Oral Carcinogenesis

口腔癌发生

• 批准号: 8743737
• 负责人: J Gutkind
• 金额: $ 161.15万
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8743737
• 关键词: Address; Adverse effects; Affect; Animal Model; Animals; Antineoplastic Agents; Apoptotic; Automobile Driving; Biological Markers; Biological Preservation; CDKN2A gene; Cancer Patient; Carcinogen exposure; Cell Aging; Cell Differentiation process; Cell Surface Receptors; Cell physiology; Cells; Cessation of life; Clinical; Clinical Research; Collaborations; Collection; Cytotoxic agent; Detection; Development; Diagnostic; Disease Progression; Drug Delivery Systems; Effectiveness; Epigenetic Process; Epithelial; Epithelial Cells; Event; Evolution; Experimental Models; Future; Gene Expression; Gene Silencing; Genes; Genetic; Genetically Engineered Mouse; Genomics; Glutathione; Goals; Gold; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Human papilloma virus infection; Immune; Incidence; Individual; Ionizing radiation; Knowledge; Label; Lesion; Lip structure; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical Oncology; Modeling; Molecular; Molecular Target; Monitor; Mouth Diseases; Mouth Neoplasms; Mucositis; Mus; Mutation; Natural regeneration; Neoplasm Metastasis; Oral; Oral cavity; Pathway interactions; Patients; Pharyngeal structure; Phosphoric Monoester Hydrolases; Phosphotransferases; Predisposition; Prevention; Proteins; Proteomics; Radiation; Radiation Tolerance; Reproducibility; Resistance; Role; Route; Screening for cancer; Series; Signal Pathway; Signal Transduction; Sirolimus; Stem cells; Stratum Basale; Stromal Cells; Surface; System; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Tumor Burden; Xenograft Model; base; cancer genome; cancer therapy; carcinogenesis; cell growth; chemical carcinogenesis; deep sequencing; falls; human FRAP1 protein; improved; inhibitor/antagonist; laser capture microdissection; mTOR Inhibitor; mTOR inhibition; malignant mouth neoplasm; mouse model; nanoparticle; neoplastic; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; oral carcinogenesis; oral cavity epithelium; particle; prevent; prognostic; programs; protein expression; response; senescence; sensor; tissue regeneration; translational medicine; treatment response; tumor; tumor growth; tumor progression

50% Effort. Dysregulated signaling networks in HNSCC: novel mechanism-based approaches for HSNCC prevention and treatment There is an urgent need for new treatment options for HNSCC patients, considering that their overall 5-year survival is relatively low (50%) and has improved only marginally over the past 3 decades. The emerging knowledge of how the dysregulated function of signaling networks contributes to the initiation, malignant growth, and metastasis of HNSCC can now be exploited to identify novel mechanism-based anti-cancer treatments. mTOR as a novel molecular target for HNSCC treatment. We have shown that the persistent activation of the kinase Akt and its downstream target mTOR is a frequent event in HNSCC, and that inhibition of mTOR by the use of rapamycin causes the rapid apoptotic death of HNSCC tumors in multiple experimental HNSCC models, thereby inducing tumor regression. We have continued our concerted effort to use novel genetically-defined and chemically-induced carcinogenesis models to evaluate the effectiveness of mTOR inhibitors for the prevention and treatment of HNSCC. This includes the demonstration that rapamycin reduces the tumor burden and prolongs the survival of mice harboring mutations in TGF- and Akt-mTOR pathways. In addition, there has been a remarkable increase in the incidence of HNSCC associated with human papillomavirus (HPV) infection. Although HPV+ HNSCCs represent a distinct clinicopathological subset of HNSCC lesions, we observed that these HPV+ lesions also display increased Akt-mTOR activity. mTOR inhibitors induced a rapid tumor collapse and decreased tumor burden concomitant with inhibition of the Akt-mTOR pathway in multiple HPV+ HNSCC xenograft models. In a recent study, we showed that concomitant administration of rapamycin enhances the therapeutic response of HPV+ tumors to standard therapies with cytotoxic agents and the immune recognition of tumor cells in a syngeneic animal model. Thus, mTOR inhibitors may also represent attractive candidates for the treatment of HPV-positive HNSCC lesions. Novel genetically-defined and chemically induced oral-specific animal models to study SCC: We have made significant contributions to the development of genetically engineered mouse models (GEMM) for HNSCC. We have continued with these studies, including the recent analysis of the interplay between the TGFbeta and Akt-mTOR pathway in collaboration with Ashok Kulkarni. We have now focused in the development of oral specific systems enabling the activation/inactivation of genes in the epithelial stem cell compartment. We have also began exploring the use of genetically engineered mice conferring increased susceptibility or resistance to oral cancer, a possibility afforded by our recently developed oral-specific chemical carcinogenesis model. Current studies are aimed at recapitulating HNSCC progression, with emphasis on the activation of the PI3K/mTOR pathway, thus providing a suitable system to investigate targeted anticancer agents. This includes the deletion of the PIP3 phosphatase Pten. Recently, we have shown that mice lacking Pten in the basal layer of the oral epithelium, a frequent event in HNSCC due to epigenetic silencing of Pten, develop oral cancer lesions at very high rate upon carcinogen exposure, resulting in rapid animal cancer-related death. 