Wednesday, April 17, 2024
4/17/2024
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), TGFß signaling, immunosuppressive (M2) macrophages (Mf) 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 aPD-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 aPD-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 aPD-L1 treated patients associated with better outcome, supporting a role for DES genes in progression and aPD-L1 response. Remarkably, MMP10 or S100A2 expression each alone stratified outcome nearly as well as the DES score in surgery and aPD-L1 treatment and they were implicated in Mf, TGFß 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 Mf and cancer-associated fibroblasts (CAFs) to promote metastasis and aPD-(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 Mf defects, with aPD-1, to test the hypothesis that cancer cell DDR2 drives MMP10 and S100A2 and via their actions in Mf and fibroblasts contribute to metastasis and aPD-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.
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