Targeting OSCC cells with a lozenge to treat oral cancer

用含片靶向 OSCC 细胞治疗口腔癌

基本信息

批准号：
10915138
负责人：
Gary Goldberg
金额：
$ 24.77万
依托单位：
SENTRIMED, INC.
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：
2023-11-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10915138
关键词：
Behavior Benign Biological Markers Biopsy Biopsy Specimen Board Certification Breast Businesses Cancer Etiology Cancer Patient Cancer Survivor Caspase Cell Culture Techniques Cell Survival Cells Certification Clinical Clinical Trials Cultural Sensitivity Cytotoxic agent Data Dental Dysplasia Excision Glioma Growth Human Immunohistochemistry Inflammation Institutional Review Boards Intervention Trial Lectin Legal patent Lesion Lesion by Morphology Leukoplakia Lung Maackia amurensis Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Membrane Methods Microscopy Migration Assay Morphology Mus Necrosis Oncology Operative Surgical Procedures Oral Oral Administration Oral Surgeon Oral cavity Pathologist Patients Persons Phase Phase I Clinical Trials Placebos Positioning Attribute Quality of life Radiation Reagent Resistance Sampling Skin Cancer Survivors T cell infiltration Technology Tissues Vascularization Weight Western Blotting Work angiogenesis cancer infiltrating T cells cell motility chemotherapeutic agent chemotherapy clinical effect combat commercialization drug market effector T cell improved malignant mouth neoplasm mortality mouth squamous cell carcinoma mucin receptor nanomolar oral lesion podoplanin premalignant prevent receptor therapeutic target treatment response tumor tumor growth tumor progression wound healing

项目摘要

Abstract/Summary Oral cancer kills over 8,000 people in the USA and 120,000 people worldwide every year. Over 90% of oral cancers are caused by oral squamous cell carcinoma (OSCC), and these cells are notoriously resistant to chemotherapeutic agents. Radiation and surgery are used to treat oral cancer patients, but cause disfigurations and sequelae that drastically decrease the quality of life for survivors. The vast majority of OSCC cells express PDPN, which is a transmembrane mucin receptor that promotes oral cancer progression. Precancerous oral lesions (e.g. leukoplakia) that express high levels of PDPN are several times more likely to become oral cancers than lesions that do not express PDPN. Thus, PDPN presents a functionally relevant target that can be used to detect and treat oral cancer. We found that Maackia amurensis seed lectin (MASL) targets PDPN to kill OSCC cells. Moreover, MASL is nontoxic and can be administered orally to inhibit tumor growth and vascularization in mice. We propose 3 Specific Aims to evaluate the effects of MASL on OSCC cells ex vivo and in a Phase 1 human clinical trial. In Aim 1, we will evaluate OSCC morphology, PDPN expression, vascularization, and T- cell infiltration in oral cancer patients by IHC. Patients with lesions containing OSCC cells that express robust levels of PDPN will be considered for treatment. In Aim 2, we will evaluate effects of MASL on OSCC morphology, PDPN expression, angiogenesis, and T-cell infiltration in oral cancer lesions taken from patients by biopsy or resections. In Aim 3, we will evaluate the effects of MASL on PDPN expression, motility, and growth of OSCC cells cultured from oral cancer patients examined in Aims 1 and 2. We will produce oral lozenges containing MASL that will dissolve in the mouths of oral cancer patients for direct and systemic administration to treat oral lesions that express PDPN as defined in Aim 1. We will analyze OSCC morphology, PDPN expression, angiogenesis, and T-cell infiltration in samples taken from these excisions. We hypothesize that MASL will decrease OSCC dysplasia, PDPN expression, and vascularization in these patients. We also suspect that MASL will increase T-cell tumor infiltration since PDPN has been identified as an inhibitory receptor on effector T-cells. These data will also determine how PDPN expression and MASL sensitivity in actual patients compares to their ex vivo cell culture studies from Aim 2. Positive results from this project will change the clinical paradigm currently used to treat oral cancer. Benign oral lesions are currently “watched and waited”, while OSCC is treated by surgery and radiation. Our new paradigm will use MASL to target PDPN, which enables benign cells to develop into OSCC. Therefore, this work should improve our ability to treat oral cancer, and other malignancies that express PDPN including breast, glioma, lung, and skin cancer.

摘要/总结口腔癌每年导致美国 8,000 多人死亡，全球 120,000 人以上死于口腔癌。口腔癌是由口腔鳞状细胞癌（OSCC）引起的，众所周知，这些细胞对化疗药物和手术用于治疗口腔癌患者，但会引起口腔癌。毁容和后遗症极大地降低了幸存者的生活质量。绝大多数 OSCC 细胞表达 PDPN，这是一种跨膜粘蛋白受体，促进表达高水平的口腔癌前期病变（例如白斑）。 PDPN 成为口腔癌的可能性是不表达 PDPN 的病变的数倍。 PDPN 提供了一个功能相关的靶点，可用于检测和治疗口腔癌。山槐种子凝集素 (MASL) 靶向 PDPN 杀死 OSCC 细胞，而且 MASL 无毒且可以杀死 OSCC 细胞。口服给药可抑制小鼠肿瘤生长和血管形成。我们的 3 个具体目标是提出 MASL 对体外和第一阶段 OSCC 细胞的影响在目标 1 中，我们将评估 OSCC 形态、PDPN 表达、血管化和 T-。通过 IHC 检测口腔癌患者的细胞浸润，病变中含有表达强健的 OSCC 细胞。在目标 2 中，我们将评估 MASL 对 OSCC 的影响。口腔癌患者病灶的形态、PDPN 表达、血管生成和 T 细胞浸润在目标 3 中，我们将评估 MASL 对 PDPN 表达、运动和功能的影响。目标 1 和 2 中检查的口腔癌患者培养的 OSCC 细胞的生长。我们将生产含有 MASL 的口腔含片，可溶解在口腔癌患者的口腔中用于直接和全身给药以治疗表达目标 1 中定义的 PDPN 的口腔病变。我们将分析 OSCC 形态、PDPN 表达、血管生成和 T 细胞浸润样本我们认为 MASL 会减少 OSCC 发育不良、PDPN 表达和我们还怀疑，自 PDPN 以来，MASL 会增加 T 细胞肿瘤浸润。已被确定为效应 T 细胞的抑制性受体。这些数据也将确定 PDPN 的作用。实际患者的表达和 MASL 敏感性与目标 2 中的离体细胞培养研究进行比较。该项目的积极结果将改变目前用于治疗口腔癌的临床模式。目前，良性口腔病变需要“观察和等待”，而口腔鳞癌则通过手术和放射治疗。新的范例将使用 MASL 来靶向 PDPN，从而使良性细胞发展为 OSCC。这项工作应该提高我们治疗口腔癌和其他表达 PDPN 的恶性肿瘤的能力，包括乳腺癌、神经胶质瘤、肺癌和皮肤癌。