# Targeting the MICAL2 signaling axis in pancreatic cancer

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $217,163

## Abstract

PROJECT SUMMARY/ABSTRACT
There is a critical need for novel therapeutic approaches for pancreatic ductal adenocarcinoma (PDAC) as the
current chemotherapeutic regimens fail to control the disease for a majority of patients. To identify novel
regulators of PDAC we compared the epigenetic landscape of surgically resected tumors to normal pancreas
using histone-3 lysine-27 acetylation (H3K27ac). This analysis revealed super-enhancer regions which are “hot-
spots” for transcription factor binding. Super-enhancer profiling of PDAC tissue revealed a distinctive landscape
compared to that of normal pancreas. Amongst the most highly acetylated enhancers mapped to the MICAL2
gene. The MICAL2 enzyme is a flavin monooxygenase that regulates nuclear actin dynamics resulting in
downstream modulation of transcription by myocardin-related transcription factor-A and serum response factor.
As an enzyme whose class has been successfully inhibited in human disease, we believe MICAL2 represents
an exciting and potentially tractable target for pancreatic cancer therapy.
We examined human and murine pancreatic cancer cell lines and organoids as well as several independent
datasets and confirmed that MICAL2 is overexpressed in PDAC and that its overexpression confers a poor
prognosis. In addition, we have generated robust preliminary data demonstrating that loss of MICAL2 results in
downregulation of key cell cycle regulators which slows proliferation and causes stalling in G1 and G2/M phases.
Furthermore, silencing of MICAL2 inhibits colony formation and cell migration in vitro which are key phenotypes
of advanced disease. Importantly, these phenotypes are conserved in vivo, where the loss of MICAL2 in either
mouse or human PDAC cells markedly inhibits tumor growth, as well as metastatic spread to both liver and lung.
Finally, MICAL2 appears to promote chemoresistance to gemcitabine, a common PDAC chemotherapeutic.
The evidence we have gathered strongly suggests that targeting the MICAL2 program in PDAC will be
therapeutically effective. To validate our hypothesis, our goals are to determine how inhibition of MICAL2 impacts
PDAC response to cytotoxic therapies and to define the cell extrinsic effects of MICAL2 inhibition in PDAC
models. To accomplish this, we will use orthogonal approaches to define the potential benefits and outcomes of
MICAL2 targeting. We will leverage our extensive pre-clinical modeling expertise to assess cell intrinsic and
extrinsic effects of MICAL2 inhibition. We will define MICAL2 dependent programs that promote chemoresistance
and assess novel drug combinations to overcome these programs. Importantly, we will thoroughly investigate
the potential toxicity of our therapeutic approach. The findings from these studies will enhance our understanding
of MICAL2 biology and thereby serve to inform the development and testing of MICAL2-directed therapies in
pancreatic cancer.

## Key facts

- **NIH application ID:** 10676946
- **Project number:** 5R21CA273973-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** ANDREW M LOWY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $217,163
- **Award type:** 5
- **Project period:** 2022-08-04 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10676946

## Citation

> US National Institutes of Health, RePORTER application 10676946, Targeting the MICAL2 signaling axis in pancreatic cancer (5R21CA273973-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10676946. Licensed CC0.

---

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