Microgranular Curcumin Biomarker Trial in Head and Neck Squamous Cell Carcinoma

头颈鳞状细胞癌微粒姜黄素生物标志物试验

• 批准号: 8099780
• 负责人: CHERIE-ANN O NATHAN
• 金额: $ 15.06万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099780
• 关键词: Address; Adjuvant; Adjuvant Study; Affect; Aftercare; Animals; Apoptosis; Apoptotic; Archives; Biological; Biological Markers; Biopsy; Bypass; Cancer Biology; Cancer Patient; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Chemoprevention; Clinical Trials; Colon Carcinoma; Control Groups; Curcumin; Cyclin D1; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Dietary Intervention; Disease; Dose; Drug Formulations; Dysplasia; Esophagus; Event; Excision; Fibroblast Growth Factor; Future; Gelatinase B; Genes; Goals; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Health Care Costs; Heterogeneity; High Pressure Liquid Chromatography; Histologic; Immunohistochemistry; Inflammatory Infiltrate; Intervention; Intervention Studies; Length; Lesion; Louisiana; Lung; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of pancreas; Measures; Mission; Molecular; Molecular Target; Mucous Membrane; Neoplastic Cell Transformation; Newly Diagnosed; Nutraceutical; Nutritional; Oncogenic; Oral cavity; PECAM1 gene; Pancreas; Pathway interactions; Patients; Pharmacodynamics; Pharmacologic Substance; Phase; Phosphorylation; Pilot Projects; Plasma; Population; Premalignant; Prevention Research; Prevention strategy; Preventive; Primary Cancer Prevention; Problem behavior; Proteins; Proto-Oncogene Proteins c-akt; Recurrence; Sample Size; Sampling; Screening procedure; Signal Transduction Pathway; Site; Smokeless Tobacco; Spices; Staging; Surgical margins; Survival Rate; Testing; Time; Tissue Banking; Tissue Banks; Tissues; Tobacco; Toxic effect; Tumor Markers; Tumor stage; absorption; angiogenesis; base; bioactive food component; c-myc Genes; cancer prevention; cancer recurrence; capsule; carcinogenesis; cost; head and neck cancer patient; human FRAP1 protein; improved; liver metabolism; novel; oral tissue; overexpression; prevent; public health relevance; response; standard care; time interval; tumor; tumor progression

* DESCRIPTION (provided by applicant): Up to 50% of head and neck cancer (HNSCC) patients with advanced stage disease develop recurrences and early stage disease patients develop second primaries. Therefore preventing any of the steps of neoplastic transformation is a promising strategy. The mission of this RFA is to explore the mechanisms involved in nutritional agents in cancer, and the overall goal of this study is to determine whether curcumin can be used as a nutritional intervention agent in precancerous lesions of the upper aerodigestive tract to prevent cancer recurrence and ultimately reduce future health care costs. However the first step is to validate clinically useful biomarkers as indicators of curcumin response, which is best achieved in HNSCC patients where the biomarkers being tested is activated in 100% of tumors. There is a worldwide need for intervention studies using intermediate and surrogate biomarkers as endpoints to identify potential agents for chemoprevention of recurrence. Intermediate endpoints are necessary to more rapidly assess interventions for primary cancer prevention and address the feasibility posed by large patient numbers, length of study, and cost when cancer occurrence or recurrence is used as an endpoint. This clinical trial with curcumin could validate important biomarkers for studies with curcumin and correlate the biological effect of modulating these biomarkers, thus decreasing the number of subjects required in future interventional studies. In this proposal we will determine if the Akt/mTOR pathway components, overexpressed in ~90% of HNSCC, are potential biomarkers for future chemoprevention/adjuvant studies with curcumin, and decipher the mechanism of the nutritional interventional agent curcumin on cancer biology and prevention. To achieve this goal, 15 newly diagnosed head and neck cancer patients will receive a microgranular formulation of curcumin that allows for prolonged contact that has achieved double the plasma concentrations in two pilot patients compared to the standard capsule formulation used in a phase 2 pancreatic cancer trial, and has also achieved biological response for 3-4 weeks prior to standard treatment in these same two patients. Levels of curcumin will be determined in the plasma and tumor using HPLC, and repeat biopsies taken before and after curcumin treatment will be used to evaluate biomarker response to curcumin. The change in biomarkers in tumors from initial biopsy to final biopsy will be compared to a control group of patients with biopsies taken at the same time interval from our existing tissue bank and will be used to identify and validate biomarkers affected by the nutritional intervention agent curcumin. Results from this study will be used for subsequent studies with preneoplastic lesions patients. PUBLIC HEALTH RELEVANCE: Overall survival rates for head and neck squamous cell cancers have not improved significantly in the last few decades, due to the development of recurrences and second primaries as a result of precancerous changes from tobacco. Curcumin, a novel safe nutritional interventional agent has exciting potential usage as a preventive/adjuvant agent, and prevents tumor formation by inhibiting an important molecular pathway AKT/MTOR that is shown to cause cancer progression, which we will test as a tumor marker in this clinical trial with curcumin. We will also determine curcumin's effects on gene products regulated by AKT/MTOR shown to be important in the step-wise progression to invasive cancer.

