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Principal Investigator: Dan Theodorescu
Organization: CEDARS-SINAI MEDICAL CENTER
Fiscal Year: 2024
Award: $392,659
Funding agency: National Cancer Institute
PROJECT SUMMARY
Even with immune checkpoint blockade therapy (ICBT), most patients with metastatic bladder cancer (BC) die
of their disease. In the previous funding period, we studied CD24, a metastasis driver and prognostic marker.
Our most translationally significant finding is induction of CD24 expression by Discoidin Domain Receptor
Tyrosine Kinase 2 (DDR2), a collagen-activated receptor that is therapeutically actionable. In human BC, DDR2
expression was associated with poor patient prognosis, the aggressive and ICBT insensitive basal squamous
tumor subtype (BSS), TGFβ signaling, immunosuppressive (M2) macrophages (Mφ) and a fibroblast-enriched,
tumor microenvironment. These results raised the intriguing possibility that DDR2 is a lynchpin driver of both
metastasis and ICBT resistance. To explore this possibility, we developed an shRNA based functional screen in
syngeneic murine BC models to probe DDR2 and other selected “druggable” targets evaluated in BC clinical
trials for their synergism with αPD-1, a common ICBT in BC. We found the most robust tumor reduction with
depletion of DDR2 and this was recapitulated with the Tyr kinase inhibitor, dasatinib. This result was compelling
because it defined a novel synergistic combination therapy with αPD-1 that, unlike CD24 targeting, is actionable
in the near term in patients. To begin elucidating the mechanisms DDR2 may use to drive tumor metastasis and
ICBT resistance, we profiled DDR2-silenced murine BC tumors with RNA-seq. We identified 69 genes
downregulated >2 fold by DDR2 depletion and used these to construct a DDR2 Effector Signature (DES). Low
tumor DES scores of surgically or αPD-L1 treated patients associated with better outcome, supporting a role for
DES genes in progression and αPD-L1 response. Remarkably, MMP10 or S100A2 expression each alone
stratified outcome nearly as well as the DES score in surgery and αPD-L1 treatment and they were implicated
in Mφ, TGFβ and fibroblast biology. These findings and the lack of genes associated with T-cell exhaustion in
DES, lead us to propose our innovative Guiding Hypothesis that cancer cell DDR2 establishes the BSS and
uses MMP10 and S100A2 to engage M2 Mφ and cancer-associated fibroblasts (CAFs) to promote metastasis
and αPD-(L)1 resistance. Specific Aims test this hypothesis with the Objective to develop new effective
treatments for metastatic BC. Aim 1 will use full and conditional DDR2-null mice exposed to chemical
carcinogens to test the hypothesis that DDR2 expression in basal urothelial cells is necessary for BSS tumor
development and progression. Aim 2 will treat murine tumors with alterations in DDR2, MMP10 and S100A2
expression grown in genetically engineered mice with fibroblast and Mφ defects, with αPD-1, to test the
hypothesis that cancer cell DDR2 drives MMP10 and S100A2 and via their actions in Mφ and fibroblasts
contribute to metastasis and αPD-1 resistance. Since even with DDR2+PD-1 blockade, not all tumors are cured,
Aim 3 will test the hypothesis that inhibition DPP4, a peptidase and Coronavirus receptor we discovered as a
potential driver of resistance to DDR2+PD-1 blockade, can improve effectiveness of such therapy.
