California Cancer Research Program

 

Completed Projects

 

 

The following Principal Investigators have completed their research as funded by CRP. Where applicable, publications resulting from CRP funding are also included.

 

 

CYCLE I FINAL LAY ABSTRACTS

[GENERAL CANCER BIOLOGY]  

General Cancer Biology

 

 

Investigator-Initiated Award

 

         Nuria Assa-Munt, Ph.D: NMR Structure of BIR-Biochemical Inhibitor of Apoptosis and of Survivin

 

         Richard C. Boland, M.D.: Chromosomal Instability in Colorectal Cancer

 

         Stanley N. Cohen, M.D.: Genes that Suppress Metastasis of Human Ovarian Cancers

 

         James R. Feramisco, Ph.D.:Molecular Basis of the Childhood Tumor, Rhabdomyosarcoma

 

         Jiahuai Han, Ph.D.: Signaling Mechanisms of Radiation-Induced Cancer Cell Death

 

         Shi Huang, Ph.D.: The p53 Pathway in Ovarian Cancer

 

         Michael Karin, Ph.D.: Inhibition of Survival Responses as an Anti-cancer Strategy

 

         Joseph P. Konopelski, Ph.D.: Synthesis of Novel Anticancer Agents from Marine Sources

 

         Hsing-Jien Kung, Ph.D.: Kinases as Prostate Cancer Markers and Regulators

 

         Jiing-Dwan Lee, Ph.D.: The Role of BMK1/ERK5 Pathway in Cancer Cell Growth

 

         Sergei R. Malkhosyan, Ph.D.: DNA Mismatch Repair Defects and Mutator Phenotype in Cancer

 

         Thomas Quertermous, M.D.: An Embryonic Angiogenic Factor is a Target for Tumor Therapy

 

         Nicholas J. Rampino, Ph.D.: Select Microsatellite Mutations in Key Cancer Genes

 

         Juergen K.V. Reichardt, Ph.D.: Benign Prostatic Hypertrophy (BPH) and the SRD5A2 Gene

 

         Michael G. Rosenfeld, M.D.: Roles of Nuclear Receptor Coregulators in Prostate Cancer

 

         Kathleen M. Sakamoto, M.D.: Cell Cycle Control and Cancer

 

         Eli E. Sercarz, Ph.D.: Targeting the T Cell Repertoire Against Tumor-Specific Determinants

 

         Branimir I. Sikic, M.D.: Genomic Profiling of Ovarian Cancers

 

         Geoffrey M. Wahl, Ph.D.: Novel Treatment of Targeting Cancer Cell Genetic Instability

 

         John Yu, M.D., Ph.D.: Clinical Relevance of Thioredoxin in Ovarian Cancer

 

 

Pilot and Feasibility Study Award

 

         Roymarie Ballester, Ph.D.: Identification of Wsc Homologs in Animal Cells

 

         Christina L. Chang, Ph.D.: Molecular Mechanism of NDP Kinase A in Tumor Metastasis

 

         Graeme J. Dougherty, Ph.D.: Combining Radiation Therapy with Cancer Gene Immunotherapy

 

         Steven M. Dubinett, M.D.: Genetic Immunotherapy for Prostate Cancer

 

         Kathryn R. Ely, Ph.D.: Molecular Basis of Signal Transduction Mediated by p130Cas

 

         Ruth A. Gjerset, Ph.D.: A Novel Tumor Suppressor Approach to Cancer Therapy

 

         Edward J. Goetzl, M.D.: Lysophopholipid Receptors and Effects in Ovarian Cancer

 

         Peter L. Greenberg, M.D.: Gene Expression in Myelodysplastic Syndromes

 

         Luisa Iruela-Arispe, Ph.D.: Anti-Angiogenic Activity of METH-1 in Tumors

 

         Sergei R. Malkhosyan, Ph.D.: Therapy of the Cancer of the Microsatellite Mutator Phenotype

 