* 描述（由申请人提供）：高达 50% 的晚期头颈癌 (HNSCC) 患者会出现复发，早期疾病患者会出现第二次原发。因此，阻止肿瘤转化的任何步骤是一个有前途的策略。本次RFA的任务是探讨营养剂在癌症中的作用机制，本研究的总体目标是确定姜黄素是否可以作为上呼吸消化道癌前病变的营养干预剂，以预防癌症复发和最终降低未来的医疗费用。然而，第一步是验证临床上有用的生物标志物作为姜黄素反应的指标，这最好在 HNSCC 患者中实现，因为所测试的生物标志物在 100% 的肿瘤中被激活。全世界都需要使用中间生物标志物和替代生物标志物作为终点来进行干预研究，以确定化学预防复发的潜在药物。中间终点对于更快速地评估初级癌症预防的干预措施是必要的，并解决以癌症发生或复发作为终点时大量患者数量、研究时间和成本所带来的可行性。这项姜黄素临床试验可以验证姜黄素研究的重要生物标志物，并将调节这些生物标志物的生物效应关联起来，从而减少未来介入研究所需的受试者数量。在本提案中，我们将确定在约 90% 的 HNSCC 中过度表达的 Akt/mTOR 通路成分是否是未来姜黄素化学预防/辅助研究的潜在生物标志物，并破译营养干预剂姜黄素在癌症生物学和预防方面的机制。为了实现这一目标，15 名新诊断的头颈癌患者将接受姜黄素微粒制剂，该制剂允许长期接触，与 2 期胰腺癌试验中使用的标准胶囊制剂相比，两名试点患者的血浆浓度达到了两倍，并且在这两名患者接受标准治疗前 3-4 周也达到了生物反应。将使用 HPLC 测定血浆和肿瘤中的姜黄素水平，并使用姜黄素治疗前后重复进行活检来评估生物标志物对姜黄素的反应。从初始活检到最终活检的肿瘤生物标志物的变化将与在我们现有组织库中相同时间间隔进行活检的对照组患者进行比较，并将用于识别和验证受营养干预剂姜黄素影响的生物标志物。这项研究的结果将用于随后对癌前病变患者的研究。 公共健康相关性：过去几十年来，由于烟草引起的癌前变化导致复发和第二原发，头颈鳞状细胞癌的总体生存率并未显着提高。姜黄素是一种新型安全营养干预剂，作为预防/辅助剂具有令人兴奋的潜在用途，并通过抑制重要的分子途径 AKT/MTOR 来预防肿瘤形成，AKT/MTOR 已被证明会导致癌症进展，我们将在本研究中将其作为肿瘤标志物进行测试。姜黄素的临床试验。我们还将确定姜黄素对 AKT/MTOR 调节的基因产物的影响，这些基因产物在逐步进展为侵袭性癌症中很重要。

项目成果

Enhanced Systemic Bioavailability of Curcumin Through Transmucosal Administration of a Novel Microgranular Formulation.

通过新型微粒制剂的经粘膜给药增强姜黄素的全身生物利用度。

• 发表时间: 2015-12
• 影响因子: 2
• 作者: Latimer, Brian;Ekshyyan, Oleksandr;Nathan, Neil;Moore;Rong, Xiaohua;Ma, Xiaohui;Khandelwal, Alok;Christy, Hunter T;Abreo, Fleurette;McClure, Gloria;Vanchiere, John A;Caldito, Gloria;Dugas, Tammy;McMartin, Kenneth;Lian, Timothy
• 通讯作者: Lian, Timothy