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Genitourinary Program
Program Leaders: Roberto Pili, MD and Gary J. Smith, PhD
| Contact Persons: | Karen Madden Telephone: 716-845-3851 Fax: 716-845-8232 karen.madden@roswellpark.org | Marie Rosati Telephone: 716-845-4155 Fax: 716-845-4165 marie.rosati@roswellpark.org |
Click to read the Scientific Report 2007 Overview of this program.
Click here to view the 2007-08 Scientific Annual Report.
Both files are PDF documents and require Adobe Acrobat to view.
Program Goals
The shared central interest of the Genitourinary Program members is to identify and target changesinduced/unmasked in the prostate by androgen deprivation therapy to avert or delay the transition from androgen-stimulated growth to castration-resistant or castration-recurrent growth. The Prostate Program has three inter-related themes: Androgen Axis, Angiogenesis, and Chemosensitization and Alternative Targets. The thematically-based, translationally oriented, basic, pre-clinical and clinical research in the Prostate Program focuses on identification of unique targets within the androgen-deprived prostate that are associated causally with the transition to metastatic, castration-recurrent CaP, the lethal phenotype. Current research programs in the Prostate Program are focused specifically on: 1) androgen receptor (AR) and vitamin D receptor (VDR) mediated signaling; 2) cellular targets in endothelial cells, pericytes and tumor stem cells; and 3) novel molecular targets, including prostate-specific antigen (PSA), tumor cell antigens, CaP-specific glycan signatures, 24-hydroxylase (CYP24) and cytokines. Targets and candidate agents validated in basic and pre-clinical investigations are translated into clinic studies that supplement ongoing interventional and non-interventional clinical studies. The highly collaborative, translational research programs of the investigators of the Prostate Program exist within the scientific environment enabled by the CCSG that uniquely facilitates interaction between clinicians and basic researchers, and rely heavily on the following CCSG Shared Resources: the Laboratory Animal Resource (LAR) and Mouse Tumor Model Resource (MTMR) to provide experimental animals model systems; the IRB, Data Base and Bio-Repository (DBBR) and clinical data bases to provide specimen annotation; and the Pathology Resource Network (PRN) and Rapid Tissue Acquisition Program (RTAP) to provide human specimens.
The organ system-oriented Prostate Program, in contrast to the other CCSG programs, is primarily focused on a vertical integration of research efforts and clinical expertise to overcome the challenge of curing patients undergoing the transition to the lethal phenotype. Consequently, the Prostate Program goals are to:
1) Develop a collaborative, integrated basic research and clinical research/trial program that focuses on translating basic findings associated with the androgen axis, angiogenesis and novel micro-environmental targets into NIH funded, investigator-initiated clinical studies;
2) Develop, validate and distribute to members of the Prostate Program, as well as members of other CCSG programs whose research focuses on prostate cancer, cutting-edge human models of prostate cancer that are based on human cells, human tissues and human xenografts, and access to prostate cancer patients; and
3)Submit multi-investigator research grants, including SPORE and PO1 grants, to facilitate collaborative, integrated studies of investigators within the Prostate Program, with investigators of other CCSG programs and with investigators from other institutions, and to support the development and maintenance of the shared resources, particularly tissue procurement, preclinical models, clinical data collection and collection of human specimens through RTAP.
Accomplishments and Major Achievements
Moray Campbell, PhD focused on characterization of the functional and prognostic significance in prostate cancer of altered expression of the AR co-repressors NCOR1 and NCOR2/SMRT. These studies utilized specimens provided through the Pathology Resource Network. A second area of research activity focused on defining molecular models of histone codes predicative of vitamin D receptor action in prostate epithelial cells.
Kailash Chadha, PhD focused on characterization of the biological role of the intact PSA sequestered within prostate tissue. Unlike serum PSA levels, tissue PSA levels were lower in prostate cancer tissue, and tissue PSA had a significant role in regulating gene and protein expression of several genes known to have direct roles in angiogenesis, include: FAK, FLT, KDR, TWIST 1, P-38 and Cathepsin-D. In collaboration with Dr. Smith, PSA was demonstrated to inhibit angiogenesis by human prostate endothelial cells in the Matrigel tube formation assay, independent of enzymatic function or androgen stimulation.
Barbara Foster, PhD in collaboration with Dr. Campbell, demonstrated that the co-repressor, LSD1, implicated in histone methylation, interacts with the vitamin D receptor on target DNA. Primary cell cultures from tumors that have been exposed in vivo for long terms to vitamin D have a reduced transcriptional response to vitamin D, and the vitamin D receptor is complexed with LSD1 on vitamin D target DNA. In addition, early treatment of TRAMP mice with high dose vitamin D (calcitriol) was demonstrated to increase differentiation. However, these animals eventually developed aggressive prostate cancer and increased numbers of metastatses.
Kenneth Gross, PhD validated the in vivo importance of the major transcriptional regulatory sequences of the renin gene, including a proximal promoter Hox-Pbx DBA recognition element and a distal enhancer element that consists of a dense cluster of DNA recognition elements for nuclear effectors of signal transduction cascades implicated in regulating renin expression. Expression analysis of the rare renin-expressing cell of adult kidney, the juxtaglomerular cell (JG cell), demonstrated a remarkable similarity to the expression profile of the renin-expressing cell found in developing vasculature, which suggested the retention into adulthood of a lineal precursor cell, the activated pericyte of the developing renal vasculature, that normally goes on to differentiate into smooth muscle in larger caliber renal arteries.