         Kathleen L. McGuire, Ph.D.: Mimicking Natural Products to Develop Novel Cancer Drugs

 

         Brian J. Murphy, Ph.D.: Heme Oxygenase Inhibition for Prostate Tumor Treatment

 

         Francisco J. Piedrafita, Ph.D.: Apoptotic Retinoids and JNK Activity in Prostate Cancer

        

         Wanda F. Reynolds, Ph.D.: Myeloperoxidase as a Gender-Specific Risk Factor for Cancer

        

         Andrew A. Stolz, M.D.: Molecular Epidemiology of 3a-HSD in Prostate Cancer

        

         Ameae M. Walker, Ph.D.: Prostate Cancer Treatment with Prolactin Receptor Antagonist

        

         Edward T. Wei, Ph.D.: Melanocortin Receptor Antagonists as Adjunct Therapy for Melanoma

 

         Matthew D. Weitzman, Ph.D.: Viral Vectors for Gene Therapy of Prostate Cancer

 

 

New Investigator Award

 

         Robert A. Bok, M.D., Ph.D.: The Role of Proteases in Prostate Cancer Progression

 

         Christopher P. Evans, M.D.: Targeting Androgen-Regulated Transcription in Prostate Cancer

 

         Gourisankar Ghosh, Ph.D.: Structure/Function Studies of Oncogenic Proteins vRel and cRel

 

         Diane M. Harris, Ph.D.: Nutrient/Gene Interactions in Apcmin, a Mouse Model of Colon Cancer

 

         Carson D. Liu, M.D.: Synthetic Gut Hormones in the Treatment of Pancreatic Cancer

 

         David A. Calderwood, Ph.D.: The Function of PEA-15, a Gene Overexpressed in Cancer

 

         Chih-Jian (Jason) Lih, Ph.D.: Identification of Genes Involved in Chemotherapy Resistance

        

         Shinichi Takayama, Ph.D.: BAG-Family Proteins in Prostate Cancer

 

Lily Wu, M.D., Ph.D.: Targeted Prostate Cancer Gene Therapy Using Potent Herpes Thymidine Kinase Variants Delivered by Adenovectors

 

 

 

 

 

 

ABSTRACTS

 

NMR Structure of BIR-Biochemical Inhibitor of Apoptosis and of Survivin

Nuria Assa-Munt, Ph.D.

The Burnham Institute

Investigator-Initiated Award, $984,506 / 36 mos.

General Cancer

 

Regulation of cell death and cell survival must be balanced in processes that range from ordered organ development to excessive number of cells,that is,to tumors and cancer.The interplay between the proteins involved in these mechanisms translates to interactions between whole proteins and recognition of particular structural elements which accelerate or inhibit a given process.During programmed cell death (apoptosis)intracellular enzymes,called caspases,are activated in a cascade leading to the degradation of cellular proteins and ultimately to cell death.The activity of caspases is regulated by intracellular proteins belonging to the inhibitor of apoptosis protein (IAP)family. These proteins have in common up to three homologous domains in their amino-terminal region which bind activated caspases and inhibit cell death.Our work entailed identifying protein domains active in the regulation of apoptosis that could be expressed in stable form and characterized biochemically and structurally.In the first part of this project,we determined the minimal domain from XIAP and a homolog (“survivin ”)capable of inhibiting caspases and suitable for structural studies by nuclear magnetic resonance spectroscopy. Mutational work was also performed to test the role of a crucial tryptophan residue placed in a loop area exposed to solvent.We showed that change of this tryptophan to alanine abrogated the caspase inhibition.The three-dimensional structure of the same short BIR domain was published by Dr.Fesik from Abbot Laboratories with caspase obtained from IDUN Laboratories.We handed our BIR-2 protein and plasmids to our colleague Dr.Robert Liddington for the crystallization efforts carried on the BIR/caspase complex in his laboratory,in collaboration with Dr.Guy Salvesen. The crystal structure was subsequently obtained,revealing the nature of enzyme inhibition by BIR,and offering the prospect of rational inhibitor design for cancer therapy.With the advent of a completed human genome,the search for new proteins and new protein domains or substructures has been boosted.Bioinformatic approaches have recognized a new domain called either Pyrin domain (based on the homonymous protein found in Mediterranean fever)or PACS (based on the initials of 4 proteins where this protein has been found.)The exact role of the pyrin domain is still under study.A tool to understand how certain proteins may have surfaces where other proteins anchor themselves is the solution structure.We have advanced our studies of the structure of Pyrin by solution NMR methods and hope to find surfaces that,once they are identified,may serve to test possible inhibitors of destructive interactions or to synthesize pharmacophores that aid in cancer therapy.

