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

> **NIH NIH R41** · PAZ PHARMACEUTICALS · 2022 · $385,139

## Abstract

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.

## Key facts

- **NIH application ID:** 10546773
- **Project number:** 1R41CA275625-01
- **Recipient organization:** PAZ PHARMACEUTICALS
- **Principal Investigator:** Haiyong Han
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,139
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546773

## Citation

> US National Institutes of Health, RePORTER application 10546773, Development of (R,S')-MNF as a dual-targeted therapy for pancreatic cancer (1R41CA275625-01). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10546773. Licensed CC0.

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