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

• 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
• 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

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.

肝细胞癌已成为世界上第二大癌症相关死亡原因， 美国的死亡率为72%。肝癌发病率的上升是由于重大风险的稳步增加 肝纤维化、肝硬变和乙肝/丙型肝炎的因素，现有治疗方法赋予的疗效有限。 这种疾病的晚期。使用酪氨酸激酶抑制剂，最著名的是索拉非尼的全身治疗 现在大多数指南推荐给那些不符合肝切除条件的患者。绝大多数人 肝细胞癌伴有潜在的肝损害(以病理性血管、炎症和促进性肝损害为特征)。 纤维化反应)；以及具有旺盛血管生成的高度异常的肿瘤微环境(TME)， 免疫抑制和纤维化。索拉非尼单一疗法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，尚未得到满足。 用于治疗肝细胞癌。肝细胞癌一个新的靶点是G蛋白偶联的、蛋白酶激活的 受体2(PAR2)。PAR2是凝血和肿瘤相关蛋白酶的信号受体，高度依赖于 富含各种肝细胞(肝细胞、内皮细胞、星状细胞、炎性细胞)，控制 纤维化、炎症和代谢过程导致严重的NASH、肝硬变和肝细胞癌。PAR2 肝细胞癌中的表达与低生存期、低分化和晚期显著相关 肿瘤-淋巴结-转移期。我们发现患者肝脏中PAR2的表达显著增强 108例合并高水平肝纤维化和肝硬变。除了参与纤维化和炎症， PAR2激活包括GI-PI3K、TGFb、磷酸化AKT和GI-PI3K在内的多个促进肝癌的通路 RAF-MAPK信号刺激癌细胞迁移/侵袭、EMT、转移、抗凋亡存活 允许肿瘤微环境的增殖、血管生成和促进。试点数据表明， PAR2肽治疗可能潜在地抑制肝癌肿瘤的发展，这一点将得到详细验证 采用体外和体内小鼠肝细胞肿瘤生长和存活模型。目标1和2大纲 作为绿洲制药公司(马萨诸塞州列克星敦)和塔夫茨公司(波士顿， Ma)，这将为推动PAR2肽蛋白的临床开发提供关键的可行性里程碑 肝细胞癌的指征。6个月末的主要里程碑是对肝癌小鼠模型的疗效 (显著抑制肿瘤生长和提高存活率)(目标1)，以及28天安全性/毒性 索拉非尼联合治疗的评估(&gt；10倍治疗安全指数)(目标2)。如果此阶段I STTR研究成功地达到了概述的疗效和安全里程碑，这将提供 与FDA召开IND前会议的基础，IND提交的文件，并启动肝细胞癌的一期临床试验 病人。