Current Research Projects
Kenneth V. Honn, Principal Investigator
Title – Role of Thromboxane in Prostate Cancer Progression
Funding Agency – NIH/NCI
Period – Aug 15, 2006 - July 31, 2011
Total Funding – $1,618,300
Description – The major goals of this project are: (1) Define the expression and function of TX synthase and TPs during prostate carcinogenesis using the TRAMP transgenic mouse model; (2) Characterize TXA2 receptors expressed in prostate cancer cells and elucidate how TXA2 signaling loop regulates tumor cell motility; (3) Study the functional role for TX synthase and TXA2 receptors in tumor formation, progression, and metastasis, and its relationship with hemostatic components, platelets in particular.
Title – Characterization of a Novel 12(S)-HETE Receptor and Role in Prostate Cancer Progression
Funding Agency – DOD
Period – Oct. 1, 2005 - Oct. 1, 2008
Total Funding – $565,398
Description – The major goals of this project are: (1) Characterize the biochemical properties of GPR31 as a 12(S)-HETE receptor; (2) Study the expression profile of GPR31 in invasion and tumor progression; (3) Study the roles of GPR31 in tumor survival and invasion by overexpressing GPR31 in DU145 cells and silencing GPR31 in PC3 cells.
Title – 12-Lipoxygenase as a Target for Radiosensitization
Funding Agency – NIH/STTR
Period – April 1, 2005 - March 31, 2007
Total Funding – $99,744
Description – The major goals of this project are to: (1) Evaluate proprietary compounds for radiosensitizing activity against androgen-dependent LNCap cells; (2) Evaluate the selected compounds for radiosensitizing activity against androgen independent DU145 and PC-3 cells; and (3) Study the effects of the compounds identified on radiation-induced apoptosis in normal prostate epithelial cells as well as prostate cancer cells.
Title – Role of Eicosanoids in Tumor Cell Metastasis
Funding Agency – NIH/NCI
Period – April 1, 2004 - March 31, 2009
Total Funding – $1,359,000
Description – The major goals of this project are: (1) Determine the structural basis for the interaction between beta4 integrin subunit and 12-LOX; (2) Study how alpha6beta4 regulates 12-LOX cellular localization and activity; (3) Determine whether 12-LOX regulates the function of alpha6beta4 in hemidesmosomes; (4) Study whether and how 12-LOX and beta4 integrin contribute to the survival of carcinoma cells; and (5) Determine whether and how 12-LOX and beta4 collaborate in carcinoma invasion in vitro and tumor progression in animal models. The proposed studies, when accomplished, will provide significant insights into eicosanoid regulation of tumor progression.
Title – Naturally Occurring Truncated Beta3 Integrins (Alphabbeta3 and Alphavbeta3) In Prostate Cancer Metastasis
Funding Agency – Department of Defense - Fellowship Grant
Period – Jan. 01, 2004 - Jan. 31, 2007
Total Funding – $ 97,828
Description – The major goals of this project are: (1) To illustrate whether and to what extent, overexpression and/or blocking of tr/wt beta3 integrins in PCa cells influences tumor cell adhesion and invasion; (2) To determine the spatial and temporal distribution of tr- beta3 integrins and wt- beta3 integrins in PCa cells undergoing migration; (3) To evaluate the role of wt/tr- beta3 integrins in tumor growth and metastasis of PCa cells in vivo, and to detect tr- beta3 integrins in mouse serum from PCa mouse models.
Title – Eicosanoid Regulation of Prostate Cancer Progression: Disruption of Hemidesmosomes and Collaboration in Tumor Invasive Growth
Funding Agency – Department of Defense
Period – April 1, 2003 - March 31, 2007
Total Funding – $ 558,472
Description – The major goals of this study are: (1) To determine whether the dissolution of hemidesmosomes is correlated with increased 12-LOX expression; (2) If mobilized beta4 integrin is co-localized with 12-LOX and correlated with tumor grade and stage; (3) Study the effects of 12-LOX inhibitors and 12(S)-HETE on hemidesmosomes in prostate epithelium; (4) Study the signal transduction pathways that underlie the disassembly of hemidesmosomes by 12(S)-HETE or an increasse in 12-LOX activity; (5) Overexpress beta4 integrin in PC-3 cells, in the presence or absence of 12-LOX expression, and evaluate the capacity of transfected cells to form hemidesmosome and whether an increase in surface expression of alpha6beta4 alters cell proliferation, adhesion, migration, and survival, in response to HGF/SF; (6) Evaluate the growth and progression of s.c. tumors derived from alpha6beta4 expression PC-3 cells, in the presence or absence of stable 12-LOX expression, and compare with control PC-3 cells.
