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.
Public Health Relevance Statement: Narrative Conventional cytotoxic drugs are very toxic, and more targeted chemotherapies are limited to only a handful of reagents. Malignant oral cancers do not respond well to current chemotherapies. Developing a strategy target to target PDPN on OSCC cells, could open new ways to prevent and treat cancer.
Project Terms: Behavior; Biopsy; Western Blotting; Immunoblotting; Western Immunoblotting; protein blotting; Breast; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Skin Cancer; Malignant Skin Neoplasm; malignant skin tumor; Cell Culture Techniques; cell culture; cell cultures; cell motility; Cell Locomotion; Cell Migration; Cell Movement; Cellular Migration; Cellular Motility; Motility; Cells; Cell Body; Clinical Trials; Caspase; Caspase Gene; Cell-Death Protease; Cysteine Endopeptidases; Cysteine Protease; Cysteine Proteinases; ICE-like protease; cystein protease; cystein proteinase; cysteine endopeptidase; Glioma; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Neuroglial Neoplasm; Neuroglial Tumor; glial-derived tumor; neuroglia neoplasm; neuroglia tumor; Growth; Generalized Growth; Tissue Growth; ontogeny; Human; Modern Man; Immunohistochemistry; Immunohistochemistry Cell/Tissue; Immunohistochemistry Staining Method; Inflammation; Lectin; Leukoplakia; Keratotic Plaque; Methods; Microscopy; mortality; Mus; Mice; Mice Mammals; Murine; Persons; Patents; Legal patent; Patients; Sham Treatment; sham therapy; Placebos; QOL; Quality of life; Reagent; Plant Embryos; Plant Zygotes; seed; Seeds; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Technology; Time; Tissues; Body Tissues; Vascularization; Weight; Work; wound healing; Wound Repair; wound resolution; Businesses; oral lesion; mouth lesion; malignant mouth neoplasm; Malignant Oral Cavity Neoplasm; Malignant Oral Cavity Tumor; Malignant Oral Neoplasm; Mouth Cancer; Oral Cancer; malignant mouth tumor; oral cavity cancer; tumor progression; cancer progression; neoplasm progression; neoplastic progression; improved; Benign; Clinical; Malignant - descriptor; Malignant; Phase; Survivors; Lesion; Buccal Cavity; Buccal Cavity Head and Neck; Cavitas Oris; Mouth; Oral cavity; Dental; Malignant Tumor of the Lung; Pulmonary Cancer; Pulmonary malignant Neoplasm; lung cancer; Malignant neoplasm of lung; mucin receptor; Oral Surgeon; Oncology Cancer; Oncology; angiogenesis; Cytotoxic drug; Cytotoxic agent; Morphology; Infiltration; dyscrasia; Dysplasia; Pathologist; Oral; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; Oral Cavity Squamous Cell Carcinoma; Oral squamous cell carcinoma; mouth SCC; oral cavity SCC; oral squamous cancer; oral squamous carcinoma; mouth squamous cell carcinoma; Tumor Cell; neoplastic cell; Receptor Protein; receptor; tumor growth; Biopsy Sample; Biopsy Specimen; drug market; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; chemotherapeutic agent; Position; Positioning Attribute; podoplanin; Interventional trial; Intervention Trial; Radiation; Sampling; response; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; Maackia amurensis; Skin; preventing; prevent; Data; Cell Migration Assay; Migration Assay; precancerous; premalignant; Cancer Etiology; Cancer Cause; Cancer Patient; Cancer Survivor; survive cancer; Lesion by Morphology; Malignant Epithelial Cell; Carcinoma Cell; Resistance; resistant; clinical effect; chemotherapy; tumor; combat; Biological Markers; bio-markers; biologic marker; biomarker; Institutional Review Boards; IRB; IRBs; nanomolar; nano-molar; Tumor-infiltrating immune cells; Immune infiltrates; T cell infiltration; T cell tumor trafficking; immune cell infiltrate; immune infiltration; intratumoral immune cell; tumor immune cell; effector T cell; Teff cell
