Grant R21CA158902

Effectiveness of minocycline for reducing symptoms in pancreatic cancer patients

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.