30% effort. Genomic and proteomic approaches to understand oral cancer We have conducted gene and protein expression analysis of HNSCC by combining laser capture microdissection (LCM), gene arrays, next-gen sequencing and proteomic platforms. These efforts are providing a wealth of information about the dysregulated molecular circuitries driving HNSCC development, hence facilitating the identification of new therapeutic targets and suitable biomarkers for monitoring HNSCC progression and treatment response. Exploiting the head and neck cancer oncogenome. The recent development of deep sequencing approaches to study human cancer genomes in individual tumor lesions is already revolutionizing medical oncology and translational medicine. This large and growing body of information is now contributing to the elucidation of aberrant molecular mechanisms driving tumor progression, hence revealing novel druggable targets for therapeutic intervention to prevent and treat human cancers. The emerging picture is that despite the remarkable complexity of genomic alterations found in HNSCC, most of them fall within few major driver-signaling pathways, with the majority of the HNSCC lesions harboring genetic and epigenetic alterations that converge on the persistent activation of the PI3K-mTOR pathway. While representing a major HNSCC driver, this likely overreliance on the PI3K-mTOR signaling route for tumor growth can in turn expose a cancer vulnerability that can be exploited for therapeutic purposes. Indeed, the have documented the sensitivity of HNSCC to mTOR inhibition in multiple experimental models and encouraging recent clinical studies. The presence of genomic alterations in the PI3K pathway may also represent a suitable biomarker predicting a clinical response to its pharmacological inhibitors. Nanoparticle-based immunosensensors for cancer biomarkers and drug delivery systems for cell-surface receptor-guided cancer therapy: The genomic and proteomic analysis of HNSCC may now allow the development of novel biomarkers of diagnostic and prognostic value. We continued developing nanoparticle-based systems for the detection of HNSCC biomarkers. In particular, we have now developed an ultrasensitive immunosensor based on a glutathione-protected gold nanoparticle sensor surface. When combined with novel massively labeled paramagnetic particles for the electrochemical detection of a panel of cancer biomarkers, we obtained an unprecedented detection limit in the attomolar range, with high level of reproducibility and accuracy. This nanoparticle-based strategy for single-protein sensors has great promise for the future development of nanodetection arrays for clinical cancer screening and therapy monitoring. 20% effort. The role of signaling circuitries in epithelial stem cell function, tissue regeneration, and malignant reprogramming In prior studies we have shown that epithelial stem cells are endowed with a protective mechanism that results in cell senescence upon the persistent stimulation of proliferative pathways that activate mTOR, ultimately suppressing tumor formation. These studies and ongoing activities in the branch prompted us to begin investigating the molecular events controlling epithelial stem cell function, with emphasis on the preservation of the stem cell pool, or its demise by death, differentiation, and senescence (DDS response). Targeting mTOR and TGFbeta to prevent epithelial stem cell senescence and radiation-induced mucositis. We have recently found that whereas inhibition of mTOR does not affect the radiosensitivity of a collection of HNSCC cells, blockade of mTOR protects epithelial stem cells from radiation-induced senescence, thereby preserving their tissue repopulating capacity. We also observed that blocking mTOR leads to the decreased expression of p16INK4a, a key senescence gene that mediates the demise of epithelial stem cells from the tissue regenerating pool. This results in a dramatic decrease in radiation-induced mucositis, which may have a direct impact for thousands of cancer patients that develop this debilitating oral disease as a side effect of cancer treatment. As part of a collaborative effort, we have also shown that TGFbeta expression by epithelial and stromal cells contributes to mucositis, and that its blockade can reduce the epithelial damage upon ionizing radiation of the oral cavity.

