EBNA1 Inhibitor for Treatment of EBV-positive DLBCL

EBNA1 抑制剂用于治疗 EBV 阳性 DLBCL

• 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
• 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' 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

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.

项目概要 Epstein-Barr 病毒 (EBV) 每年导致全球约 200,000 例新癌症病例。 其中，EBV+ 弥漫性大 B 细胞淋巴瘤 (DLBCL) 是一种新出现的全球癌症威胁 无论年龄大小，都没有明显的免疫抑制，并且代表着日益增长的未满足的医疗需求。新的 需要治疗方法来治疗 EBV+ DLBCL。只有一种病毒编码蛋白 EBNA1 在所有已知的 EBV 相关恶性肿瘤中一致表达，是抑制 EBV 的有效靶标 依赖性转化和致癌作用。 Wistar 研究所的研究人员开发了 VK-2019，这是一种一流的 EBNA1 抑制剂，可用于治疗 剂，在先导化合物和先导化合物优化过程中从超过 2500 种候选抑制剂化合物中进行选择 阶段。 VK-2019 达到或超过行业公认的效力、选择性、代谢稳定性、药物标准 适用性、药物安全性、毒理学和生物利用度。我们预计VK-2019将具有良好的安全性 因为没有 EBNA1 的人类直系同源物。基于临床前证据和首次人体试验 晚期鼻咽癌（NPC）患者的I期临床研究，VK-2019满足所有安全性， 耐受性和药代动力学终点，几乎没有记录的不良事件 (AE) 或严重不良事件 事件 (SAE)。在这项早期研究中，我们观察到超过三分之一的患者病情稳定，并且病情显着下降 在超过一半的患者中，EBV 血浆水平（一种已知的鼻咽癌进展生物标志物）的水平与 与药代动力学暴露。我们相信，第一阶段研究的数据在以下两个方面都令人鼓舞 目标效果和临床效益，并支持针对 EBV 阳性患者的后续概念验证研究 弥漫大B细胞淋巴瘤。 这笔赠款的目的是资助每日口服 VK-2019 的 Ib 期临床试验，以 (1) 进一步 确认晚期 EBV+ DLBCL 患者的安全性并确定任何剂量限制毒性 (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 (3)研究治疗对肿瘤微环境和免疫反应的影响。 进行这项研究所需的临床试验基础设施已经在 Sidney Kimmel 就位 托马斯杰斐逊大学癌症中心。该临床试验将提供有关安全性的重要信息， VK-2019 在 EBV+ DLBCL 患者群体中的耐受性和初步疗效。这个应用程序带来了 与基础研究人员和转化研究人员一起了解 EBNA1 抑制剂是否可以作为治疗药物 潜在 EBV 感染和癌症的选择并检查其作用机制。