 

 

1.       Espejo F, Green M, Preece NE, Assa-Munt N. NMR assignment of human ASC2, a self  contained protein interaction domain involved in apoptosis and inflammation. J Biomol NMR,  2002; 23: 151-2.

 

 

 

Identification of Wsc Homologs in Animal Cells

Roymarie Ballester, Ph.D.

University of California, Santa Barbara

Pilot and Feasibility Study Award, $132,440 / 24 mos.

General Cancer

 

Normally, a cell’s growth is controlled by a steady stream of cues from its surroundings, both positive cues (telling it to grow) and negative cues (telling it not grow).  Negative cues like the environmental stresses of irradiation and oxidation are especially important in cell growth, as these cues cause mutations that lead to cancer.  Every cell in every organism, from the single-celled yeast to the multi-cellular human, has developed a molecular-level system, referred to as the "stress response," to cope with these environmental stresses.  Our laboratory has identified a family of proteins in the cells of brewer’s yeast that may control and regulate the stress response.  These proteins are called Wsc (pronounced "whisk"), which is short for cell Wall and Stress response Component.

 

Wsc proteins regulate a signaling pathway, an internal communication system, in yeast.  The same signaling pathway in human cells regulates normal cell growth in the presence of environmental stresses like radiation and oxidizing agents.  We know that a malfunction of this signaling pathway in human cells has been directly linked to tumor formation.  Because many of the components of the stress response have been so highly conserved, there may proteins in mammalian cells that function like Wsc.  To identify these proteins we are using yeast as a tool. 

 

We expressed in yeast mammalian genes encoding for proteins that can rescue defects of mutant yeast cells that lack a normal stress response and identified 5 different mammalian genes.  Of these 2 encode proteins that we were expecting would function in yeast, whereas the other 3 are proteins of unknown function.

 

In addition to the genetic screens we have been searching different databases to identify proteins that have sequence similarity to the yeast Wsc proteins.  We recently identified a human protein with similarity to the yeast Wsc proteins.  The highest degree of homology is in what is called the WSC domain, which is that region of highest homology between the Wsc proteins themselves.

 

Our findings suggest that the approaches we have taken to identify mammalian genes in yeast is valid and that further characterization of the function of the remaining genes in mammalian cells may give us relevant information as it relates to the cells response to stress and its relation to the etiology of cancer. 

 

Recommendations about future research in the field:  Identified clones should be further characterized and tested for function in mammalian cells.  Putative Wsc proteins identified by sequence homology should be tested for function both in yeast and in mammalian cells.

 

 

1.       Chen RA, Michaeli T, Van Aelst L, Ballester R A role for the noncatalytic N terminus in the function of Cdc25, a Saccharomyces cerevisiae Ras-guanine nucleotide exchange factor. Genetics. 2000 Apr;154(4):1473-84.

 

2.       Zu T, Verna J, and Ballester R. Mutations in WSC genes for putative stress receptors result in sensitivity to multiple stress conditions and impairment of Rlm1-dependent gene expression in Saccharomyces cerevisiae. Mol Genet Genomics. 2001. 266: p. 142-155.

 

 

 

The Role of Proteases in Prostate Cancer Progression

Robert A. Bok, M.D., Ph.D.