50% 的努力。 HNSCC 信号网络失调：基于机制的 HSNCC 预防和治疗新方法 考虑到 HNSCC 患者的总体 5 年生存率相对较低 (50%)，并且在过去 30 年中仅略有改善，因此迫切需要新的治疗方案。 关于信号网络功能失调如何导致 HNSCC 的发生、恶性生长和转移的新知识现在可用于确定基于机制的新型抗癌治疗。 mTOR 作为 HNSCC 治疗的新型分子靶点。 我们发现激酶 Akt 及其下游靶标 mTOR 的持续激活是 HNSCC 中的常见事件，并且在多个实验性 HNSCC 模型中使用雷帕霉素抑制 mTOR 会导致 HNSCC 肿瘤快速凋亡死亡，从而诱发肿瘤回归。我们继续共同努力，使用新型基因定义和化学诱导的致癌模型来评估 mTOR 抑制剂预防和治疗 HNSCC 的有效性。这包括证明雷帕霉素可以减轻肿瘤负荷并延长携带 TGF-和 Akt-mTOR 通路突变的小鼠的存活时间。此外，与人乳头瘤病毒（HPV）感染相关的 HNSCC 发病率显着增加。尽管 HPV+ HNSCC 代表了 HNSCC 病变的一个独特的临床病理学子集，但我们观察到这些 HPV+ 病变也表现出 Akt-mTOR 活性增加。在多个 HPV+ HNSCC 异种移植模型中，mTOR 抑制剂可诱导肿瘤快速崩溃并减少肿瘤负荷，同时抑制 Akt-mTOR 通路。在最近的一项研究中，我们表明，在同基因动物模型中，同时给予雷帕霉素可增强 HPV+ 肿瘤对细胞毒性药物标准疗法的治疗反应以及肿瘤细胞的免疫识别。因此，mTOR 抑制剂也可能是治疗 HPV 阳性 HNSCC 病变的有吸引力的候选药物。 用于研究 SCC 的新型基因定义和化学诱导的口腔特异性动物模型：我们为 HNSCC 基因工程小鼠模型 (GEMM) 的开发做出了重大贡献。我们继续进行这些研究，包括最近与 Ashok Kulkarni 合作分析 TGFbeta 和 Akt-mTOR 通路之间的相互作用。我们现在专注于口腔特异性系统的开发，该系统能够激活/失活上皮干细胞区室中的基因。我们还开始探索使用基因工程小鼠来提高对口腔癌的易感性或抵抗力，这是我们最近开发的口腔特异性化学致癌模型提供的可能性。目前的研究旨在重现 HNSCC 的进展，重点关注 PI3K/mTOR 通路的激活，从而提供合适的系统来研究靶向抗癌药物。这包括 PIP3 磷酸酶 Pten 的删除。最近，我们发现，口腔上皮基底层缺乏 Pten 的小鼠（由于 Pten 表观遗传沉默而导致的 HNSCC 中常见的事件）在暴露于致癌物质后以非常高的比率发生口腔癌病变，导致动物迅速与癌症相关的死亡。 30%的努力。了解口腔癌的基因组学和蛋白质组学方法 我们结合激光捕获显微切割（LCM）、基因阵列、下一代测序和蛋白质组平台，对 HNSCC 进行了基因和蛋白质表达分析。