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 美国每年有8000多人死于口腔癌，全球每年有12万人死于口腔癌。90%以上的 口腔癌是由口腔鳞状细胞癌(OSCC)引起的，这些细胞对 化疗药物。放射和手术被用来治疗口腔癌患者，但引起 毁容和后遗症极大地降低了幸存者的生活质量。 绝大多数口腔鳞状细胞癌细胞表达PDPN，它是一种跨膜粘蛋白受体， 促进口腔癌进展。高水平表达的癌前病变(如白斑) 与不表达PDPN的病变相比，PDPN发展为口腔癌的可能性高出数倍。因此， PDPN是一种功能相关的靶点，可用于口腔癌的检测和治疗。我们发现 山玛瑙种子凝集素(MASL)以PDPN为靶点杀伤口腔鳞癌细胞。此外，MASL是无毒的，可以 口服给药以抑制小鼠肿瘤生长和血管生成。 我们提出了3个特定的指标来评估MASL对口腔鳞状细胞癌细胞体外和1期的影响 人体临床试验。在目标1中，我们将评估口腔鳞状细胞癌的形态、PDPN的表达、血管形成和T- 应用免疫组织化学方法检测口腔癌患者的细胞浸润。病变中含有表达强健的口腔鳞癌细胞的患者 PDPN水平将被考虑用于治疗。在目标2中，我们将评估MASL对口腔鳞癌的影响 口腔癌患者皮损的形态、PDPN表达、血管生成和T细胞浸润 通过活组织检查或切除。在目标3中，我们将评估MASL对PDPN表达、运动性和 AIMS 1和2中口腔癌患者口腔鳞状细胞癌细胞培养的生长情况。 我们将生产含有MASL的口服含片，它将在口腔癌患者的口腔中溶解 为了直接和系统地给药来治疗目标1中定义的表达PDPN的口腔病变。我们将 分析口腔鳞癌的形态、PDPN的表达、血管生成和T细胞的渗透 这些摘除。我们假设MASL可以减少口腔鳞癌不典型增生、PDPN的表达和 这些患者的血管形成。我们还怀疑MASL会增加PDPN后T细胞肿瘤的侵袭 已被确定为效应性T细胞的抑制性受体。这些数据还将决定PDPN如何 实际患者的表达和MASL敏感性与他们来自AIM 2的体外细胞培养研究进行了比较。 该项目的积极结果将改变目前用于治疗口腔癌的临床范例。 口腔良性病变目前还在“观察和等待”，而口腔鳞状细胞癌则需要手术和放射治疗。我们的 新的范例将使用MASL靶向PDPN，使良性细胞发展为口腔鳞状细胞癌。因此， 这项工作将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、胶质瘤、肺癌和皮肤癌。