Title – Tumor Cell Adhesive Glycoproteins and Metastasis
Funding Agency – NIH/NCI
Period – Aug. 14, 2001- July 31, 2007
Total Funding – $1,038,947
Description – The major goals of this project are: (1) Sequence full-length tr- alphaIIb and tr- beta3 and demonstrate that they can pair with each other; (2) Compare ligand binding specificity of tr- alphaIIbbeta3 and wt- alphaIIbbeta3; (3) Determine whether tr- alphaIIb and/or tr- beta3 modulate the affinity state of alphaIIbbeta3; (4) Evaluate whether overexpression of wt- alphaIIbeta3 and tr- alphaIIbeta3 integrin in human prostate carcinoma and/or melanoma cells influences tumor cell motility; and (5) Determine the role of wt- alphaIIbbeta3 and tr- alphaIIbbeta3 in tumor growth and metastasis of human tumor cells in vivo.
Krishnarao Maddipati, Principal Investigator
Title – Anticancer Prodrug Development Program
Funding Agency – Michigan Technology Tri-Corridor
Period – Sept. 1,2005 – Aug. 31, 2008
Total Funding – $569,977
Description - The major goals of this projects are: (1) Development of synthetic procedure(s) for glucuronides of BMD122 and BMD188; (2) In vitro characterization of BMD122 and BMD188 glucuronides for biological activity against prostate cancer cells; (3) Development and validation of HPLC methology for BMD122, BMD188, and their glucuronides; (4) In vivo evaluation of the efficacy of BMD122 and BMD188 glucuronides in animal model of prostate cancer; and (5) Pharmacokinetics of BMD122 and BMD188 glucuronides in normal rats and in mice harboring prostate carcinoma xenografts.
Funding Agency – NIH/NCI
Period – Aug 15, 2006 - July 31, 2011
Total Funding – $1,618,300
Description – The major goals of this project are: (1) Define the expression and function of TX synthase and TPs during prostate carcinogenesis using the TRAMP transgenic mouse model; (2) Characterize TXA2 receptors expressed in prostate cancer cells and elucidate how TXA2 signaling loop regulates tumor cell motility; (3) Study the functional role for TX synthase and TXA2 receptors in tumor formation, progression, and metastasis, and its relationship with hemostatic components, platelets in particular.
Title – Characterization of a Novel 12(S)-HETE Receptor and Role in Prostate Cancer Progression
Funding Agency – DOD
Period – Oct. 1, 2005 - Oct. 1, 2008
Total Funding – $565,398
Description – The major goals of this project are: (1) Characterize the biochemical properties of GPR31 as a 12(S)-HETE receptor; (2) Study the expression profile of GPR31 in invasion and tumor progression; (3) Study the roles of GPR31 in tumor survival and invasion by overexpressing GPR31 in DU145 cells and silencing GPR31 in PC3 cells.
Title – 12-Lipoxygenase as a Target for Radiosensitization
Funding Agency – NIH/STTR
Period – April 1, 2005 - March 31, 2007
Total Funding – $99,744
Description – The major goals of this project are to: (1) Evaluate proprietary compounds for radiosensitizing activity against androgen-dependent LNCap cells; (2) Evaluate the selected compounds for radiosensitizing activity against androgen independent DU145 and PC-3 cells; and (3) Study the effects of the compounds identified on radiation-induced apoptosis in normal prostate epithelial cells as well as prostate cancer cells.
