Effectiveness of minocycline for reducing symptoms in pancreatic cancer patients

米诺环素减轻胰腺癌患者症状的有效性

• 批准号: 8242916
• 负责人: Xin Shelley Wang
• 金额: $ 20.62万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242916
• 关键词: Active Biological Transport; Advanced Malignant Neoplasm; Animals; Anorexia; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Behavioral; Biological; Biological Markers; Blood - brain barrier anatomy; Brain; Cachexia; Cancer Patient; Caring; Chronic; Chronic Disease; Clinical; Consensus; Control Groups; Controlled Clinical Trials; Cytokine Network Pathway; Data; Desire for food; Development; Diagnosis; Disease; Disease Progression; Distress; Double-Blind Method; Drowsiness; Drug toxicity; Effectiveness; Exhibits; Fatigue; Food; Future; Human; Hyperalgesia; Inflammation; Inflammatory; Interleukin-6; Intervention Studies; Learning; Life; Literature; MAPK14 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Mediating; Microglia; Minocycline; Multicenter Studies; Nerve Fibers; Newly Diagnosed; Onset of illness; Pain; Pathway interactions; Patient Care; Patients; Peripheral; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Play; Production; Randomized; Reporting; Role; Serum; Signal Pathway; Sleep; Staging; Symptoms; System; TNFR-Fc fusion protein; Testing; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Water consumption; advanced disease; arm; base; chemotherapy; cohort; cost; cytokine; experience; gemcitabine; human MAPK14 protein; improved; inflammatory marker; inhibitor/antagonist; innovation; insight; pre-clinical; prevent

DESCRIPTION (provided by applicant): Most patients with advanced pancreatic cancer suffer from significant symptom burden during a median survival of approximately 6 months. This indicates a great need for effective, mechanism-driven symptom control for patient care. The underlying mechanisms and signaling pathways involved in human symptom experiences are not yet well understood, but increasing evidence in the literature implicates inflammation as a likely culprit in the production of symptoms. However, we only have correlational data that support the role of inflammation, such as proinflammatory cytokines, in producing severe cancer-related symptom burden. The objective of the proposed randomized placebo-controlled clinical trial is to examine whether minocycline, an anti-inflammation agent shown to modulate inflammatory biomarkers, will reduce cytokine-driven symptom burden in patients with newly diagnosed advanced pancreatic cancer, compared with placebo. We propose this study on the basis of strong preclinical evidence of decreased expression of inflammatory markers, and effect on other clinical conditions, from minocycline-a safe, inexpensive, and readily available drug. Minocycline has a wide range of anti-inflammatory effects in the brain and peripheral system, which it accomplishes by inhibiting microglial activation and proliferation through inhibition of the p38 MAKP pathway. Positive results could immediately help patients with pancreatic cancer with high symptom burden during limited survival and will evidence and support a mechanism-driven approach to managing cancer-related symptoms. SPECIFIC AIM 1: To establish the efficacy of minocycline in reducing symptoms during gemcitabine-based chemotherapy in patients with newly diagnosed pancreatic cancer. Specific Aim 1.1: to examine the effects of minocycline on reducing symptoms during standard chemotherapy. We hypothesize that patients randomized to receive 200 mg/day minocycline will report less-severe fatigue and other symptoms compared with a placebo group, controlling for disease progression. Specific Aim 1.2: to examine the effect of minocycline on de- laying the development of severe symptoms during chemotherapy. We hypothesize that patients who have mild baseline symptoms and who are treated with minocycline will show slower onset of severe symptoms, com- pared with a placebo group who also have mild baseline symptoms. SPECIFIC AIM 2: To characterize minocycline's effect on modulating inflammatory biomarkers and its possible association with symptom reduction in patients with pancreatic cancer. Specific Aim 2.1: to examine the effect of minocycline on reducing inflammatory biomarker(s). We hypothesize that, compared with a placebo group, patients who receive minocycline will exhibit greater reductions in serum IL-6, sTNF-R1, and p38 MAPK activation. Specific Aim 2.2: to examine potential effects of minocycline on preventing rapid increase in cytokine release in patients with mild baseline symptoms. We hypothesize that patients receiving minocycline will exhibit a slower increase in the examined biomarkers, compared with a placebo group. PUBLIC HEALTH RELEVANCE: For patients with advanced pancreatic cancer, there are limited approaches for effectively reducing symptom burden during their short survival period (often, approximately 6 months postdiagnosis). Inflammation has been identified as a major factor in disease progression in patients with advanced cancer and possibly plays a strong role in the development of significant cancer-related symptom burden. This study proposes to investigate whether an anti-inflammation agent, minocycline, could reduce symptoms or delay the onset of disease- related symptoms by modulating the inflammatory pathway and biomarkers in patients with newly diagnosed advanced pancreatic cancer.

描述（由申请人提供）：大多数晚期胰腺癌患者在大约6个月的中位生存期间遭受重大症状负担。这表明需要有效的，机构驱动的症状控制患者护理。人类症状经历中涉及的基本机制和信号通路尚未得到充分的理解，但是文献中越来越多的证据表明炎症是症状产生的可能性。但是，我们只有相关数据支持炎症的作用，例如促炎细胞因子，在产生严重的癌症相关症状负担中。 拟议的随机安慰剂对照临床试验的目的是检查与安慰剂相比，与安慰剂相比，米诺环素是一种调节炎症生物标志物的抗炎剂是否会减轻新诊断的晚期胰腺癌患者的细胞因子驱动症状负担。我们根据炎症标志物表达降低以及对其他临床状况的影响（Minocycline-A安全，廉价且随时可用的药物）的强烈临床前证据提出了这项研究。米诺环素在大脑和外围系统中具有广泛的抗炎作用，通过抑制p38 makp途径来抑制小胶质细胞激活和增殖来实现。积极的结果可以立即帮助胰腺癌患者在有限的生存期间具有高症状负担，并将证明并支持以机制驱动的癌症相关症状的方法。 具体目的1：确定米诺环素在新诊断的胰腺癌患者中基于吉西他滨化疗期间减少症状的功效。具体目标1.1：检查米诺环素对标准化疗期间减少症状的影响。我们假设随机接受200 mg/天米诺环素的患者与安慰剂组相比会报告较少的疲劳和其他症状，从而控制了疾病进展。具体目标1.2：检查米诺环素对化疗期间严重症状发展的影响。我们假设患有轻度基线症状并接受米诺环素治疗的患者会显示出严重症状的发作较慢，这与安慰剂组相对，他们也患有轻度的基线症状。 具体目标2：表征米诺环素对调节炎症生物标志物的影响及其与胰腺癌患者症状的可能相关性。具体目标2.1：检查米诺环素对减少炎症生物标志物的影响。我们假设，与安慰剂组相比，接受米诺环素的患者将在血清IL-6，STNF-R1和p38 MAPK激活中表现出更大的降低。特定目标2.2：检查米诺环素对轻度基线症状患者的细胞因子释放迅速增加的潜在影响。我们假设接受米诺环素的患者与安慰剂组相比，所检查的生物标志物的增长速度较慢。 公共卫生相关性：对于患有晚期胰腺癌的患者，在短期生存期（通常在诊断后约6个月）中有效减轻症状负担的方法有限。炎症已被确定为晚期癌症患者疾病进展的主要因素，并且可能在与癌症相关症状的重大症状负担的发展中起着重要作用。这项研究建议研究抗炎剂Minocycline是否可以通过调节新诊断的晚期胰腺癌患者的炎症途径和生物标志物来减轻症状或延迟疾病相关症状的发作。