Combination of FasL Gene Therapy and Acid Ceramidase Inhibitors: A Novel Therapeutic Approach for the Treatment of Head and Neck Cancer

Despite significant advances in the diagnosis and treatment of head and neck cancer, the survival rate of patients has not changed significantly during the last decade suggesting that novel therapeutic approaches are worth investigation. In this project, we investigate the use of FasL gene therapy in combination with acid ceramidase (AC) inhibitors as a new promising modality for the treatment of head and neck cancer. We first demonstrate the in vitro and in vivo efficacy of FasL gene therapy for the treatment of head and neck squamous cell carcinoma (HNSCC). Next, we show that the ceramide metabolizing enzyme AC is over-expressed in 70% of head and neck squamous cell tumors and that AC over-expression increases resistance to Fas-induced cell killing. Conversely, AC inhibition using specific AC siRNA sensitizes the head and neck cancer cell line SCC-1 to Fas-induced apoptosis. We also introduce a new family of lysosomotropic acid ceramidase inhibitors (LCL 204 and its analogues) developed at the lipidomics core at the Medical University of South Carolina. We demonstrate that these small molecule inhibitors lead to acid ceramidase inhibition in cancer cell lines in vitro and in head and neck tumor tissues in nude mice experiments. Importantly, the lysosomotropic acid ceramidase dosage used to inhibit acid ceramidase is also shown to be non-toxic in vivo as confirmed by their minimal effects_ on bone marrow, liver and kidney functions. Finally, pretreatment with LCL 204 significantly enhances FasL gene therapy effect on HNSCC cell lines as confirmed by in-vitro cytotoxicity, apoptotic assays, and in vivo xenographs tumor growth and survival. In summary, this work demonstrates critical roles for acid ceramidase in head and neck cancer therapy and that combination of lysosomotropic acid ceramidase inhibitors with FasL gene therapy may become a new treatment option for advanced stage head and neck cancer worthy of a clinical trial

Pictorial Review of Congenital Anomalies of the Gallbladder and Biliary Ducts: Findings on Hepatobiliary Iminodiacetic Acid Scan

Learning Objectives: To become familiar with the imaging appearance on Hepatobiliary Iminodiaceetic Acid (HIDA) scan of congenital gallbladder and biliary duct anomalies, and to understand the diagnostic utility of functional imaging with HIDA when evaluating biliary tract anomalies

Pictorial Review of Congenital Anomalies of the Gallbladder and Biliary Ducts: Findings on Hepatobiliary Iminodiacetic Acid Scan

Poster presented at SNMMI 2016 Annual Meeting June 11 – June 15, 2016, San Diego, CALearning Objectives: To become familiar with the imaging appearance on Hepatobiliary Iminodiaceetic Acid (HIDA) scan of congenital gallbladder and biliary duct anomalies, and to understand the diagnostic utility of functional imaging with HIDA when evaluating biliary tract anomalies

Calciphylaxis on bone scan: correlation between molecular and cross-sectional findings

Calciphylaxis is a rare devastating medical condition commonly associated with end-stage renal disease and characterized by extensive microvascular calcifications. We describe a case of calciphylaxis presenting on Tc-99m MDP bone scan imaging with asymmetric radiotracer uptake within the lower extremities corresponding to extensive soft tissue calcifications on Computed tomography. Familiarity with the classic clinical presentation and imaging features of this rare entity may help its early identification and treatment

Acid Ceramidase but Not Acid Sphingomyelinase Is Required for Tumor Necrosis Factor-α-induced PGE2 Production

Sphingolipids are well established effectors of signal transduction downstream of the tumor necrosis factor (TNF) receptor. In a previous study, we showed that the sphingosine kinase/sphingosine 1-phosphate (S1P) pathway couples TNF receptor to induction of the cyclooxygenase 2 gene and prostaglandin synthesis (Pettus, B. J., Bielawski, J., Porcelli, A. M., Reames, D. L., Johnson, K. R., Morrow, J., Chalfant, C. E., Obeid, L. M., and Hannun, Y. A. (2003) FASEB J. 17, 1411-1421). In this study, the requirement for acid sphingomyelinase and sphingomyelin metabolites in the TNFα/prostaglandin E2 (PGE2) pathway was investigated. The amphiphilic compound desipramine, a frequently employed inhibitor of acid sphingomyelinase (ASMase), blocked PGE2 production. However, the action of desipramine was independent of its action on ASMase, since neither genetic loss of ASMase (Niemann-Pick fibroblasts) nor knockdown of ASMase using RNA interference affected TNFα-induced PGE2 synthesis. Further investigations revealed that desipramine down-regulated acid ceramidase (AC), but not sphingosine kinase, at the protein level. This resulted in a time-dependent drop in sphingosine and S1P levels. Moreover, exogenous administration of either sphingosine or S1P rescued PGE2 biosynthesis after desipramine treatment. Interestingly, knockdown of endogenous AC by RNA interference attenuated cyclooxygenase 2 induction by TNFα and subsequent PGE2 biosynthesis. Taken together, these results define a novel role for AC in the TNFα/PGE2 pathway. In addition, the results of this study warrant careful reconsideration of desipramine as a specific inhibitor for ASMase

New insights on the use of desipramine as an inhibitor for acid ceramidase

Treatment of different cancer cell lines with desipramine induced a time- and dose-dependent downregulation of acid ceramidase. Desipramine’s effect on acid ceramidase appeared specific for amphiphilic agents (desipramine, chlorpromazine, and chloroquine) but not other lysomotropic agents such as ammonium chloride and bafilomycin A1, and was not transcriptionally regulated. The cathepsin B/L inhibitor, CA074ME, but not the cathepsin D inhibitor, pepstatin A, blocked desipramine’s effect on acid ceramidase. Desipramine led to a more pronounced downregulation of sphingosine compared to ceramide suggesting acid ceramidase inhibition is important to desipramine’s mechanism of action. This study reveals a new mechanism of action for desipramine

European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma

PurposeDiverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results.MethodsGuidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals.ConclusionSince the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (Ga-68)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (I-123)/iodine-131 (I-131)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance