# Project 2: Chemoprevention of pancreatic cancer with lipid-lowering and antidiabetic agents

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $242,953

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human diseases. The focus of research,
which had been placed mostly on development of therapeutic agents, has shifted gradually towards its
prevention. In this context, many studies have linked obesity and long-standing type-2 diabetes mellitus with
PDAC development. These metabolic diseases are characterized by peripheral insulin resistance,
hyperinsulinemia, increased IGF-1 and chronic inflammation. Previously, crosstalk mechanisms between
insulin/IGF-1 receptors, G protein-coupled receptor (GPCR) and EGF receptor (EGFR) signaling systems have
been identified that potently stimulate proliferation of PDAC cells harboring a KRAS mutations. Mitogenic
crosstalk depended on the function of mTORC1, ERK and PKD and opposed by AMPK, a target for the
antidiabetic agent metformin. The identification of the key downstream targets of this signaling network is of
fundamental significance and major translational interest. The YAP/TAZ transcriptional co-activators are
emerging as points of integration in the action of KRAS, GPCRs and AMPK, all signaling pathways highly
relevant in PDAC. New preliminary studies demonstrate that YAP/TAZ activation is a crucial point of
convergence in the crosstalk between GPCR and insulin signaling in PDAC cells. Importantly, lipid-lowering
drugs of the statin family potently blocked YAP/TAZ activity, including YAP/TAZ/TEAD-regulated genes, such
as CTGF, Cyr61 and NUAK2. Lipophilic statins, including cerivastatin, simvastatin and atorvastatin, strikingly
inhibited colony formation of human and mouse PDAC cells. Statins inhibited PDAC colony formation acting
synergistically with metformin. Further preliminary results in vivo show that oral administration of simvastatin
attenuated the loss of intact acini and the development of pre-neoplastic lesions in the pancreas promoted by
an obesogenic diet in conditional KrasG12D (KC) mice. Accordingly, the central hypothesis to be explored in
Project 2 of this P01 is that the well tolerated cholesterol-lowering drugs of the statin family inhibit obesity-induced
promotion of PDAC via inhibition of PKD/YAP/TAZ. The Specific Aims of Project 2 have been designed to
investigate important gaps in current knowledge: 1) Characterize the chemopreventive effects of statins on the
progression of PanINs and development of PDAC using the conditional KrasG12D model (KC mice) subjected to
control or diet-induced obesity (DIO) and in KC mice carrying a homozygous deletion of the ob gene. 2) Identify
a novel molecular mechanism by which statins inhibit YAP/TEAD signaling in mouse and human pancreatic cells.
3) Characterize the inhibitory effect of a low-dose combination of statin and metformin on the development of
PDAC: a novel chemopreventive strategy. The studies proposed in Project 2 of this P01 will provide mechanisms
and rationale for novel chemo-preventive strategies in obesity-related PDAC. Since statins and metformi...

## Key facts

- **NIH application ID:** 10147871
- **Project number:** 5P01CA236585-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** JUAN ENRIQUE ROZENGURT
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $242,953
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147871

## Citation

> US National Institutes of Health, RePORTER application 10147871, Project 2: Chemoprevention of pancreatic cancer with lipid-lowering and antidiabetic agents (5P01CA236585-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10147871. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*