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: 10661041
• 负责人: Gary Goldberg
• 金额: $ 3.36万
• 依托单位: SENTRIMED, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661041
• 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/概要 口腔癌每年在美国造成8,000多人死亡，在全世界造成120,000人死亡。超过90%的 口腔癌是由口腔鳞状细胞癌（OSCC）引起的，并且这些细胞众所周知地对抗肿瘤药物具有抗性。 化疗剂。放射和手术用于治疗口腔癌患者，但 畸形和后遗症，大大降低了幸存者的生活质量。 绝大多数OSCC细胞表达PDPN，PDPN是跨膜粘蛋白受体， 促进口腔癌进展。口腔癌前病变（如白斑）表达高水平的 PDPN成为口腔癌的可能性是不表达PDPN的病变的几倍。因此，在本发明中， PDPN是一种功能相关的靶点，可用于检测和治疗口腔癌。我们发现 怀槐种子凝集素（MASL）靶向PDPN以杀死OSCC细胞。此外，MASL无毒， 口服给药以抑制小鼠中的肿瘤生长和血管形成。 我们提出了3个具体的目的，以评估MASL对口腔鳞癌细胞的影响离体和在1期 人体临床试验在目标1中，我们将评估OSCC的形态学、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OSCC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OSCC的影响 患者口腔癌病变的形态学、PDPN表达、血管生成和T细胞浸润 通过活检或切除。在目标3中，我们将评估MASL对PDPN表达、运动性和细胞增殖的影响。 在目的1和2中检查的从口腔癌患者培养的OSCC细胞的生长。 我们将生产含有MASL的口腔含片，它将在口腔癌患者的口中溶解。 用于直接和全身给药以治疗如目的1中定义的表达PDPN的口腔病变。我们将 分析口腔鳞状细胞癌的形态、PDPN表达、血管生成和T细胞浸润， 这些切除。我们假设MASL可以减少口腔鳞癌的异型增生，PDPN的表达， 这些患者的血管化。我们还怀疑MASL会增加T细胞肿瘤浸润，因为PDPN 已被鉴定为效应T细胞上的抑制性受体。这些数据也将决定PDPN如何 在实际患者中的MASL表达和MASL敏感性与来自Aim 2的它们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。 良性口腔病变目前是“观察和等待”，而口腔鳞状细胞癌是通过手术和放射治疗。我们 新的范例将使用MASL靶向PDPN，这使得良性细胞能够发展成OSCC。因此，我们认为， 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， 乳腺癌神经胶质瘤肺癌和皮肤癌