Development of (R,S')-MNF as a dual-targeted therapy for pancreatic cancer

Summary Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the U.S. with a 5-year survival rate of andlt;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% (pandlt;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.PROJECT NARRATIVE Pancreatic cancer is the third leading cause of cancer death in the U.S. with a 5-year survival rate of andlt;9%. This proposal seeks to develop a dual-target drug for use with standard of care therapies to treat patients with pancreatic cancer. The results generated from this proposal have the potential to directly benefit pancreatic cancer patients with improved cancer therapy.