-MAPK信号传导刺激癌细胞迁移/侵袭、EMT、转移、抗凋亡存活，增殖、血管生成和促进容许的肿瘤微环境。试点数据显示， PAR 2肽蛋白治疗可能潜在地抑制HCC肿瘤的发展，这将被详细验证。使用肿瘤生长和存活的体外和体内肝细胞小鼠模型。目标1和2概述作为OasisPharmaceuticals（列克星敦，MA）和Tufts（波士顿， MA），这将提供关键的可行性里程碑，以推进PAR 2肽蛋白的临床开发， HCC的适应症。6个月结束时的主要里程碑是在HCC小鼠模型中的疗效（显著抑制肿瘤生长和改善生存期）（目标1）和28天安全性/毒性与索拉非尼联合治疗的评估（>10倍治疗安全指数）（目的2）。如果第一阶段 STTR研究成功实现了概述的疗效和安全性里程碑，这将提供与FDA的preIND会议、IND提交和启动HCC I期临床试验的基础患者