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:
- 金额:$ 39.25万
- 依托单位:
- 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:
- 关键词:AddressAmerican Cancer SocietyApoptoticBAY 54-9085Biological AssayBlood VesselsBostonCYP2C19 geneCYP2D6 geneCYP3A4 geneCancer EtiologyCause of DeathCell Surface ReceptorsCell SurvivalCellsCessation of lifeCirrhosisClinicalClinical ResearchClinical TrialsCoagulation ProcessCombined Modality TherapyComplementCoupledCytochrome P450DataDevelopmentDiseaseDoseDrug InteractionsDrug KineticsEndotheliumEnzymesEpidemicExcisionExtracellular Matrix ProteinsFatty LiverFeasibility StudiesFibrosisGTP-Binding ProteinsGoalsGoldGuidelinesHematologyHepG2HepaticHepatitis BHepatocyteHepatologyHomingHumanImmune checkpoint inhibitorImmunosuppressionImmunotherapyIn VitroIncidenceInflammationInflammatoryInterstitial CollagenaseInvestigationLeadLiverLiver CirrhosisLiver FibrosisLiver Function TestsLiver diseasesMAP Kinase GeneMMP2 geneMMP9 geneMalignant neoplasm of liverMedicalMedical centerMetabolicMetabolismModelingMusNeoplasm MetastasisObesityOutcomePAR-2 ReceptorPathologicPathway interactionsPatientsPeptide HydrolasesPharmaceutical PreparationsPharmacologic SubstancePhasePhase I Clinical TrialsPrimary carcinoma of the liver cellsProductionProto-Oncogene Proteins c-aktReceptor SignalingRegimenReportingRisk FactorsSafetySignal TransductionSmall Business Technology Transfer ResearchSystemic TherapyTechnologyTestingTherapeuticTimeToxic effectToxicologyTumor SuppressionTyrosine Kinase Inhibitorangiogenesisbiomarker evaluationbiomarker panelcancer cellcell motilitychronic liver diseaseclinical developmentclinical toxicologycyr61 proteineffective therapyfirst-in-humanhealthy volunteerimprovedin vitro testingin vivoin vivo Modelindexinginhibitorinterestliver cancer modelliver developmentliver injurymeetingsmigrationmortalitymouse modelmultiplexed imagingnonalcoholic steatohepatitisnovelnovel strategiesphase 1 studypre-clinicalpreclinical studyresearch clinical testingresponsesafety studyside effectstandard of carestellate celltherapy outcometumortumor growthtumor microenvironmenttumor xenograftwound 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(>;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。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Athan Kuliopulos其他文献
Athan Kuliopulos的其他文献
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{{ truncateString('Athan Kuliopulos', 18)}}的其他基金
Lipid Receptor GPR31 as a Target for Anti-Thrombotic and Stroke Therapy
脂质受体 GPR31 作为抗血栓和中风治疗的靶点
- 批准号:
10603440 - 财政年份:2023
- 资助金额:
$ 39.25万 - 项目类别:
Lipid Receptor GPR31 as a Target for Anti-Thrombotic and Stroke Therapy
脂质受体 GPR31 作为抗血栓和中风治疗的靶点
- 批准号:
10325956 - 财政年份:2021
- 资助金额:
$ 39.25万 - 项目类别:
PAR2 Pepducins as a Novel Treatment of Idiopathic Pulmonary Fibrosis
PAR2 Pepducins 作为特发性肺纤维化的新型治疗方法
- 批准号:
9906265 - 财政年份:2018
- 资助金额:
$ 39.25万 - 项目类别:
Development of PAR4 Pepducins as a Novel Antithrombotic Treatment
开发 PAR4 Pepducins 作为新型抗血栓治疗方法
- 批准号:
9254228 - 财政年份:2017
- 资助金额:
$ 39.25万 - 项目类别:
Development of PAR2 Inhibitors for the Treatment of Nonalcoholic steatohepatitis
开发用于治疗非酒精性脂肪性肝炎的 PAR2 抑制剂
- 批准号:
8781807 - 财政年份:2014
- 资助金额:
$ 39.25万 - 项目类别:
Development of PAR2 Pepducins as a Novel NASH Treatment
开发 PAR2 Pepducins 作为一种新型 NASH 治疗方法
- 批准号:
9408141 - 财政年份:2013
- 资助金额:
$ 39.25万 - 项目类别:
Development of PAR2 Inhibitors for the Treatment of Nonalcoholic steatohepatitis
开发用于治疗非酒精性脂肪性肝炎的 PAR2 抑制剂
- 批准号:
8648560 - 财政年份:2013
- 资助金额:
$ 39.25万 - 项目类别:
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