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中的信号网络失调：基于新型机制的HSNCC预防和治疗方法 考虑到他们的总体5年生存率相对较低（50％），并且在过去30年中仅略有改善，因此迫切需要针对HNSCC患者的新治疗选择。 现在，可以利用HNSCC的发起，恶性增长和转移来识别新型基于机制的抗癌治疗方法的新兴知识如何有助于HNSCC的起始，恶性增长和转移。 MTOR是HNSCC治疗的新型分子靶标。 我们已经表明，激酶AKT及其下游靶标MTOR的持续激活是HNSCC中的常见事件，并且通过使用雷帕霉素对MTOR的抑制作用会导致HNSCC肿瘤在多种实验性HNSCC模型中迅速凋亡的凋亡死亡，从而导致诱导肿瘤回归。我们继续进行一致的努力，以使用新颖的遗传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。这包括雷帕霉素减轻肿瘤负担并延长其在TGF-和AKT-MTOR途径中携带突变的小鼠的存活的演示。此外，与人乳头瘤病毒（HPV）感染相关的HNSCC的发生率显着增加。尽管HPV+ HNSCCS代表了HNSCC病变的独特临床病理学子集，但我们观察到这些HPV+病变也显示出增加的Akt-MTOR活性。 MTOR抑制剂诱导肿瘤快速塌陷，并减轻肿瘤负担与多种HPV+ HNSCC异种移植模型中Akt-MTOR途径的抑制作用。在最近的一项研究中，我们表明，雷帕霉素同时给药可增强HPV+肿瘤对具有细胞毒性剂的标准疗法的治疗反应，并在合成动物模型中对肿瘤细胞的免疫识别。因此，MTOR抑制剂也可能代表用于治疗HPV阳性HNSCC病变的有吸引力的候选者。 新型的遗传定义和化学诱导的口腔特异性动物模型研究SCC：我们为HNSCC的基因工程小鼠模型（GEMM）做出了重大贡献。我们继续进行这些研究，包括与Ashok Kulkarni合作的TGFBETA和AKT-MTOR途径之间的相互作用的分析。现在，我们专注于口服特定系统的发展，从而实现上皮干细胞室中基因的激活/失活。我们还开始探索使用基因工程的小鼠的使用，这些小鼠赋予了对口腔癌的敏感性或耐药性，这是我们最近开发的口腔特异性化学癌变模型提供的一种可能性。当前的研究旨在概括HNSCC的进展，重点是PI3K/MTOR途径的激活，从而提供了一个合适的系统来研究靶向的抗癌药物。这包括删除PIP3磷酸酶PTEN。最近，我们已经表明，由于PTEN的表观遗传沉默，口服上皮基底层缺乏PTEN，这是HNSCC的常见事件，在暴露致癌物后以很高的速度发展口腔癌病变，导致与动物癌症相关的快速死亡。 30％的努力。理解口腔癌的基因组和蛋白质组学方法 我们通过将激光捕获显微解剖（LCM），基因阵列，下一代测序和蛋白质组学平台相结合，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开发的分子电路失调的大量信息，从而有助于鉴定新的治疗靶标和合适的生物标志物，以监视HNSCC的进展和治疗反应。 利用头部和颈部癌致癌组。在单个肿瘤病变中研究人类癌症基因组的最新测序方法的最新发展已经彻底改变了医学肿瘤学和转化医学。现在，大量的信息体系正在促进驱动肿瘤进展的异常分子机制的阐明，因此揭示了可预防和治疗人类癌症的治疗干预措施的新型可药物靶标。新兴的情况是，尽管HNSCC中发现的基因组改变存在显着的复杂性，但其中大多数属于少数主要的驾驶员信号途径，大多数HNSCC病变都具有遗传和表观遗传变化，它们伴随着PI3K-MTOR途径的持续激活。在代表主要的HNSCC驱动因素的同时，这种对PI3K-MTOR信号生长途径的过度依赖又可能会暴露出可用于治疗目的的癌症脆弱性。实际上，这些证明了HNSCC对MTOR抑制的敏感性在多个实验模型中，并鼓励了最近的临床研究。 PI3K途径中基因组改变的存在也可能代表一种适当的生物标志物，可预测对其药理抑制剂的临床反应。 基于纳米颗粒的癌症生物标志物和用于细胞表面受体引导的癌症治疗的药物输送系统的免疫传感器：HNSCC的基因组和蛋白质组学分析现在可以允许开发新的诊断和预后价值生物标记物。我们继续开发基于纳米颗粒的系统来检测HNSCC生物标志物。特别是，我们现在基于受谷胱甘肽保护的金纳米颗粒传感器表面开发了一种超敏化免疫传感器。当与新型标记的副磁颗粒结合使用，用于对癌症生物标志物的电化学检测，我们在attomolar范围内获得了前所未有的检测极限，具有高度的可重复性和准确性。这种基于纳米颗粒的单蛋白传感器的策略对未来开发纳米探测阵列的发展有很大的希望，用于临床癌症筛查和治疗监测。 20％的努力。信号电路在上皮干细胞功能，组织再生和恶性重编程中的作用 在先前的研究中，我们表明上皮干细胞具有一种保护性机制，该机制导致细胞衰老，这是对激活MTOR的增殖途径的持续刺激，最终抑制了肿瘤的形成。这些分支机构中的研究和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，重点是保存干细胞池，或者通过死亡，分化和衰老（DDS反应）来保存其灭亡（DDS反应）。 靶向MTOR和TGFBETA，以防止上皮干细胞衰老和辐射诱导的粘膜炎。我们最近发现，尽管MTOR的抑制作用不影响HNSCC细胞集合的放射敏性，但MTOR的阻断可保护上皮干细胞免受辐射诱导的衰老，从而保留其组织重新填充能力。 我们还观察到阻塞MTOR导致P16INK4A的表达降低，P16INK4A是一种关键的衰老基因，可介导组织再生池的上皮干细胞的灭亡。这导致辐射诱导的粘膜炎的急剧下降，这可能会对成千上万的癌症患者产生直接影响，这些患者发展为衰弱的口腔疾病，这是癌症治疗的副作用。作为协作努力的一部分，我们还表明，上皮细胞和基质细胞的TGFBETA表达有助于粘膜炎，并且其阻塞可以减少口腔电离辐射时上皮损伤。