Targeting OSCC cells with a lozenge to treat oral cancer

用含片靶向 OSCC 细胞治疗口腔癌

• 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
• 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

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/摘要 口腔癌在美国造成超过8,000人，全球12万人丧生。超过90％ 口服癌症是由口服鳞状细胞癌（OSCC）引起的，众所周知，这些细胞对 化学治疗剂。放射和手术用于治疗口腔癌患者，但导致 毁容和后遗症大大降低了生存的生活质量。 绝大多数OSCC细胞表达PDPN，这是一种跨膜粘蛋白接收器， 促进口腔癌的进展。表达高水平的前癌口服病变（例如白细胞） PDPN成为口服癌的可能性比不表达PDPN的病变要高几倍。那， PDPN提出了一个与功能相关的靶标，可用于检测和治疗口腔癌。我们发现 Maackia amurensis种子讲座（MASL）靶向PDPN杀死OSCC细胞。而且，MASL是无毒的，可以 口服以抑制小鼠的肿瘤生长和血管化。 我们提出了3个具体旨在评估MASL对OSCC细胞的影响的特定目的 人类临床试验。在AIM 1中，我们将评估OSCC形态，PDPN表达，血管化和T- IHC口腔癌患者的细胞浸润。患有含有OSCC细胞的病变的患者表达鲁棒 PDPN水平将被考虑进行治疗。在AIM 2中，我们将评估MASL对OSCC的影响 从患者接受的口腔癌病变中的形态，PDPN表达，血管生成和T细胞浸润 通过活检或切除。在AIM 3中，我们将评估MASL对PDPN表达，运动性和 在目标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的口服lozenges，可以溶解在口腔癌患者口中 为了直接和系统地治疗AIM 1中定义的PDPN的口腔病变。我们将 分析从取自的样品中的OSCC形态，PDPN表达，血管生成和T细胞浸润 这些惊喜。我们假设MASL会降低OSCC发育不良，PDPN表达和 这些患者的血管化。我们还怀疑MASL自PDPN以来会增加T细胞肿瘤的浸润 已被确定为效应T细胞的抑制受体。这些数据还将决定PDPN 实际患者的表达和MASL敏感性与AIM 2的离体细胞培养研究相比。 该项目的积极结果将改变目前用于治疗口腔癌的临床范例。 目前，良性口服病变“观察和等待”，而OSCC则通过手术和辐射治疗。我们的 新的范式将使用MASL靶向PDPN，这使良性细胞能够发展为OSCC。所以， 这项工作应提高我们治疗口腔癌的能力，以及表达PDPN的其他Malignancys 乳腺癌，神经胶质瘤，肺和皮肤癌。