University of California, San Francisco

New Investigator Award, $197,991 / 36 mos.

Prostate Cancer

 

Despite the advent of PSA screening and improved modalities of local therapy, prostate cancer (PCA) was responsible for about 39,000 deaths in 1998, with an estimated 184,500 new cases diagnosed that same year.  The pathogenesis of this malignancies is still poorly understood, but, as with a number of other carcinomas, the acquisition of invasive and metastatic capacity ultimately determines its lethality.  Cancer growth, invasion and metastasis are complex processes that entail significant tissue remodeling, which involves degradation of proteins in the extracellular matrix.  Extracellular proteases, which mediate such protein degradation, are thus thought to play a central role in tumor progression and dissemination.  Investigating the natural stages of PCA progression in humans in a temporal fashion, with respect to protease expression, is difficult for several reasons, including limitations on available tissues for analysis, the need for therapeutic intervention, and the potentially long time course of human PCA.  We therefore chose to use a transgenic mouse model for PCA to carry out initial protease analyses across the course of prostate tumor progression.  The TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) model developed by Greenberg et al. (1995), seemed most appropriate for these studies.  All males of this autochthonous model spontaneously develop adenocarcinoma of the prostate that closely mimics the natural history of the human disease.  Tumorigenesis initiates at puberty and progresses from early to advanced (late) cancer.  Dissemination to lymph nodes and distant organs also occur in this model.  Making no apriori assumptions about which proteases might be most important in prostate tumor progression, we have carried out analyses for different serine, cysteine, and matrix metallo-class proteases. Various protein and enzymatic detection techniques (zymography, immunohistochemistry, fluorogenic substrate assays, Western blotting, and suicide substrates) have been employed to analyze normal, early, and late (advanced) TRAMP prostate/tumors and disseminated disease (lymph node metastases).  Our analyses reveal minimal expression of metalloproteases in normal murine prostate, substantial levels of a precursor, pro-metalloprotease (pro-MMP-9) in early TRAMP tumor, and much greater production of activated metallo-proteases (MMP-2 and MMP-9) in late TRAMP tumors.  MT1-MMP (a membrane-type metalloprotease) shows a progressive increase in expression from normal prostate to early TRAMP to late TRAMP.  Interesting patterns of MMP-7 and MMP-3 expression are also emerging.  Fluorogenic substrate analyses, zymography, and Western analyses also indicate alterations in cysteine and serine protease activity from normal prostate to early TRAMP to advanced lesions.  In particular, urokinase plasminogen activator (UPA) expression appears decreased in primary tumors but substantially increased in lymph node metastases.  MT-SP1, a recently discovered membrane-type serine protease, shows upregulation in advanced TRAMP tumor.  To further elucidate the role of various proteases on prostate tumor progression, crossings of TRAMP mice with strains deficient in components of the major protease systems were undertaken.  Genetic deletion of the UPA receptor by these means appears to impair tumor spread to the seminal vesicles.  Crosses of TRAMP with other such strains are being pursued.  We have also initiated preliminary studies on the effects of a novel protease inhibitor compound in TRAMP as a therapeutic agent.  Administration of this inhibitor has shown promising biological effects, including improvements in survival and normalization of prostate glandular architecture and biochemical profile.

 

 

1.       Bok RA, Hansell EJ, Nguyen TP, Greenberg NM, McKerrow JH, Shuman MA. Patterns of protease production during prostate cancer progression: proteomic evidence for cascades in a transgenic model Prostate Cancer and Prostatic Diseases (2003) 6, 272–280.

 

 

Chromosomal Instability in Colorectal Cancer

Richard C. Boland, M.D.

University of California, San Diego

Investigator-Initiated Award, $982,671 / 36 mos.

Colorectal Cancer

 

No final report submitted.

 

1.       Boland CR, Ricciardiello L. How many mutations does it take to make a tumor? Proc Natl Acad  Sci U S A, 1999; 96: 14675-7.

