Inhibiting beta-adrenergic and COX-2 signaling during the perioperative period to reduce ovarian cancer progression

Inhibiting beta-adrenergic and COX-2 signaling during the perioperative period to reduce ovarian cancer progression Abstract: The short perioperative period, days before and after surgery, is commonly not exploited for anti-metastatic interventions. During this short but critical period, stress and inflammatory responses are prevalent among cancer patients. In vitro studies indicate that β-adrenergic and prostanoid signaling can accelerate ovarian tumor cells’ growth and pro-metastatic characteristics. In several animal models, including in ovarian cancer (OC), in vivo perioperative pharmacological blockade of β-adrenergic stress responses and/or activity of prostaglandin- synthesis COX-2 enzyme, was shown to reduce cancer metastasis and improve long-term survival rates. Epidemiological studies suggest survival benefits of incidental perioperative use of such pharmacological blockade in many solid cancers, including OC. Recent perioperative small randomized clinical trials (RCTs) in breast and colorectal cancer patients (n=38 & 34) indicated beneficial effects of the β-blocker, propranolol, with or without the COX-2 synthesis inhibitor, etodolac, on molecular biomarkers of cancer progression in excised tumors. The drugs were well tolerated, exhibited high safety profile, and in colorectal cancer patients, preliminary findings also suggested improved 5-year disease free survival. Herein we propose to conduct a small exploratory two-arm placebo-controlled RCT in 60 women undergoing OC debulking surgery. Patients will be treated with both propranolol and etodolac (or placebo), starting 5 days before surgery and up to 3 weeks following it. Propranolol (extended release) will be initiated at a low dose (20mg, BID), increased on surgery day (80mg, BID), and gradually decreased during the following 3 weeks back to the low dose, while etodolac will be given in parallel at a steady moderate dose (400mg BID). Thereafter, to address the unmet need of alleviating increased anxiety across treatment spectrum, and to attenuate stress-related β-adrenergic stimulation, propranolol (which is also anxiolytic), or placebo, will be continued for additional 2 months at the low dose. Primary outcomes of the study will include (i) recruitment rate, (ii) perioperative drug safety, tolerability, and adherence, and (iii) molecular characteristics of excised tumors with respect to tumor infiltrating leukocytes and transcriptional activity related to pro-metastatic (e.g., EMT), pro-growth (STAT and GATA families), and stress and inflammatory signaling (NF- κB/cRel, AP-1, CREB and GR). Secondary outcomes will include 3-year recurrence rates, based on signed agreements with the medical centers and without additional costs. If promising outcomes will be evident in this RCT, a larger multicenter RCTs can be justified to identify additional mediating mechanisms of the intervention, devise novel biomarkers for treatment efficacy and for OC progression, and to test whether this intervention can improve long-term cancer outcomes and overall survival of OC patients. As the intervention is based on repurposing of inexpensive off-patent safe and easily administered medications, it can easily be implemented clinically in most medical centers worldwide.