Khurshid Guru, MD collaborated with Dr. Kesavadas, Director, Computer Simulation Laboratory of the University at Buffalo Department of Mechanical and Aerospace Engineering, to develop a prototype Robotic Surgical Simulator (RoSS). He reported clinical data that led to a change in the technique of apical dissection of prostates, which reduced the incidence of positive surgical margins. In addition, Dr. Guru has collaborated in establishing surgical parameters to maximize xenograft viability, and yield of viable prostate endothelial and stem cells, from radical prostatectomy and cystoprostatectomy.
Wendy Huss, PhD demonstrated that Oct4 expression was not a marker of prostate stem cells/cancer stem cells, as anticipated, but was a marker of neuroendocrine (NE) cells, particularly the NE cells typical of advanced prostate cancer tissues. Oct4 was co-expressed with the markers of immature NE cells chromogranin A and synaptophysin, which suggested Oct4 cells represent a precursor cell of NE cells in advanced prostate cancer. In addition, Dr. Huss, in collaboration with Dr. Smith, demonstrated that DyeCycle Violet was a suitable, and preferable, substitute for Hoechst 33343 for FACS-based isolation of prostate stem cells from human prostate tissue.
Candace Johnson, PhD demonstrated that epigenetic modulation of CYP24 expression rendered endothelial cells from prostate cancer are more sensitive to calcitriol than endothelial cells from benign tissue. CYP24, the catabolic enzyme involved in calcitriol signaling, becomes epigenetically silenced selectively in tumor-derived endothelial cells (TDEC). The CYP24 promoter is hypermethylated at two CpG island regions located at the 5'-end, causing gene silencing. In TDEC, calcitriol induces G0/G1 arrest, modulated p27 and p21, and induced apoptotic cell death and decreases P-Erk and P-Akt. In addition, calcitriol enhanced the in vitro and in vivo antitumor efficacy of the platinum analogues, cisplatin and carboplatin, and the taxanes, paclitaxel and docetaxel. Enhancement of drug-mediated apoptosis by calcitriol was associated with increased PARP-, MEK- and caspase-cleavage and MEKK-1, induction of p73, and decreased P-Erk, P-Akt, p53 and p21 expression.
Hyung Kim, MD demonstrated that covalently cross-linking a tumor antigen led to cytokine secretion, cross-presentation and anti-tumor immunity, even when HSP is not included in the vaccine, leading to the hypothesis that HSPs are “natural” cross-linkers. In a separate approach, carbonic anhydrase IX (CA9) was characterized as the best tumor antigen for vaccines for renal cell carcinoma: high CA9 expression was associated with favorable prognosis because of a chaperone-like function.
Khushi Matta, PhD discovered a novel enzymatic mechanism for sialylation of glycans catalyzed by the mammalian ST3Gal-II protein. Since this reaction occurs in a direction opposite to normal sialyl-T function, the novel enzyme activity was termed “reversible sialylation”. ST3Gal-II was demonstrated to act as an enzymatic exchanger of sialyl residues and to provide a tool for studying mucin-type sialylated structures. A significant level of “reversible sialylation” activity was demonstrated in the human prostate cancer cell lines, LNCaP and PC-3.
James Mohler, MD collaborated in multiple clinical and basic research projects during the past year. A clinical trial based on basic research studies on the role of the AR in castration-recurrent prostate cancer was completed that demonstrated men with castration-recurrent prostate cancer esponded rarely to the bi-specific 5α-reductase inhibitor, dutasteride. Laboratory studies demonstrated that prostate cancer may use thioredoxin reductase-1 or peroxiredoxin 1 to survive the acute stresses of castration or hypoxia, respectively. An inter-institutional collaboration supported by a PO1 demonstrated another mechanism of hypersensitization of AR activity in an androgen-deprived microenvironment, phosphorylation of AR by the cdc42-associated kinase (Ack1).
Roberto Pili, MD research focused on translation into clinical trials with prostate cancer and RCC patients of his basic studies on combinations of novel histone deacetylase inhibitors (HDACI) with a variety of other targeted agents, such as retinoic acid and VEGF-targeted therapies, and MTOR inhibitors. Dr. Pili continued his characterization of the role of specific HDACs in the modulation of HIF-1 and angiogenesis using xenograft models and an in vitro model of the bone-microenvironment supportive of prostate cancer metastases.
Gary Smith, PhD demonstrated that human endothelial cells in primary xenografts of fresh surgical tissue specimens exhibited a marked apoptotic response to androgen deprivation, followed by a complete re-endothelialization of the vascular channels in the absence of androgen. Vascular recovery was driven by autocrine VEGF stimulation. Human prostate endothelial cells expressed AR, and all of the metabolic enzymes involved in activation/de-activation of testicular and adrenal androgen precursors, and the survival/proliferation of the endothelial cells was dependent on AR-mediated signaling. In collaboration with Dr. Chadha, PSA was demonstrated to have marked anti-angiogenic effects on prostate endothelial cells.
Mark Titus, PhD in collaboration with the Pharmacokinetic/Pharmacodynamic (PK/PD) Resource developed the techniques for small molecule tandem mass spectrometry (MS/MS) analysis of 7 hydrophobic androgens/metabolites and the hydrophilic adrenal androgen, dehydroepiandrosteronesulfate. These androgen assays are essential to evaluation of androgen biosynthetic and catabolic pathways, and adrenal androgen transport, in prostate cancer epithelial cells and clinical specimens of prostate tissue. When Dr. Titus becomes an independent investigator, he will be under consideration for CCSG membership.
Program Members
Moray Campbell, PhD | Ellis Levine, MD |
Related link: North Carolina - Louisiana Prostate Cancer Project (PCaP)
