Phase II year
2009
(last award dollars: 2010)
Pancreatic cancer is the fifth leading cause of cancer death in the US. Despite tremendous efforts aimed at understanding its molecular biology, conventional treatment has had little impact. Due to the highly metastatic nature of the disease, surgery is available to only 15- 20% of patients. Thus, the development and characterization of new therapeutic agents that can be used alone or together with conventional therapies is desperately needed. There are 4 classes of HDACs, and it is hypothesized that increased HDAC activity in cancer cells may contribute to the epigenetic silencing of tumor suppressor genes such as p16, p21 and gelsolin. In fact, treatment of pancreatic cancer cells with the broad spectrum classI/II HDAC inhibitor (HDACI), SAHA, leads to upregulation of p21, growth inhibition and induction of apoptosis. The team of Professor Kozikowski at UIC has recently generated novel classes of HDACIs, several of which show low pM activity toward HDAC6 and HDAC3 in vitro. Treatment of pancreatic cancer cells with these compounds results in a G1 and/or G2 arrest and induction of apoptosis. In addition, the data indicate that some of these novel HDACIs cause loss of the DNA damage checkpoint kinase, Chk1. It is hypothesized that they can sensitize pancreatic tumor cells to genotoxic agents. We believe that a combination of these HDACIs with DNA damage-inducing agents, such as gemcitabine, will provide significant therapeutic benefit compared to the conventional treatment, gemcitabine alone. To test this hypothesis, we propose to (1) re-synthesize the 12 most active HDACIs made at UIC, and to synthesize 10 new analogs and test them for isoform selectivity; (2) to define biological effects of HDACIs on pancreatic tumor cell proliferation and survival in vitro; and (3) to determine the in vivo efficacy of the 5 best HDACIs on established pancreatic tumor cell line xenografts with co-administration of gemcitabine. These studies will provide important information regarding the use of HDACIs in combination with therapeutic agents that cause DNA damage, and valuable structure-activity relationship (SAR) data relevant to the safety and efficacy of these compounds in the treatment of pancreatic cancer, while allowing to gauge the extent to which isoform selectivity is required in finding a ""safe"" therapy. The biological characterization of the HDACIs presented herein may also allow to better link specific isoforms to tumorigenic events. The two or three best HDACIs identified in this Phase I proposal will be the subject of a Phase II application to fund ADMET work aimed at advancing one of these compounds into clinical studies.
Public Health Relevance: Pancreatic cancer is the fifth leading cause of cancer death in the US and is poorly treatable by conventional chemotherapy, while surgery is available to only 15-20% of patients due to the highly metastatic nature of the disease. The present application aims at investigating the ability of a novel series of inhibitors of histone deacetylases (HDACs), which have been shown to inhibit pancreatic cancer cell growth in vitro and lead to apoptosis, to inhibit the growth of pancreatic tumor cell line xenografts in mice in combination with the conventional chemotherapeutic agent, gemcitabine. Positive results would lead to a Phase II application to fund ADMET work aimed at advancing one of these compounds into clinical studies.
