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.

Grant Number: 5R21CA291683-02
NIH Institute/Center: NIH
Principal Investigator: Shamgar Ben-Eliyahu