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/总结 口腔癌每年在美国夺去 8,000 多人的生命，在全球夺去 120,000 人的生命。 90%以上 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 化疗剂。放射线和手术用于治疗口腔癌患者，但会导致 毁容和后遗症大大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， 促进口腔癌的进展。表达高水平的癌前口腔病变（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。因此， PDPN 提供了一个功能相关的靶点，可用于检测和治疗口腔癌。我们发现 山槐种子凝集素 (MASL) 靶向 PDPN 来杀死 OSCC 细胞。此外，MASL 无毒，可以 口服给药可抑制小鼠肿瘤生长和血管形成。 我们提出了 3 个具体目标来评估 MASL 对体外和第 1 阶段 OSCC 细胞的影响 人体临床试验。在目标 1 中，我们将评估 OSCC 形态、PDPN 表达、血管化和 T- 通过 IHC 观察口腔癌患者的细胞浸润情况。病变含有表达强健的 OSCC 细胞的患者 PDPN 水平将被考虑进行治疗。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 通过活检或切除术。在目标 3 中，我们将评估 MASL 对 PDPN 表达、运动性和 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 这些切除。我们假设 MASL 会减少 OSCC 发育不良、PDPN 表达和 这些患者的血管化。我们还怀疑，自 PDPN 以来，MASL 会增加 T 细胞肿瘤浸润 已被鉴定为效应 T 细胞的抑制性受体。这些数据也将决定 PDPN 如何 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。我们的 新范例将使用 MASL 来靶向 PDPN，从而使良性细胞发展为 OSCC。所以， 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。