Terms: <Adenosine Deaminase-Binding Proteins><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Animal Model><Animal Models and Related Studies><Animals><Biological Markers><Biology><Bladder Cancer><Bone-Derived Transforming Growth Factor><CD143 Antigens><CD26><CD26 Antigens><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Model><Cancer Patient><CancerModel><Cancers><Candidate Disease Gene><Candidate Gene><Carboxycathepsin><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical><Collagen><Combined Modality Therapy><DDR2 Protein><DDR2 kinase><Dasatinib><Data><Defect><Development><Dipeptidyl Peptidase A><Dipeptidyl-Peptidase IV><Discoidin Domain Receptor Family Member 2><Disease><Disorder><Drug Combinations><Drugs><Effectiveness><Esteroproteases><Evaluation><Exposure to><Fibroblasts><Fibrosis><Funding><Future><GEM model><GEMM model><Gene Alteration><Gene Expression><Gene Mutation><Gene Transcription><Genes><Genetic Transcription><Genetically Engineered Mouse><Human><Implant><Intracellular Communication and Signaling><KO mice><Kinases><Kinetics><Kininase A><Kininase II><Knock-out Mice><Knockout Mice><Knowledge><MMP-10><Macrophage><Malignant Bladder Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Bladder><Malignant neoplasm of urinary bladder><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Milk Growth Factor><Modern Man><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mφ><Neoplasm Metastasis><Null Mouse><Operative Procedures><Operative Surgical Procedures><Outcome><PD 1><PD-1><PD-1 blockade><PD-L1 therapy><PD-L1 treatment><PD1><PD1 blockade><PDL1 therapy><PDL1 treatment><PTK Receptors><Patients><Peptidases><Peptide Hydrolases><Peptidyl-Dipeptidase A><Persons><Pharmaceutical Preparations><Phosphotransferase Gene><Phosphotransferases><Platelet Transforming Growth Factor><Prognostic Marker><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Proteomics><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Receptor Protein-Tyrosine Kinase TKT><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Receptor-Related 3 Neurotrophic Tyrosine Kinase><Recurrence><Recurrent><Resistance><Role><S100 Calcium Binding Protein A2><S100A2><S100A2 gene><S100L><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Surgical><Surgical Interventions><Surgical Procedure><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Technology><Testing><Therapeutic><Transcription><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transmembrane Receptor Protein Tyrosine Kinase><Transphosphorylases><Tumor Cell><Tumor Subtype><Tumor-infiltrating immune cells><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptor Related to Neurotrophic TRK><Tyrosine Kinase Receptors><Tyrosine-Protein Kinase TYRO 10><Urinary Bladder Cancer><Urinary Bladder Malignant Tumor><Urothelial Cell><Urothelium><aPD-1><aPD-L1><aPD-L1 therapy><aPD-L1 treatment><aPD1><aPDL1><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-PD-(L)1><anti-PD-1><anti-PD-1 blockade><anti-PD-L1><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PD1><anti-PD1 blockade><anti-PDL-1><anti-PDL1><anti-PDL1 therapy><anti-PDL1 treatment><anti-programmed cell death protein 1><antiPD-1><antiPD-L1><antiPD1><antiPDL1><bio-markers><biologic marker><biological signal transduction><biomarker><cancer cell><cancer cell subtype><cancer clinical trial><cancer metastasis><cancer microenvironment><cancer progression><candidate identification><cell engineering><cell type><cellular engineering><check point blockade><checkpoint blockade><chemical carcinogen><combination therapy><combined modality treatment><combined treatment><coronavirus receptor><developmental><discoidin domain receptor><discoidin domain receptor 2><discoidin receptor><drug/agent><druggable target><effective therapy><effective treatment><exhaustion><functional genomics><gene signatures><genetic signature><genetically engineered mouse model><genetically engineered murine model><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point blockade><immune checkpoint blockade><improved><infiltration of tumors by immune cells><inhibitor><innovate><innovation><innovative><intratumoral immune cell><intratumoral immune infiltrate><kinase inhibitor><malignancy><matrix metalloproteinase 10><model of animal><mosaic analysis><multi-modal therapy><multi-modal treatment><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new approaches><new technology><novel><novel approaches><novel strategies><novel strategy><novel technologies><oncology clinical trial><patient prognosis><prognostic biomarker><programmed cell death 1><programmed cell death protein 1><programmed death 1><receptor><recombinase-mediated cassette exchange><recombination-mediated cassette exchange><resistant><response><shRNA><short hairpin RNA><sle2><small hairpin RNA><social role><stromelysin 2><surgery><surgery outcome><surgical outcome><synergism><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><transin 2><tumor><tumor cell metastasis><tumor growth><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><tumor microenvironment><tumor progression><tyrosine kinase receptor type 10><αPD-1><αPD-L1><αPD-L1 therapy><αPD-L1 treatment><αPD1><αPDL1>