2.       Ricciardiello L, Laghi L, Ramamirtham P, Chang CL, Chang DK, Randolph AE, Boland  CR. JC virus DNA sequences are frequently present in the human upper and lower  gastrointestinal tract. Gastroenterology, 2000; 119: 1228-35.

3.       Ricciardiello L, Chang DK, Laghi L, Goel A, Chang CL, Boland CR. Mad-1 is the exclusive  JC virus strain present in the human colon, and its transcriptional control region has a deleted 98base-pair sequence in colon cancer tissues. J Virol, 2001; 75: 1996-2001.

4.       Laghi L, Randolph AE, Malesci A, Boland CR. Constraints imposed by supercoiling on in vitro amplification of polyomavirus DNA. J Gen Virol. 2004 Nov;85(Pt 11):3383-8.

 

 

  

Molecular Mechanism of NDP Kinase A in Tumor Metastasis

Christina L. Chang, Ph.D.

University of California, San Diego

Pilot and Feasibility Study Award, $199,002 / 24 mos.

Prostate/Ovarian Cancer                                                     

 

Tumor metastasis is the major cause of death in cancer patients. However, the molecular mechanism of this process is largely unknown. NDP kinase A is one of the molecules participating in tumor metastasis. A strong correlation exists between the level of NDP kinase A expression and tumor metastatic potential. In certain tumor types (i.e., ovarian and breast tumors), a reduced level of NDP kinase A expression is correlated with high metastatic potential, indicating that NDP kinase A behaves as a metastasis suppressor. In fact, animal studies demonstrated that the metastasis of breast tumors is reduced by increasing NDP kinase A level. On the other hand, an elevated NDP kinase A expression has been detected in other types of tumors with high metastatic potential, including prostate tumor and neuroblastoma. This suggests that NDP kinase A may act as a metastasis promoter in the latter tumor types. 

 

In this pilot study, we hypothesize that NDP kinase A interacts with tissue-specific proteins in order to act as either a metastasis suppressor or a metastasis promoter. With a powerful and sensitive yeast two-hybrid system, we screened two cDNA libraries derived from ovarian and prostatic tissues. A number of protein partners of NDP kinase A were found. The identities of these partners of NDP kinase A were obtained by DNA sequencing followed by searching the DNA databases. Northern blot analysis indicates that the partners of NDP kinase A are expressed differentially in various human tissues examined. For example, the mRNA level of  #101-24 partner in the prostate tissue is 3-fold higher than that in the ovary tissue, whereas the mRNA levels of #102-1 and #102-7 partners in prostate are 2-fold lower than that in ovary.

 

The results from this pilot study will allow us to reveal pathway(s) via which NDP kinase A contributes to tumor metastasis in tissue-specific manner, which in turn may facilitate therapeutic interventions for cancer patients.

 

 

 

 

 

The experiments we are carrying out use a novel approach developed in our lab (Random Homozygous Knock-Out; RHKO) to identify genes whose actions affect the ability of ovarian and prostate cancers s to metastasize.  We have designed and tested novel procedures that allow this procedure to be used for the isolation of genes whose abnormal regulation leads to the acquisition of metastatic properties by previously non-metastatic human cancer cells. Of particular interest among the genes we have identified in prostate cancers using this approach is one that encodes a recently-discovered enzyme that affects the "tagging" of certain proteins for degradation. The product of this gene, which is designated Li-3, has structural features in common with ubiquitin ligases, which are known to be able to control cancer cell growth.  We currently are focusing on understanding the molecular basis for the effects of the Li-3 gene product on metastasis.

 

 

1.       Li L, Liao J, Ruland J, Mak TW, and Cohen SN. A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control. Proc Natl Acad Sci U S A. 2001. 98(4): p. 1619-24.

 

 

Combining Radiation Therapy with Cancer Gene Immunotherapy

Graeme J. Dougherty, Ph.D.

