# Phosphodiesterase 10A, a novel target for lung cancer chemoprevention

> **NIH NIH R01** · AUBURN UNIVERSITY AT AUBURN · 2020 · $267,424

## Abstract

Abstract
 Preclinical, clinical and epidemiological studies provide compelling evidence that
nonsteroidal anti-inflammatory drugs (NSAIDs) have antineoplastic activity and significantly
reduce the incidence and risk of death from multiple cancer types, including lung cancer.
Unfortunately, the long-term use of NSAIDs for chemoprevention and their potential application
for therapy are not recommended because of the risk of potentially fatal side-effects resulting
from cyclooxygenase (COX) inhibition and the suppression of physiologically important
prostaglandins. However, numerous investigators have concluded that the pharmacological
basis for their antineoplastic activity may not require COX inhibition, which suggests the
feasibility of developing safer and more efficacious non-COX inhibitory derivatives for cancer by
targeting the underlying mechanism. We have extensively studied the mechanism by which the
NSAID, sulindac inhibits tumor cell growth and have reported that this activity results from cyclic
guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition and the activation of
cGMP/protein kinase G signaling to suppress oncogenic β-catenin/Tcf-transcriptional activity
and the synthesis of key proteins, such as cyclin D1 and survivin that drive tumor cell
proliferation and survival. Here we show that the cGMP degrading PDE isozyme, PDE10A is a
critically important target of sulindac that is elevated in lung tumors and essential for lung tumor
cell growth. Guided by molecular modeling using the crystal structure of PDE10, we synthesized
a novel series of sulindac derivatives that potently and selectively inhibit lung tumor cell growth
without inhibiting COX-1 or COX-2. These compounds have attractive drug-like properties
whereby high lung concentrations relative to plasma and other tissues can be safely achieved
by oral administration. A lead compound, MCI-048 was identified that displays strong antitumor
activity in an orthotopic mouse model of lung cancer. Further analog development to identify a
preclinical drug development candidate and studies to better define the role of PDE10 in lung
cancer are therefore urgently needed. The following aims are proposed: 1) synthesize a novel
series of sulindac derivatives to improve potency and selectivity, 2) evaluate PDE10 and lung
tumor cell growth inhibitory activity of sulindac derivatives, 3) evaluate antitumor activity of
sulindac derivatives in mouse models of lung cancer, and 4) further define the role of PDE10 in
lung cancer. The focus of this project on the development of novel anticancer drugs and target
validation for chemoprevention or therapy have the potential to impact individuals at risk of
developing lung cancer as well as patients with advanced stage malignant disease.

## Key facts

- **NIH application ID:** 10456469
- **Project number:** 7R01CA197147-06
- **Recipient organization:** AUBURN UNIVERSITY AT AUBURN
- **Principal Investigator:** Gary A Piazza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $267,424
- **Award type:** 7
- **Project period:** 2021-07-23 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456469

## Citation

> US National Institutes of Health, RePORTER application 10456469, Phosphodiesterase 10A, a novel target for lung cancer chemoprevention (7R01CA197147-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10456469. Licensed CC0.

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