Thesaurus Terms: 1-(2-Oxo-4-Amino-1,2-Dihydropyrimidin-1-Yl)-2-Deoxy-2,2-Difluororibose; 2',2'-Dfdc; 2',2'-Difluoro-2'-Deoxycytidine; 2',2'-Difluorodeoxycytidine; 2'-Deoxy-2'-Difluorocytidine; 2'deoxy-2',2'-Difluorocytidine; 2,2 Difluorodexoycytidine; 2-Cyclopentyl-5-(5-Isoquinolylsulfonyl)-6-Nitro-1h-Benzo(D)Imidazole; Akt; Abscission; Acetylation; Akt Protein; Anti-Oncogenes; Antioncogenes; Apoptosis; Apoptosis Pathway; Area; Biological; Cancer Cause; Cancer Cell Growth; Cancer Etiology; Cancer Treatment; Cancer Cell Line; Cancers; Cell Cycle; Cell Cycle Control; Cell Cycle Regulation; Cell Cycle Regulation, Including Apoptosis; Cell Death, Programmed; Cell Division Cycle; Cell Growth In Number; Cell Line, Tumor; Cell Multiplication; Cell Proliferation; Cell Survival; Cell Viability; Cellular Expansion; Cellular Growth; Cellular Proliferation; Cessation Of Life; Checkpoint Kinase 1; Chemicals; Client; Clinical Research; Clinical Study; Dna Damage; Dna Injury; Dna Molecular Biology; Dna Damage Checkpoint; Dna Damage Checkpoint Response; Dna Damage Response, Signal Transduction Resulting In Cell Cycle Arrest; Data; Death; Development; Difluorodeoxycytidine; Disease; Disorder; Egfr; Erbb Protein; Erbb1; Emerogenes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Euchromatin; Event; Excision; Extirpation; Funding; Gfac; Gelsolin; Gene Expression; Generalized Growth; Genes, Cancer Suppressor; Genes, Onco-Suppressor; Genes, P53; Genetic Alteration; Genetic Change; Genetic Defect; Genotoxins; Growth; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Hd3; Hdac; Hdac Agent; Hdac Proteins; Hdac3; Hdac3 Gene; Hdac6; Hdac6 Gene; Her1; Hsp-90; Hsp90; Heat-Shock Proteins 90; Heterograft; Histone Acetylase; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; In Vitro; Incidence; Induction Of Apoptosis; Isoenzymes; Isoforms; Isozymes; Jm21; Kiaa0901; Lead; Learning; Left; Link; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Pancreatic Neoplasm; Malignant Tumor; Malignant Neoplasm Of Pancreas; Mammals, Mice; Mice; Modification; Molecular Biology; Mortality; Mortality Vital Statistics; Murine; Mus; Mutagens; Mutation; Nature; Normal Cell; Oncogenes, Recessive; Oncogenes-Tumor Suppressors; Oncogenic; Operation; Operative Procedures; Operative Surgical Procedures; P53; Pkb Protein; Pancreas Cancer; Pancreas Neoplasms; Pancreatic Cancer; Pancreatic Tumor; Patients; Pb Element; Phase; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; Protein Acetylation; Protein Isoforms; Protein Kinase B; Protein Modification; Protein Modification, Post-Translational; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Proto-Oncogene Proteins C-Akt; Rac-Pk Protein; Rpd3; Rpd3-2; Receptor, Egf; Receptor, Tgf-Alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Removal; Saha; Safety; Series; Structure-Activity Relationship; Suberoylanilide Hydroxamic Acid; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; Tp53; Tp53 Gene; Trp53; Testing; Therapeutic; Therapeutic Agents; Tissue Growth; Transforming Growth Factor Alpha Receptor; Transplantation, Heterologous; Tumor Cell; Tumor Cell Line; Tumor Protein P53 Gene; Tumor Suppressing Genes; Tumor Suppressor Genes; Tumor Of The Pancreas; United States; Up-Regulation; Up-Regulation (Physiology); Upregulation; Vorinostat; Work; Xenograft; Xenograft Procedure; Xenotransplantation; Alternative Treatment; Analog; Angiogenesis; Anticancer Therapy; C-Akt Protein; C-Erbb-1; C-Erbb-1 Protein; Cancer Cell; Cancer Therapy; Cell Growth; Chemical Structure Function; Chemotherapeutic Agent; Chemotherapy; Chk1 Kinase; Chk1 Protein Kinase; Compound-1; Conventional Therapy; Dfdc; Dfdcyd; Disease/Disorder; Erbb-1; Erbb-1 Proto-Oncogene Protein; Erbbl; Experiment; Experimental Research; Experimental Study; Gemcitabine; Gene Product; Genome Mutation; Genotoxic Agent; Hd6; Heavy Metal Pb; Heavy Metal Lead; Histone Acetyltransferase; Hsp90 Family; Improved; In Vivo; Inhibitor; Inhibitor/Antagonist; Insight; Malignancy; Neoplasm/Cancer; Neoplastic Cell; New Therapeutics; Next Generation Therapeutics; Novel; Novel Therapeutics; Oncosuppressor Gene; Ontogeny; Overexpression; Pancreatic Neoplasm; Professor; Protein-Serine-Threonine Kinase (Rac); Proto-Oncogene Protein Rac; Proto-Oncogene Protein Akt; Proto-Oncogene Protein C-Erbb-1; Public Health Relevance; Rac Protein Kinase; Related To A And C-Protein; Research Study; Resection; Structure Function Relationship; Suberanilohydroxamic Acid; Surgery; Tumorigenic