University of California, Los Angeles

Pilot and Feasibility Study Award, $169,927 / 24 mos.

Prostate Cancer

 

There is a need to improve on the current treatment of prostate cancer. Although radiation therapy is an effective means of controlling localized disease, at time of diagnosis tumor cells may have already spread from the prostate in one out of every two patients. Reflecting this situation, as many as one in three patients with apparently localized prostate cancer may relapse following treatment.

 

The objective of this study was to improve the efficacy of radiation therapy in the treatment of locally advanced and metastatic prostate cancer. Specifically, we explored the possibility of using gene transfer technology to enhance the ability of the immune system to recognize and respond to tumor cells killed by exposure to radiation. It was hoped that immune cells activated in this way would seek out and destroy tumor cells lying outside the initial treatment field and prevent regrowth of the primary tumor.

 

Using a preclinical model of prostate cancer, we have demonstrated that a soluble molecule known as IL-3 can dramatically enhance the generation of antitumor immunity following both radiation therapy and photodynamic therapy. We have gained insights into the mechanisms by which IL-3 mediates this effect and have demonstrated that the immune responses produced can be of sufficient magnitude to prevent local relapse and/or the growth of small tumor deposits at distant tissue sites. Together, these data provide evidence that gene therapy-based approaches may indeed improve the effectiveness of radiation therapy in the treatment of prostate cancer. Since prostate cancer is the major malignancy affecting Californian males improving, therapeutic outcome would be of immense benefit to the community as a whole.

 

1.       Chiang CS, Hong JH, Wu YC, McBride WH, Dougherty GJ. Combining radiation therapy  with interleukin-3 gene immunotherapy. Cancer Gene Ther, 2000; 7: 1172-8.

2.       Wu YZ, Hong JH, Huang HH, Dougherty GJ, McBride WH, Chiang CS. Mechanisms  mediating the effects of IL-3 gene expression on tumor growth.[In Process Citation]. J Leukoc  Biol, 2000; 68: 890-6.

 

 

 

Genetic Immunotherapy for Prostate Cancer

Steven M. Dubinett, M.D.

University of California, Los Angeles

Pilot and Feasibility Study Award, $201,630 / 24 mos.

Prostate Cancer

 

Prostate cancer is the most common cancer in men in the United States. New therapies are needed for prostate cancer to either prevent or treat its spread throughout the body. This research focuses on boosting the immune system against prostate cancer by using specialized immune enhancing cells called dendritic cells. This new form of therapy uses dendritic cells that are removed from the blood, activated in test tubes, and then injected into prostate tumors. This type of therapy is able to completely cure mice with cancer. In order to develop dendritic cell immunotherapy for patients with prostate cancer, this research focuses on determining how this therapy works in mice with prostate cancer. This is research that can be translated from laboratory studies into clinical trials in patients with prostate cancer. Thus, results of this study may have a major impact on the treatment of prostate cancer. Our current data on trafficking suggests that intratumoral dendritic cell administration leads to accumulation of dendritic cells at lymph node sites. This is an important contribution because it begins to explain systemic antitumor responses. Our studies have documented that intratumoral injection of the potent immune activating cells called dendritic cells are able to significantly reduce the size of tumors in mice. This therapy leads to activation of immunity against the tumor cells.

 

 

 

 

Molecular Basis of Signal Transduction Mediated by p130Cas

Kathryn R. Ely, Ph.D.

The Burnham Institute

Pilot and Feasibility Study Award, $257,400 / 24 mos.

