Microgranular Curcumin Biomarker Trial in Head and Neck Squamous Cell Carcinoma

* 描述(申请人提供)：高达50%的晚期头颈癌(HNSCC)患者复发，早期疾病患者发展为第二原发。因此，防止肿瘤转化的任何步骤都是一个有希望的策略。这项RFA的使命是探索营养制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营养干预剂用于上呼吸道癌前病变，以防止癌症复发，并最终降低未来的医疗成本。然而，第一步是验证临床上有用的生物标记物作为姜黄素反应的指标，这在HNSCC患者中实现得最好，那里正在测试的生物标记物在100%的肿瘤中被激活。世界范围内需要使用中间生物标记物和替代生物标记物作为终点的干预研究，以确定潜在的化学预防复发的药物。当癌症发生或复发被用作终点时，中间终点对于更快速地评估初级癌症预防的干预措施以及解决大量患者数量、研究时间和成本所带来的可行性是必要的。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学效应联系起来，从而减少未来介入研究所需的受试者数量。在这项提案中，我们将确定Akt/mTOR途径组件是否为未来姜黄素化学预防/佐剂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中的作用机制。为了实现这一目标，15名新诊断的头颈部癌症患者将接受姜黄素的微粒制剂，该制剂允许长时间接触，使两名试点患者的血浆浓度达到2期胰腺癌试验中使用的标准胶囊制剂的两倍，并在这两名患者接受标准治疗前3-4周实现生物反应。姜黄素水平将用高效液相色谱法测定血浆和肿瘤中的水平，姜黄素治疗前后的重复活组织检查将用于评估生物标记物对姜黄素的反应。从最初的活检到最后的活检，肿瘤中生物标志物的变化将与我们现有组织库中同一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后续对癌前病变患者的研究。 公共卫生相关性：在过去的几十年里，由于烟草癌前病变导致的复发和二次初发，头颈部鳞状细胞癌的总体存活率没有显著提高。姜黄素是一种新型安全的营养干预剂，具有作为预防/佐剂的令人兴奋的潜在用途，并通过抑制一个重要的分子途径AKT/MTOR来预防肿瘤形成，该途径被证明会导致癌症进展，我们将在这次姜黄素临床试验中测试该途径作为肿瘤标志物的作用。我们还将确定姜黄素对AKT/MTOR调控的基因产物的影响，这被证明在向侵袭性癌症的逐步进展中是重要的。

* 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.