EBNA1 Inhibitor for Treatment of EBV-positive DLBCL

EBNA1 抑制剂用于治疗 EBV 阳性 DLBCL

基本信息

批准号：
10719866
负责人：
PAUL M LIEBERMAN
金额：
$ 74.58万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-07 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10719866
关键词：
Adverse event Affect Aftercare Age Antineoplastic Agents Biological Biological Availability Biological Markers Biopsy Cell Communication Cell Cycle Arrest Cell Maintenance Cell Proliferation Cell Survival Cells Cessation of life Clinical Clinical Research Clinical Trials DNA Binding Data Disease Dose Dose Limiting Drug Kinetics Ecosystem Enrollment Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr Virus-Related Lymphoma Epstein-Barr Virus-Related Malignant Neoplasm Exhibits Funding Gene Expression Genes Grant Human Human Herpesvirus 4 Image Immune Evasion Immune response Immunity Immunofluorescence Immunologic Immunosuppression In Vitro Industry Infection Inferior Infrastructure Investigation Kimmel Cancer Center at the Thomas Jefferson University Lead Link Lymphoid Cell Lymphoma Maintenance Malignant Neoplasms Measures Medical Metabolic Metabolic Pathway Modality Modeling Mus Myeloid Cells Nasopharynx Carcinoma Oncogenic Viruses Oral Administration Orthologous Gene Pathway Analysis Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phase Ib Clinical Trial Plasma Process Prognosis Property Proteins RNA Recommendation Research Personnel Role Safety Serious Adverse Event Signal Pathway Signal Transduction Specimen Stable Disease Stromal Cells Testing The Wistar Institute Therapeutic Therapeutic Agents Toxic effect Toxicology Universities Viral Viral Genes Viral Genome Viral Load result Viral Oncogene cancer stem cell carcinogenesis cell growth chemotherapy clinical candidate first-in-human genetic regulatory protein human study immune function in vivo inhibitor large cell Diffuse non-Hodgkin&apos s lymphoma lead optimization medication safety neoplastic cell novel novel therapeutic intervention open label patient population pharmacologic phase 1 study pre-clinical preclinical study prevent response small molecule inhibitor specific biomarkers stem cell population stem cells transcriptomic profiling transcriptomics translational scientist treatment effect tumor tumor growth tumor microenvironment tumor-immune system interactions tumorigenesis

Adverse event Affect Aftercare Age Antineoplastic Agents Biological Biological Availability Biological Markers Biopsy Cell Communication Cell Cycle Arrest Cell Maintenance Cell Proliferation Cell Survival Cells Cessation of life Clinical Clinical Research Clinical Trials DNA Binding Data Disease Dose Dose Limiting Drug Kinetics Ecosystem Enrollment Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr Virus-Related Lymphoma Epstein-Barr Virus-Related Malignant Neoplasm Exhibits Funding Gene Expression Genes Grant Human Human Herpesvirus 4 Image Immune Evasion Immune response Immunity Immunofluorescence Immunologic Immunosuppression In Vitro Industry Infection Inferior Infrastructure Investigation Kimmel Cancer Center at the Thomas Jefferson University Lead Link Lymphoid Cell Lymphoma Maintenance Malignant Neoplasms Measures Medical Metabolic Metabolic Pathway Modality Modeling Mus Myeloid Cells Nasopharynx Carcinoma Oncogenic Viruses Oral Administration Orthologous Gene Pathway Analysis Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phase Ib Clinical Trial Plasma Process Prognosis Property Proteins RNA Recommendation Research Personnel Role Safety Serious Adverse Event Signal Pathway Signal Transduction Specimen Stable Disease Stromal Cells Testing The Wistar Institute Therapeutic Therapeutic Agents Toxic effect Toxicology Universities Viral Viral Genes Viral Genome Viral Load result Viral Oncogene cancer stem cell carcinogenesis cell growth chemotherapy clinical candidate first-in-human genetic regulatory protein human study immune function in vivo inhibitor large cell Diffuse non-Hodgkin&apos s lymphoma lead optimization medication safety neoplastic cell novel novel therapeutic intervention open label patient population pharmacologic phase 1 study pre-clinical preclinical study prevent response small molecule inhibitor specific biomarkers stem cell population stem cells transcriptomic profiling transcriptomics translational scientist treatment effect tumor tumor growth tumor microenvironment tumor-immune system interactions tumorigenesis

