Acid ceramidase (AC) has been implicated as a novel target for cancer therapy because of its pivotal role in regulating interconversion of three key bioactive lipids; ceramide (Cer), sphingosine (Sph) and Sphingosine-1-Phosphate (S1P). It is well known that Cer functions predominantly as a tumor suppressor lipid and mediator of apoptosis following chemo and radio therapy. On the other hand, S1P is a tumor promoting lipid that counteracts the actions of Cer. Importantly, our recent studies identified AC as a negative prognostic factor in cancer therapy, since AC over-expression induces a more aggressive cancer phenotype which causes drug or radiation resistance. Reversal of AC expression utilizing siRNA or small molecule AC inhibitors clearly demonstrated a reduction in the aggressive cancer phenotype and improved chemo, gene or radiation therapy outcomes in vitro and in vivo. Up-regulated AC expression has been observed in 60-70% of cancers examined including in breast, lung, prostate, melanoma, colon, brain, and oral cancers. New cases per year totaling more than 700,000 patients are projected from these data based on ACS 2004 statistics. Thus, because of the potential for a direct benefit of improved clinical outcomes, the development of small molecule AC inhibitors by SphingoGene, Inc. is a commercially feasible proposition. Therefore, the goal of this phase I STTR application is to develop and validate targeted AC inhibitors. To achieve this goal the following specific aims will be carried out. Aim 1: Rationally design and synthesize N-alkylamino-prodrugs (Class E) that inhibit AC enzyme activity. Aim 2: Determine activity of Class E compounds in vitro and at the cellular level. Aim 3: Determine in vivo toxicity, pharmacokinetics/pharmacodynamics and AC inhibitory activity of lead Class E1 and E2-5 AC inhibitors. This research is a partnership between basic scientists at MUSC and SphingoGene, Inc. Drugs developed in this program will have a direct clinical application in cancer therapy.
Public Health Relevance: The data generated by this grant may lead to a direct clinical application. This grant proposes to develop a new class of acid ceramidase inhibitors. These inhibitors function by modifying sphingolipid metabolism and facilitating the effect of chemo, radiation or gene therapy in killing cancer cells.
Public Health Relevance Statement: The data generated by this grant may lead to a direct clinical application. This grant proposes to develop a new class of acid ceramidase inhibitors. These inhibitors function by modifying sphingolipid metabolism and facilitating the effect of chemo, radiation or gene therapy in killing cancer cells.
Project Terms: 4-Octadecene-1,3-diol, 2-amino-, (R-(R*,S*-(E)))-; 4-Sphingenine; APP Secretase; Acid Ceramidase; Amides; Amyloid Precursor Protein Secretase; Apoptosis; Apoptosis Pathway; Body Tissues; Brain; Breast; Cancer Biology; Cancer Model; Cancer Radiotherapy; Cancer Treatment; CancerModel; Cancers; Cathepsin B1; Cathepsins B; Cell Death, Programmed; Cells; Ceramide (lipids); Ceramide Trihexosidase; Ceramides; Clinical; Colon; D-Galactosyl-D-galactosyl-D-glucosyl-N-acylsphingosine galactohydrolase; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Development; Drug Kinetics; Drug Precursors; Drugs; Dysfunction; EC 3.4.22.1; Elements; Encephalon; Encephalons; Enzymes; Evaluation; Family; Functional disorder; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; General Prognostic Factor; Genes; Genetic Intervention; Genital System, Male, Prostate; Goals; Grant; Hand; Human; Human Prostate; Human Prostate Gland; Human, General; Hydrochloride; Hydrochloride Salt; Hydrolysis; In Vitro; Intermediary Metabolism; Intervention, Genetic; Killings; Lead; Lipids; Lung; Lysosomes; METBL; Malignant Cell; Malignant Melanoma; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Oral Cavity Neoplasm; Malignant Oral Cavity Tumor; Malignant Oral Neoplasm; Malignant Tumor; Malignant Tumor of the Mouth; Malignant neoplasm of mouth; Man (Taxonomy); Man, Modern; Medication; Membrane Potentials; Metabolic Processes; Metabolism; Molecular Biology, Gene Therapy; Mouth Cancer; Nervous System, Brain; Oral Cancer; Outcome; Parents; Patients; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Phase; Phenotype; Physiopathology; Preparation; Pro-Drugs; Prodrugs; Prognostic Factor; Prognostic/Survival Factor; Programs (PT); Programs [Publication Type]; Prostate; Prostate Gland; Prostatic Gland; RNA, Small Interfering; Radiation; Radiation therapy; Radio; Radiotherapeutics; Radiotherapy; Research; Respiratory System, Lung; Resting Potentials; Role; STTR; Science of Statistics; Scientist; Site; Small Business Technology Transfer Research; Small Interfering RNA; Specificity; Sphingolipids; Sphingomyelins; Sphingosine; Statistics; Structure; Therapeutic; Therapeutic Effect; Therapy, DNA; Tissues; Toxic effect; Toxicities; Transmembrane Potentials; Tumor Suppressor Proteins; Validation; Xenograft Model; acid sphingomyelinase; analog; anticancer therapy; base; cancer cell; cancer therapy; clinical applicability; clinical application; clinical data repository; clinical data warehouse; data repository; design; designing; drug/agent; enzyme activity; galactosylgalactosylglucosylceramidase; gene therapy; gene-radiation therapy; genetic therapy; heavy metal Pb; heavy metal lead; improved; in vitro Assay; in vivo; inhibitor; inhibitor/antagonist; irradiation; lipid mediator; malignancy; melanoma; neoplasm/cancer; novel; pathophysiology; programs; public health relevance; pulmonary; radiation resistance; ray (radiation); relational database; siRNA; small molecule; social role; sphingosine 1-phosphate; tumor; tumor suppressor
