Summary Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the U.S. with a 5-year survival rate of <9%. The poor prognosis is partially due to resistance to standard of care treatments including gemcitabine (Gem) and Gem+nab-paclitaxel (n-PTX). The transcription factors HIF-1α and c-MYC are at the center of the mechanisms producing Gem and n-PTX resistance and are key therapeutic targets. (R,S′)-4′-Methoxy-1-naphthylfenoterol (R,S’)- MNF is a bi-functional anti-cancer agent that acts as a competitive inhibitor of GPR55 and a biased-agonist of the β2-adrenergic receptor. In a PANC-1 xenograft tumor model (R,S’)-MNF significantly dampens tumor growth, ∼75% (p<0.01), and downregulates HIF-1α and c-MYC expression. Our overarching hypothesis is that (R,S′)-MNF will reduce PDAC tumor growth as a single agent and produce positive synergistic effects with standard of care agents. The overall goal is to determine the therapeutic potential of (R,S′)-MNF in combination with GEM+n-PTX in PDAC models. The experimental protocols will utilize our knowledge of (R,S′)-MNF pharmacokinetics and toxicity and experience with use of therapeutic agents in PDAC models. Specific aims are: Aim 1: to determine the antitumor activity of (R,S′)-MNF alone and in combination in PDAC patient derived xenograft (PDX) models: The initial step will be a dosing finding study to determine maximal tolerated dose of (R,S′)-MNF alone and in combination with GEM (70 mg/kg, i.p., once a week for 3 weeks) + n-PTX (30 mg/kg, once a week for 3 weeks). Optimal dose and schedule will be used in 2 PDX models derived from PDAC patients’ tumors expressing high levels of GPR55 and β2-AR. Each study will include 4 treatment groups of 18 mice/group: vehicle, (R,S′)-MNF alone, GEM+n-PTX, and (R,S′)-MNF + GEM+n-PTX. Blood and major organ tissues will be collected from 6 mice/group for analyses proposed in Aim 2. The remaining mice (12/group) will be monitored to determine the effect on tumor growth and survival. Aim 2: to identify treatment biomarkers and determine (R,S′)-MNF biodistributions: Plasma samples collected before and after treatment will be analyzed using LC-MS/MS to quantify small molecules such as lysophosphatidylcholines (14:0 and16:0) and lactate and ELISA assays for PDAC biomarkers such as CA19-9 and CYR61. Metabolite and protein concentrations will be compared to tumor growth and survival data and to the relative expression of GPR55 and β2-AR. Major organs collected from the (R,S′)-MNF treatment group will be analyzed using LC-MS/MS to determine drug biodistribution. Data from the Phase I study will support IND studies in a Phase II application, which will include GLP PK/PD, metabolism and toxicity studies.