Effectiveness of minocycline for reducing symptoms in pancreatic cancer patients

描述（由申请人提供）：大多数晚期胰腺癌患者在中位生存期约为6个月期间遭受显著的症状负担。这表明非常需要对患者护理进行有效的、机制驱动的症状控制。人类症状经历的潜在机制和信号通路尚不清楚，但越来越多的文献证据表明炎症可能是症状产生的罪魁祸首。然而，我们只有相关数据支持炎症的作用，如促炎细胞因子，在产生严重的癌症相关症状负担。拟议的随机安慰剂对照临床试验的目的是研究米诺环素（一种抗炎症药物，可调节炎症生物标志物）与安慰剂相比，是否会减轻新诊断的晚期胰腺癌患者细胞因子驱动的症状负担。我们提出这项研究是基于强有力的临床前证据，表明二甲胺四环素可以降低炎症标志物的表达，并对其他临床状况产生影响，二甲胺四环素是一种安全、廉价、易得的药物。米诺环素在大脑和外周系统中具有广泛的抗炎作用，它通过抑制p38 MAKP通路抑制小胶质细胞的激活和增殖来实现。阳性结果可以立即帮助有限生存期高症状负担的胰腺癌患者，并将证据和支持机制驱动的方法来管理癌症相关症状。特异性目的1：确定米诺环素在新诊断胰腺癌患者吉西他滨化疗期间减轻症状的疗效。特异性目的1.1：探讨米诺环素在标准化疗期间减轻症状的作用。我们假设随机接受200mg /天二甲胺四环素治疗的患者与安慰剂组相比，在控制疾病进展的情况下，会报告较轻的疲劳和其他症状。目的1.2：探讨二甲胺四环素对化疗期间严重症状发展的影响。我们假设，基线症状较轻且接受二甲胺四环素治疗的患者，与基线症状较轻的安慰剂组相比，出现严重症状的时间较慢。特异性目的2：表征二甲胺四环素对调节炎症生物标志物的作用及其与胰腺癌患者症状减轻的可能关联。特异性目的2.1：检验米诺环素对降低炎症生物标志物的作用。我们假设，与安慰剂组相比，接受二甲胺四环素治疗的患者血清IL-6、sTNF-R1和p38 MAPK激活的降低程度更大。特异性目的2.2：研究米诺环素在预防基线症状轻微患者细胞因子释放快速增加方面的潜在作用。我们假设，与安慰剂组相比，接受二甲胺四环素治疗的患者在检测的生物标志物中表现出较慢的增长。

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.