Title – Role of Eicosanoids in Tumor Cell Metastasis
Funding Agency – NIH/NCI
Period – April 1, 2004 - March 31, 2009
Total Funding – $1,359,000
Description – The major goals of this project are: (1) Determine the structural basis for the interaction between beta4 integrin subunit and 12-LOX; (2) Study how alpha6beta4 regulates 12-LOX cellular localization and activity; (3) Determine whether 12-LOX regulates the function of alpha6beta4 in hemidesmosomes; (4) Study whether and how 12-LOX and beta4 integrin contribute to the survival of carcinoma cells; and (5) Determine whether and how 12-LOX and beta4 collaborate in carcinoma invasion in vitro and tumor progression in animal models. The proposed studies, when accomplished, will provide significant insights into eicosanoid regulation of tumor progression.
Title – Naturally Occurring Truncated Beta3 Integrins (Alphabbeta3 and Alphavbeta3) In Prostate Cancer Metastasis
Funding Agency – Department of Defense - Fellowship Grant
Period – Jan. 01, 2004 - Jan. 31, 2007
Total Funding – $ 97,828
Description – The major goals of this project are: (1) To illustrate whether and to what extent, overexpression and/or blocking of tr/wt beta3 integrins in PCa cells influences tumor cell adhesion and invasion; (2) To determine the spatial and temporal distribution of tr- beta3 integrins and wt- beta3 integrins in PCa cells undergoing migration; (3) To evaluate the role of wt/tr- beta3 integrins in tumor growth and metastasis of PCa cells in vivo, and to detect tr- beta3 integrins in mouse serum from PCa mouse models.
Title – Eicosanoid Regulation of Prostate Cancer Progression: Disruption of Hemidesmosomes and Collaboration in Tumor Invasive Growth
Funding Agency – Department of Defense
Period – April 1, 2003 - March 31, 2007
Total Funding – $ 558,472
Description – The major goals of this study are: (1) To determine whether the dissolution of hemidesmosomes is correlated with increased 12-LOX expression; (2) If mobilized beta4 integrin is co-localized with 12-LOX and correlated with tumor grade and stage; (3) Study the effects of 12-LOX inhibitors and 12(S)-HETE on hemidesmosomes in prostate epithelium; (4) Study the signal transduction pathways that underlie the disassembly of hemidesmosomes by 12(S)-HETE or an increasse in 12-LOX activity; (5) Overexpress beta4 integrin in PC-3 cells, in the presence or absence of 12-LOX expression, and evaluate the capacity of transfected cells to form hemidesmosome and whether an increase in surface expression of alpha6beta4 alters cell proliferation, adhesion, migration, and survival, in response to HGF/SF; (6) Evaluate the growth and progression of s.c. tumors derived from alpha6beta4 expression PC-3 cells, in the presence or absence of stable 12-LOX expression, and compare with control PC-3 cells.
Title – Tumor Cell Adhesive Glycoproteins and Metastasis
Funding Agency – NIH/NCI
Period – Aug. 14, 2001- July 31, 2007
Total Funding – $1,038,947
Description – The major goals of this project are: (1) Sequence full-length tr- alphaIIb and tr- beta3 and demonstrate that they can pair with each other; (2) Compare ligand binding specificity of tr- alphaIIbbeta3 and wt- alphaIIbbeta3; (3) Determine whether tr- alphaIIb and/or tr- beta3 modulate the affinity state of alphaIIbbeta3; (4) Evaluate whether overexpression of wt- alphaIIbeta3 and tr- alphaIIbeta3 integrin in human prostate carcinoma and/or melanoma cells influences tumor cell motility; and (5) Determine the role of wt- alphaIIbbeta3 and tr- alphaIIbbeta3 in tumor growth and metastasis of human tumor cells in vivo.
Krishnarao Maddipati, Principal Investigator
Title – Anticancer Prodrug Development Program
Funding Agency – Michigan Technology Tri-Corridor
Period – Sept. 1,2005 – Aug. 31, 2008
Total Funding – $569,977
Description - The major goals of this projects are: (1) Development of synthetic procedure(s) for glucuronides of BMD122 and BMD188; (2) In vitro characterization of BMD122 and BMD188 glucuronides for biological activity against prostate cancer cells; (3) Development and validation of HPLC methology for BMD122, BMD188, and their glucuronides; (4) In vivo evaluation of the efficacy of BMD122 and BMD188 glucuronides in animal model of prostate cancer; and (5) Pharmacokinetics of BMD122 and BMD188 glucuronides in normal rats and in mice harboring prostate carcinoma xenografts.