General Cancer Biology

General Cancer

 

Interactions of cells with the extracellular matrix that surrounds them influence a variety of biological processes including cell growth, differentiation into tissue type and cell migration.  There are receptors called integrins on the surface of cells, that transmit the signal from the outside of the cell to the interior where these signals are shunted through signaling pathways to affect critical normal biochemical functions.  This integrin-mediated signaling is also involved in malignant processes such as tumor development, tumor invasion or tumor metastasis.  In this project we target a new adaptor molecule (Cas) that plays an important role in these signaling pathways.  There is evidence that Cas may act at a point of convergence of several pathways by binding to proteins in distinct cascades.  To understand the role of Cas in cancer, we began to dissect the functional domains of the protein and to analyze each of the protein-protein interactions mediated by Cas.  Ultimately, the data will contribute to an understanding of the functional role of Cas in transmitting integrin signals.  The research effort was multidisciplinary combining molecular biology and structural biology.  The work was performed under the CRP priority area of General Cancer Biology with a focus on relationships between tumors and the extracellular matrix and the integrin-mediated effect of these interactions on the proliferation and progression of the cancer cell.

 

So far, there is little structural information on the protein-protein interactions of adaptor and signaling molecules and Cas represents an innovative direction to define the contacts for such molecules.  The project provides a new perspective to look at cell signaling and cancer.  Interestingly, it has recently been shown that Cas is 90% identical to a newly discovered protein BCAR1 that is associated with resistance to tamoxifen in breast cancer cells.  Thus, this signaling molecule may be useful as a prognostic indicator for one or more types of cancer.  With funding from CRP as a Pilot and Feasibility award, milligram quantities of functional domains of Cas have been produced and characterized by biochemical and biophysical methods. These domains are highly suitable for structural analyses in future months.

 

 

1.       Briknarova K, Takayama S, Brive L, Havert ML, Knee DA, Velasco J, Homma S, Cabezas  E, Stuart J, Hoyt DW, Satterthwait AC, Llinas M, Reed JC, Ely KR. Structural analysis of  BAG1 cochaperone and its interactions with Hsc70 heat shock protein. Nat Struct Biol, 2001; 8:  349-52.

2.       Nasertorabi F, Garcia-Guzman M, Briknarova K, Larsen E, Havert ML, Vuori K, Ely KR. Organization of functional domains in the docking protein p130Cas. Biochem Biophys Res Commun. 2004 Nov 19;324(3):993-8.

 

 

 

Targeting Androgen-Regulated Transcription in Prostate Cancer

Christopher P. Evans, M.D.

University of California, Davis

New Investigator Award, $ 278,005 / 36 mos.

Prostate Cancer

 

Our California Cancer Research grant has investigated mechanisms that promote the growth, invasion and spread of human prostate cancer. This cancer is initially slow growing and effectively treated when confined to the prostate, but once it spreads to lymph nodes and bone its outcome is dismal. In fact, these patients live an average of only two years.  Prostate cancer is fueled by the male hormone, testosterone, and upon its removal the tumor regresses. However, some of the prostate cancer cells can grow and thrive without testosterone and are called androgen (testosterone)-insensitive.  Once patients have progressed to this state, their average life expectancy is only six  months. Since removal of the testicles was initiated as a treatment form for androgen-insensitive prostate cancer in the 1940s, no further advancements have been made to improve outcome in this group of patients.

 

Urokinase-type plasminogen activator (u-PA) is a small protein known to be overproduced by cancer cells, which enhances their ability to grow, invade, and spread.  Certain signals stimulate cancer cells and, through signal-transduction pathways, these signals are carried down to the nucleus of the cell and activate certain genes.  However, we have proposed and demonstrated that in prostate cancer the activation of the u-PA gene is also under the regulation of a hormone-response element (HRE). The HRE is a small sequence of DNA that we recognize to be present in the u-PA gene. When testosterone binds to the androgen receptor, this complex attaches to the HRE and either activates or represses the expression of the gene.  Our work in the past 3 years has demonstrated that activation of the HRE results in repressed expression of the u-PA gene.  These observations are important, because they delineate a mechanisms that can be targeted for therapeutic intervention.  Our work has been published in the International Journal of Cancer.  In addition, we have delineated the signal-transduction pathways that regulate u-PA expression in human prostate cancer. This is also important because these molecular pathways are potential targets as well.  This set of experiments was published in Biochemical and Biophysical Research Communications.