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Principal Investigator: Gary A Piazza
Organization: AUGUSTA UNIVERSITY
Fiscal Year: 2024
Award: $410,108
Funding agency: National Cancer Institute
Project summary/abstract
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 β-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.
Terms: <Adverse effects><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Arachidonic Acid Cyclooxygenase><Beta Cadherin-Associated Protein><Beta-1 Catenin><Binding><Biological><CAR T cell therapy><CAR T therapy><CD19><CD19 gene><COX inhibitor><COX-1><COX-1 protein><COX-2 protein><COX2 enzyme><COX2 inhibitor><CUL-2><Cancer Drug><Cancer Induction><Cancer Treatment><Cancers><Cell Communication and Signaling><Cell Signaling><Cellular Expansion><Cellular Growth><Chemicals><Chemopreventive><Chemopreventive Agent><Cialis><Colon Neoplasms><Colon Tumor><Colonic Mass><Colonic Neoplasms><Colonic Tumor><Colorectal Cancer><Complex><Coxibs><Cyclic GMP><Cyclo-Oxygenase><Cyclo-Oxygenase Inhibitors><Cyclo-Oxygenase-1><Cyclo-Oxygenase-2><Cyclooxygenase><Cyclooxygenase 2 Inhibitors><Cyclooxygenase 3><Cyclooxygenase Inhibitors><Data><Dendritic Cells><Development><Disease><Disorder><Drug Therapy><ER stress><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Fatty Acid Cyclo-Oxygenase><Fatty Acid Cyclooxygenase><Fever><Gene Transcription><Generalized Growth><Genetic Transcription><Growth><Guanosine Cyclic Monophosphate><Human><Hydroperoxide Cyclase><Ibuprofen><Immune><Immune Cell Activation><Immune Surveillance><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunomodulation><Immunomodulators><Immunopotentiation Effect><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunosurveillance><In Vitro><Incidence><Individual><Indocin><Indometacin><Indomethacin><Induction of Apoptosis><Inflammation><Intracellular Communication and Signaling><Isoenzymes><Isozymes><Knowledge><Laboratories><Lead><Lymphoma cell><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Molecular Interaction><Motrin><Murine><Mus><NSAIDs><Neoplastic Disease Chemotherapeutic Agents><Non-Steroidal Anti-Inflammatory Agents><Oncogenesis><Oncogenic><Oral Administration><Oral Drug Administration><Organ><PD-1 blockade><PD1 blockade><PGH Synthase><PGH Synthase 1><PGH Synthase 2><PGH2 Synthetase><PGHS2><PHS II><PRO2286><Pb element><Pharmacotherapy><Phosphodiesterases><Pre-Clinical Model><Preclinical Models><Property><Prostaglandin Cyclo-Oxygenase><Prostaglandin Cyclooxygenase><Prostaglandin Endoperoxide Synthase Inhibitors><Prostaglandin Endoperoxide Synthetase><Prostaglandin G-H Synthase><Prostaglandin G/H Synthase 1><Prostaglandin G/H Synthase 2><Prostaglandin H Synthase><Prostaglandin H2 Synthase><Prostaglandin H2 Synthase 1><Prostaglandin H2 Synthase 2><Prostaglandin H2 Synthetase><Prostaglandin Synthase><Prostaglandin Synthase Inhibitors><Prostaglandin Synthesis Antagonists><Prostaglandin Synthetase><Prostaglandin-Endoperoxide Synthase><Prostaglandin-Endoperoxide Synthase 1><Prostaglandin-Endoperoxide Synthase 2><Prostaglandins><Prostanoids><Pyrexia><RNA Expression><Regulatory T-Lymphocyte><Reporting><Research><Rodent Model><Series><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Sulfone Anti-Infective Agent><Sulfones><Sulindac><Synthesis Chemistry><Synthetic Chemistry><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Testing><Tissue Growth><Toxic effect><Toxicities><Transcription><Treg><Tumor Cell><Tumor Immunity><Tumor-Specific Treatment Agents><Veiled Cells><adoptive T cell transfer><adoptive T-cell therapy><anti-PD-1 blockade><anti-PD1 blockade><anti-cancer drug><anti-cancer immunotherapy><anti-cancer therapy><anti-carcinogenic><anti-tumor immune response><anti-tumor immunity><anticancer activity><anticancer immunotherapy><anticarcinogenic><antitumor immunity><beta catenin><biologic><biological signal transduction><cGMP><cancer cell><cancer chemoprevention><cancer immunity><cancer immunotherapy><cancer infiltrating T cells><cancer microenvironment><cancer therapy><cancer-directed therapy><carcinogenesis><celebrex><celecoxib><cell growth><chemical synthesis><chemoprevention agent><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor T cell therapy><chimeric antigen receptor T therapy><colon neoplasia><cyclo-oxygenase I><cyclo-oxygenase II><cyclooxygenase 1><cyclooxygenase 2><design><designing><developmental><drug candidate><drug development><drug treatment><effectiveness testing><endoplasmic reticulum stress><engineered T cells><epidemiologic investigation><epidemiology study><febrile><febris><genetically engineered T-cells><heavy metal Pb><heavy metal lead><immune activation><immune modulation><immune modulators><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune-based cancer therapies><immunogenic><immunogenic apoptosis><immunogenic cell death><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><inhibitor><intraoral drug delivery><knock-down><knockdown><malignancy><migration><mouse model><murine model><neoplasm/cancer><neoplastic cell><non-steroidal anti-inflammatory drugs><novel><ontogeny><overexpress><overexpression><pain relief><phosphoric diester hydrolase><progenitor cell function><progenitor function><programs><prostaglandin H synthase-1><prostaglandin H synthase-2><prototype><regulatory T-cells><relieve pain><screening><screenings><siRNA><stem and progenitor cell function><stem and progenitor function><stem cell function><therapeutic T-cell platform><thymus derived lymphocyte><transgenic T- cells><tumor><tumor infiltrating T cells><tumor microenvironment><tumorigenesis><β-catenin>