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Principal Investigator: Yaguang Xi
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2024
Award: $533,414
Funding agency: National Cancer Institute
Project Summary:
The overall survival of colorectal cancer (CRC) patients has improved significantly over the past few decades,
but the 5-year survival rate for patients with stage IV CRC remains below 14%. Therefore, there is an urgent
need to develop more effective and safer treatments against CRC. New immune checkpoint inhibitor (ICI)
therapies have ushered in a new era of immunotherapy and emerged as important treatment options for a variety
of solid tumors. However, ICIs are only effective in CRC patients with deficient mismatch repair (dMMR) and
microsatellite instability-high (MSI-H). For the approximately 85% of CRC patients who carry proficient mismatch
repair (pMMR) and microsatellite stable (MSS) or instability-low (MSI-L) CRCs, ICIs show little clinical benefit. In
a preliminary study, we examined the efficacy of low-dose sulindac in enhancing the response of pMMR/MSS
CRC to anti-PD-L1 immunotherapy. Utilizing a syngeneic mouse tumor model and a humanized patient-derived
xenograft (PDX) mouse model, we compared the inhibitory effects of PD-L1 antibodies (Abs), sulindac at low
doses, and their combination on pMMR/MSS CRC. Our results demonstrated that the mice treated with the
combination therapy showed a significant reduction in tumor volume, along with an increase of CD8+ tumor-
infiltrating lymphocytes (TILs) in tumor tissues. While studying the mechanism of action, we found that sulindac
could transcriptionally inhibit PD-L1 expression and ultimately reduce the release of exosomal PD-L1 into the
circulation. As exosomal PD-L1 normally binds to and depletes circulating PD-L1 Abs, the combination of
sulindac and the PD-L1 Ab can potentially enhance antibody recruitment. Therefore, we hypothesize that low-
dose sulindac can sensitize CRC to anti-PD-L1 therapy. In this application, we propose three specific aims to
systematically and rigorously investigate this new activity of sulindac. In Aim 1, we will study the mechanisms by
which sulindac sensitizes CRC to anti-PD-L1 therapy, specifically how sulindac regulates PD-L1 expression; in
Aim 2, we will use innovative and robust humanized PDX models to study the in vivo efficacy of low-dose sulindac
in enhancing anti-PD-L1 therapy. Both MSS and MSI CRC models will be tested. In Aim 3, we will investigate
whether the combination of sulindac and anti-PD-L1 therapy can block the metastatic progression of CRC. Since
sulindac and PD-L1 antibodies are FDA-approved drugs and their safety and toxicity profiles have been well-
documented, we hope that the success of our study will rapidly facilitate Phase II clinical trials to investigate the
utility of sulindac-enhanced anti-PD-L1 therapy in CRC and address the important clinical challenge of poor
response to ICI therapy in the majority of CRC patients.
Terms: <Address><Affect><Animal Model><Animal Models and Related Studies><Antibodies><B7-H1><B7H1><Basal Transcription Factor><Basal transcription factor genes><Binding><Biological Markers><Body Weight decreased><CD274><CD8><CD8B><CD8B1><CD8B1 gene><CT-26><CT26><Cancer Model><CancerModel><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Checkpoint inhibitor><Chemopreventive><Chemopreventive Agent><Chromosomal Instability><Chromosome Instability><Circulation><Clinic><Clinical><Clinical Research><Clinical Study><Colorectal Cancer><Combined Modality Therapy><DNA><DNA Damage Repair><DNA Repair><DNA Sequence><Data><Deoxyribonucleic Acid><Development><Dose><Drugs><FDA approved><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Growth><Human><Immune checkpoint inhibitor><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Intracellular Communication and Signaling><Keytruda><LYT3><MC-38><MC38><MMR deficiency><Malignant><Malignant - descriptor><Medication><Metabolic Glycosylation><Mice><Mice Mammals><Micro RNA><MicroRNAs><Microsatellite Instability><Microsatellite Markers><Microsatellite Repeats><Microsatellites><Mismatch Repair><Mismatch Repair Deficiency><Modeling><Modern Man><Molecular><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><NSAIDs><Nivolumab><Non-Steroidal Anti-Inflammatory Agents><Opdivo><PBMC><PD-L1><PD-L1 antibody><PD-L1 therapy><PD-L1 treatment><PDL-1><PDL1><PDL1 antibody><PDL1 therapy><PDL1 treatment><PDX model><Patient derived xenograft><Patients><Peripheral Blood Mononuclear Cell><Pharmaceutical Preparations><Phase 2 Clinical Trials><Phase II Clinical Trials><Post-Replication Mismatch Repair><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Publications><RNA Expression><Reporting><Research><Safety><Scientific Publication><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Sulindac><Survival Rate><Tandem Repeat Sequences><Tandem Repeats><Testing><Therapeutic><Tissue Growth><Toxic effect><Toxicities><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Tumor Tissue><Tumor Volume><Tumor-Infiltrating Lymphocytes><United States><Unscheduled DNA Synthesis><Weight Loss><Weight Reduction><Woman><Yervoy><aCTLA-4><aCTLA4><aPD-1><aPD-L1><aPD-L1 antibodies><aPD-L1 therapy><aPD-L1 treatment><aPD1><aPDL1><advanced disease><advanced illness><anti programmed cell death 1><anti programmed cell death ligand 1><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-CTLA-4><anti-CTLA4><anti-PD-(L)1><anti-PD-1><anti-PD-L1><anti-PD-L1 antibodies><anti-PD-L1 monoclonal antibodies><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PD1><anti-PDL-1><anti-PDL1><anti-PDL1 antibodies><anti-PDL1 therapy><anti-PDL1 treatment><anti-carcinogenic><anti-programmed cell death protein 1><antiPD-1><antiPD-L1><antiPD1><antiPDL1><anticarcinogenic><bio-markers><biologic marker><biological signal transduction><biomarker><body weight loss><cancer type><cell transformation><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemoprevention agent><clinical relevance><clinically relevant><colon cancer patients><colorectal cancer metastasis><colorectal cancer patients><colorectal cancer progression><colorectal cancer therapy><colorectal cancer treatment><combination therapy><combined modality treatment><combined treatment><determine efficacy><developmental><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><evaluate efficacy><examine efficacy><exosome><experiment><experimental research><experimental study><experiments><genome mutation><glycosylation><immune check point inhibitor><immune check point therapy><immune checkpoint therapy><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><implantation><improved><in vivo><innovate><innovation><innovative><interest><ipilimumab><male health><men's health><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><miRNA><miRNAs><model of animal><mouse model><multi-modal therapy><multi-modal treatment><murine model><non-steroidal anti-inflammatory drugs><ontogeny><patient derived xenograft model><pembrolizumab><phase II protocol><posttranscriptional><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><recruit><response><success><transcription factor><transformed cells><tumor><tumor xenograft><wt-loss><α-CTLA-4><α-CTLA4><αCTLA-4><αCTLA4><αPD-1><αPD-L1><αPD-L1 antibodies><αPD-L1 therapy><αPD-L1 treatment><αPD1><αPDL1>