这些努力提供了有关驱动 HNSCC 发展的失调分子电路的大量信息，从而有助于确定新的治疗靶点和合适的生物标志物，用于监测 HNSCC 进展和治疗反应。 利用头颈癌癌基因组。最近开发的用于研究个体肿瘤病变中的人类癌症基因组的深度测序方法已经彻底改变了肿瘤内科和转化医学。这一庞大且不断增长的信息现在有助于阐明驱动肿瘤进展的异常分子机制，从而揭示用于预防和治疗人类癌症的治疗干预的新的药物靶点。正在出现的情况是，尽管 HNSCC 中发现的基因组改变非常复杂，但其中大多数属于少数主要驱动信号通路，大多数 HNSCC 病变都包含遗传和表观遗传改变，这些改变集中在 PI3K- 的持续激活上。 mTOR 通路。虽然是 HNSCC 的主要驱动因素，但肿瘤生长可能过度依赖 PI3K-mTOR 信号通路，反过来又会暴露出可用于治疗目的的癌症脆弱性。事实上，他们已经在多个实验模型中记录了 HNSCC 对 mTOR 抑制的敏感性，并鼓舞了最近的临床研究。 PI3K 通路中基因组改变的存在也可能代表预测对其药理学抑制剂的临床反应的合适生物标志物。 用于癌症生物标志物的纳米粒子免疫传感器和用于细胞表面受体引导的癌症治疗的药物输送系统：HNSCC 的基因组和蛋白质组分析现在可以允许开发具有诊断和预后价值的新型生物标志物。我们继续开发基于纳米粒子的系统来检测 HNSCC 生物标志物。特别是，我们现在开发了一种基于谷胱甘肽保护的金纳米颗粒传感器表面的超灵敏免疫传感器。当与新型大量标记的顺磁颗粒结合用于一组癌症生物标志物的电化学检测时，我们在阿摩尔范围内获得了前所未有的检测限，并且具有高水平的重现性和准确性。这种基于纳米颗粒的单蛋白传感器策略对于临床癌症筛查和治疗监测的纳米检测阵列的未来发展具有巨大的前景。 20%的努力。信号通路在上皮干细胞功能、组织再生和恶性重编程中的作用 在之前的研究中，我们已经表明，上皮干细胞被赋予了一种保护机制，当持续刺激激活 mTOR 的增殖途径时，会导致细胞衰老，最终抑制肿瘤形成。这些研究和该分支正在进行的活动促使我们开始研究控制上皮干细胞功能的分子事件，重点是干细胞池的保存，或其通过死亡、分化和衰老（DDS 反应）而消亡。 靶向 mTOR 和 TGFbeta 预防上皮干细胞衰老和辐射诱发的粘膜炎。我们最近发现，虽然抑制 mTOR 不会影响 HNSCC 细胞群的放射敏感性，但阻断 mTOR 可以保护上皮干细胞免受辐射诱导的衰老，从而保留其组织再生能力。 我们还观察到，阻断 mTOR 会导致 p16INK4a 的表达下降，p16INK4a 是介导组织再生库中上皮干细胞死亡的关键衰老基因。这导致辐射引起的粘膜炎显着减少，这可能对成千上万的癌症患者产生直接影响，这些患者因癌症治疗的副作用而患上这种使人衰弱的口腔疾病。作为合作努力的一部分，我们还表明上皮细胞和基质细胞表达的 TGFbeta 会导致粘膜炎，并且阻断它可以减少口腔电离辐射对上皮的损伤。