Glioblastoma (GBM) is the most common primary malignant brain tumor. Currently, there are few effective treatment options for GBM beyond surgery and chemo-radiation, and even with these interventions, median patient survival remains poor. While immune checkpoint inhibitors (ICIs) have demonstrated therapeutic efficacy against non-central nervous system cancers, ICI trials for GBM have typically had poor outcomes. TIGIT is an immune checkpoint receptor that is expressed on activated T-cells and has a role in the suppression of T-cell and Natural Killer (NK) cell function. As TIGIT expression is reported as both prognostic and a biomarker for anti-TIGIT therapy, we constructed a molecular imaging agent, [89Zr]Zr-DFO-anti-TIGIT (89Zr-αTIGIT), to visualize TIGIT in preclinical GBM by immunoPET imaging. PET imaging and biodistribution analysis of 89Zr-αTIGIT demonstrated uptake in the tumor microenvironment of GBM-bearing mice. Blocking antibody and irrelevant antibody tracer studies demonstrated specificity of 89Zr-αTIGIT with significance at a late time point post-tracer injection. However, the magnitude of 89Zr-αTIGIT uptake in tumor, relative to the IgG tracer was minimal. These findings highlight the features and limitations of using 89Zr-αTIGIT to visualize TIGIT in the GBM microenvironment.

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-10 PROSTATE-SPECIFIC DELETION OF Cdh1 IN MICE MIMICS PROSTATIC PERFUSION OF BENIGN PROSTATIC HYPERPLASIA (BPH) PATIENTS Pradeep Tyagi, Laura Pascal, Lesley Foley, Robin Frederick, T. Kevin Hitchens, Anthony Kanai, Naoki Yoshimura, and Zhou Wang Pradeep TyagiPradeep Tyagi More articles by this author , Laura PascalLaura Pascal More articles by this author , Lesley FoleyLesley Foley More articles by this author , Robin FrederickRobin Frederick More articles by this author , T. Kevin HitchensT. Kevin Hitchens More articles by this author , Anthony KanaiAnthony Kanai More articles by this author , Naoki YoshimuraNaoki Yoshimura More articles by this author , and Zhou WangZhou Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although BPH is an age-related comorbidity of cardiovascular disease and hypertension, the investigation into the direction of the relationship will require animal models. Recently, the downregulation of E-cadherin in hyperplastic nodules of BPH patients was mechanistically linked to the prostatic inflammation and vascular defects by the recapitulation of BPH phenotype following deletion of E-cadherin gene (Cdh1-/- ) in prostatic epithelium of adult mouse (Endocrinology 2021; 162(1) : bqaa212). Since the injected T1 shortening agent, Gadobutrol only resides in vascular and extracellular space, we enquired the effect of Cdh1-/-on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). METHODS: Tamoxifen injection at 7 weeks of age generated PSA-CreERT2/Cdh1-/- mice and then anaesthetized 21-23 weeks old Cdh1-/- and wild type controls (n=3) were injected Gadobutrol 0.1mm/kg for T1 weighted DCE-MRI of prostate in 9 axial slices with number of excitations (NEX)=1 and temporal resolution of 12s in voxel size of 0.156x0.156x0.8mm3 at small animal 7T scanner followed by Masson’s trichome staining. RESULTS: Although ventral lobes of Cdh1-/- mice were similar in size to age matched controls, the kinetic modelling of DCE-MRI (repetition TR/echo time TE - 200/5.23ms) determined that clearance of Gadobutrol was four fold slower from ventral lobe of Cdh1-/- mice with efflux rate constant Kep of 0.17±1.48 min-1 vs 0.88±0.08 min-1 in controls. The prostate permeability metric, Kep of Cdh1-/- mice is determined by the widened and elongated venules (# telangiectasia) and the higher density of collagen (blue stain) in ventro/lateral lobes on Masson's trichrome staining, which retains the Gadobutrol even 30min after injection to increase T1 contrast more than adjacent dorsal lobes and ventral lobe of control mice in high resolution post-contrast images (TR/TE 2000/20ms; NEX=4). CONCLUSIONS: The link between the vascular defects and expanded extracellular space of prostate in Cdh1-/- mice with the slower clearance of Gadobutrol implicates a bidirectional relationship between prostatic inflammation and prostatic vasculature defects that are characteristic of BPH. Findings suggest that E-cadherin downregulation could be a driving force in human BPH development and progression. Source of Funding: UPMC Hillman Pilot Funding; DK112079; CA211242 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e201-e202 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pradeep Tyagi More articles by this author Laura Pascal More articles by this author Lesley Foley More articles by this author Robin Frederick More articles by this author T. Kevin Hitchens More articles by this author Anthony Kanai More articles by this author Naoki Yoshimura More articles by this author Zhou Wang More articles by this author Expand All Advertisement PDF downloadLoading ...

Abundant intraperitoneal (IP) accumulation of extracellular mucus in patients with appendiceal mucinous carcinoma peritonei (MCP) causes compressive organ dysfunction and prevents delivery of chemotherapeutic drugs to cancer cells. We hypothesized that reducing extracellular mucus would decrease tumor-related symptoms and improve chemotherapeutic effect in patient-derived models of MCP. Mucolysis was achieved using a combination of bromelain (BRO) and N-acetylcysteine (NAC). Ex vivo experiments of mucolysis and chemotherapeutic drug delivery/effect were conducted with MCP and non-MCP tissue explants. In vivo experiments were performed in mouse and rat patient-derived xenograft (PDX) models of early and late (advanced) MCP. MCP tumor explants were less chemosensitive than non-MCP explants. Chronic IP administration of BRO + NAC in a mouse PDX model of early MCP and a rat PDX model of late (advanced) MCP converted solid mucinous tumors into mucinous ascites (mucolysis) that could be drained via a percutaneous catheter (rat model only), significantly reduced solid mucinous tumor growth and improved the efficacy of chemotherapeutic drugs. Combination of BRO + NAC efficiently lyses extracellular mucus in clinically relevant models of MCP. Conversion of solid mucinous tumors into mucinous ascites decreases tumor bulk and allows for minimally invasive drainage of liquified tumors. Lysis of extracellular mucus removes the protective mucinous coating surrounding cancer cells and improves chemotherapeutic drug delivery/efficacy in cancer cells. Our data provide a preclinical rationale for the clinical evaluation of BRO + NAC as a therapeutic strategy for MCP.