展开

项目摘要

PROJECT SUMMARY The Epstein-Barr Virus (EBV) is responsible for approximately 200,000 new cancer cases each year worldwide. Among these, EBV+ Diffuse Large B-Cell Lymphoma (DLBCL) is an emergent global cancer threat in patients without overt immunosuppression, irrespective of age, and represents a growing unmet medical need. New therapeutic approaches are needed to treat EBV+ DLBCL. Only one viral-encoded protein, EBNA1, is consistently expressed in all known EBV-associated malignancies and is a validated target for inhibition of EBV- dependent transformation and carcinogenesis. Investigators at the Wistar Institute have developed VK-2019, a first-in-class EBNA1 inhibitor as a therapeutic agent, selecting it from over 2500 candidate inhibitor compounds during the hit-to-lead and lead optimization phases. VK-2019 meets or exceeds industry-accepted criteria for potency, selectivity, metabolic stability, drug suitability, drug safety, toxicology and bioavailability. We anticipated that VK-2019 would have a favorable safety profile because there are no human orthologs of EBNA1. Based on preclinical evidence and a first-in-human Phase I clinical study in patients with advanced nasopharyngeal carcinoma (NPC), VK-2019 met all safety, tolerability and pharmacokinetic endpoints with few documented adverse events (AEs) or Severe Adverse Events (SAEs). In this early study, we observed stable disease in more than a third and a significant decrease in EBV plasma levels, a known biomarker of NPC progression, in more than half of the patients, that correlated with pharmacokinetic exposure. We believe that data from this Phase I study are encouraging in terms of both on target effect and clinical benefit, and supports a follow-on proof-of-concept study in patients with EBV-positive DLBCL. The purpose of this grant is to fund a phase Ib clinical trial of daily oral administration of VK-2019 to (1) further confirm the safety profile and determine any dose-limiting toxicities (DLT) in advanced EBV+ DLBCL patient populations; (2) understand the effects of treatment on EBV-specific biomarkers, including EBV and cellular gene expression and (3) study the effects of treatment on the tumor microenvironment and immune response. The clinical trial infrastructure necessary for the conduct of this study is already in place at the Sidney Kimmel Cancer Center at Thomas Jefferson University. This clinical trial will provide critical information on the safety, tolerability, and preliminary efficacy of VK-2019 in a EBV+ DLBCL patient population. This application brings together basic and translational investigators to understand whether EBNA1 inhibitors can be a therapeutic option for latent EBV infection and cancer and examines the mechanism of action.

项目摘要 Epstein-Barr病毒（EBV）每年在全球范围内约有200,000例新的癌症病例。其中，EBV+弥漫性大B细胞淋巴瘤（DLBCL）是患者的新兴全球癌症威胁没有明显的免疫抑制，无论年龄如何，都代表了日益增长的医疗需求。新的需要治疗EBV+ DLBCL的治疗方法。只有一种病毒编码的蛋白EBNA1是在所有已知的EBV相关的恶性肿瘤中始终表达，是抑制EBV-的验证靶标依赖转化和致癌作用。 Wistar Institute的调查人员开发了VK-2019，这是一种阶级的EBNA1抑制剂作为治疗代理，在命中率和铅优化期间从2500多名候选抑制剂化合物中选择它阶段。 VK-2019符合或超过行业所接受的效力，选择性，代谢稳定性，药物的标准适用性，药物安全，毒理学和生物利用度。我们预计VK-2019将具有有利的安全性轮廓是因为没有EBNA1的人类直系同源物。基于临床前证据和人类第一 I期鼻咽癌患者（NPC）的I期临床研究，VK-2019符合所有安全性，耐受性和药代动力学终点很少有记录的不良事件（AES）或严重的不良事件事件（SAE）。在这项早期研究中，我们观察到稳定的疾病超过三分之一，显着下降在EBV等离子水平中，在超过一半的患者中，已知的NPC进展生物标志物与之相关与药代动力学暴露。我们认为，这一阶段I研究的数据在两者之间都令人鼓舞关于目标效应和临床益处，并支持EBV阳性患者的后续概念验证研究 DLBCL。这笔赠款的目的是为VK-2019每日口服给予（1）的IB期临床试验提供资金确认安全性并确定高级EBV+ DLBCL患者中的任何剂量限制毒性（DLT）人口；（2）了解治疗对EBV特异性生物标志物的影响，包括EBV和细胞基因表达和（3）研究治疗对肿瘤微环境和免疫反应的影响。这项研究所需的临床试验基础设施已经存在于Sidney Kimmel 托马斯·杰斐逊大学的癌症中心。该临床试验将提供有关安全性的关键信息， VK-2019在EBV+ DLBCL患者人群中的耐受性和初步功效。此应用程序带来基本和转化的研究人员一起了解EBNA1抑制剂是否可以成为治疗潜在EBV感染和癌症的选择，并检查作用机理。