Nonsteroidal anti-inflammatory drugs (NSAIDs) have cancer chemopreventive activity, but are not recommended for long-term use because of toxicities resulting from cyclooxygenase (COX) inhibition. However, sulindac and its congener, indomethacin (indo) inhibit the growth and induce apoptosis of tumor cells in vitro and are potentially effective for treating malignant disease by mechanisms that appear to be unrelated to COX inhibition. The Piazza lab has identified a novel series of non-COX-inhibitory sulindac derivatives with potent tumor cell growth inhibitory activity by targeting cGMP phosphodiesterase (PDE) isozymes, PDE5 and/or PDE10 to induce cGMP signaling. MCI-030 is a prototypic non-COX-inhibitory sulindac derivative with selectivity for PDE10 inhibition and strong in vitro and in vivo anti-tumor activity. Collaborative efforts from the Zhou and Piazza laboratories discovered that sulindac, MCI-030, as well as a sulindac congener, indomethacin (indo) are capable of inducing ER stress in tumor cells and can sensitize lymphoma cells to T cells engineered to express CD19-targeting chimeric antigen receptors (CD19CAR). These findings establish the premise of our hypothesis that it is feasible to design and develop novel sulindac derivatives with potent tumor cell growth inhibitory and immunostimulatory activities by targeting PDE5 and/or PDE10. The objective of our study is to define the molecular and cellular mechanisms by which sulindac and its non-COX derivatives condition an immunogenic tumor microenvironment. Specifically, we will determine how sulindac and non- COX inhibitory derivatives induce cancer immunogenic cell death, mitigate Treg and MDSC- mediated immunosuppression, and activate dendritic cells via effects on tumor cells involving ER stress induction, and suppression of oncogenic ?-catenin, which we hypothesize are triggered by PDE5/10 inhibition (aim 1). We will test the effectiveness of sulindac and non-COX inhibitory derivatives that inhibit PDE5 and/or PDE10 in potentiating cancer immunotherapies including PD1 blockade and adoptive T cell therapy in multiple preclinical models (aim 2). Knowledge obtained from Aim 1 and 2 will be integrated into a synthetic chemistry campaign to develop new sulindac derivatives with improved antitumor activity by directly suppressing tumor cell growth and by indirectly activating antitumor immunity, without the toxicities associated with COX inhibition (aim 3). Successful completion of the project will pave the way for developing novel sulindac derivatives as immunomodulators for cancer treatment in the arena of cancer immunotherapies.

Public Health Relevance

Non-steroidal anti-inflammatory drugs (NSAIDs) such as sulindac can exert immunopotentiating effect by inhibiting the activities of cyclooxygenases (COX). However, long-term inhibition of COX can cause severe toxicities in some vital organs. This project will develop novel non-COX inhibitory sulindac derivatives and employ them as immunomodulators to augment the efficacy of cancer immunotherapies by targeting specific phosphodiesterase (PDE).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA238514-02
Application #
10113565
Study Section
Mechanisms of Cancer Therapeutics - 1 Study Section (MCT1)
Program Officer
Yovandich, Jason L
Project Start
2020-03-01
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Augusta University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912