- Part 3 in the NKX3.1 Series: NKX3.1 as a Diagnostic and Therapeutic Target in Human Prostate Cancers
- New Prostate Tumor Suppressor Gene
- Part 2 in the Nkx3.1 Series: Post-Translational Regulation of the Nkx3.1 Protein
- Part 1 in the Nkx3.1 Series: Nkx3.1: A Homeobox Gene with Key Roles in Prostate Development and Cancer
- Genetic Variation and Prostate Cancer Risk in African American Men
- Erythrocyte Cell Surface Protein May Hold Link to Increased Mortality from Prostate Cancer in the African American Population
- Activating T Cells to Annihilate Prostate Cancer Cells
- The "R.I.T.E." Stuff: A New Combination Therapy for Prostate Cancer
- New Imaging Method Provides a "Before and After" Snapshot of the Prostate
- Gene Fusions: Triggers for Developing Prostate Cancer
Part 3 in the NKX3.1 Series: NKX3.1 as a Diagnostic and Therapeutic Target in Human Prostate Cancers
Posted September 11, 2006
Edward Gelmann, M.D., Georgetown University; Wen-Xin Huang, Ph.D., Georgetown University
Decreased expression of the NKX3.1 tumor suppressor is an initiating event in prostate carcinogenesis. NKX3.1 is present almost exclusively in prostate luminal epithelial cells and maps to the minimal region of chromosome 8p that undergoes loss of heterozygosity in 60% to 80% of prostate tumors. Researchers seek to understand how NKX3.1 is altered in prostate tumors and how it could be used as a biomarker for early prostate cancer.
Dr. Gelmann and Dr. Huang of Georgetown University studied alterations of NKX3.1 in human tumors with funding from a DOD PCRP FY97 Idea Development Award and a FY01 Postdoctoral Traineeship Award. The research team measured NKX3.1 protein levels in prostate tumor tissues by performing immunohistochemistry on tissue microarray samples. They found that decreased NKX3.1 levels were strongly associated with hormone-refractory disease and advanced tumor stage. The research team also examined the status of the NKX3.1 gene in these same samples. Loss of heterozygosity of NKX3.1 was observed in 27 of 43 tissues tested. In 33 of 40 samples tested, the NKX3.1 gene was methylated to a greater degree in malignant cells than in adjacent normal cells. The investigators studied the NKX3.1 gene alteration, C154T polymorphism, and found that it was present in approximately 11% of healthy men with equal distribution among Caucasians and African Americans. The presence of the polymorphism was associated with aggressive prostate cancer (defined by stage C or D or Gleason score greater than 7). This polymorphism codes for a variant protein (R52C) that is phosphorylated to a lesser degree by protein kinase C and differs from wild-type NKX3.1 in its DNA binding abilities. Collectively, these findings implicate NKX3.1 as a promising new candidate biomarker for prostate cancer with potential as both a diagnostic and therapeutic target.
The NKX3.1 highlights series illustrates the importance of critical developmental genes in regulating cell growth and how their disruption leads to cancers. The NKX3.1 story illustrates how the work of developmental biologists is helping researchers understand pathological processes and improve the diagnosis and treatment of cancer.
Publications for Dr. Gelmann and Dr. Huang:
Asatiani E, Huang WX, Wang A, Rodriguez Ortner E, Cavalli LR, Haddad BR, and Gelmann EP. 2005. Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. Cancer Research 65(4):1164-1173.
Gelmann EP, Steadman DJ, Ma J, Ahronovitz N, Voeller HJ, Swope S, Abbaszadegan M, Brown KM, Strand K, Hayes RB, and Stampfer MJ. 2002. Occurrence of NKX3.1 C154T polymorphism in men with and without prostate cancer and studies of its effect on protein function. Cancer Research 62(9):2654-2659.
Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP, Gelmann EP. 2000. Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Research 60(21):6111-6115.
Links for Dr. Gelmann and Dr. Huang:
Cancer is believed to result from an accumulation of genetic alterations; however, few prostate cancer genes have been identified. Deletions on the long arm of chromosome 16 are strongly associated with prostate cancer progression, suggesting the presence of one or more tumor suppressor genes in that region. With funding from a Department of Defense Prostate Cancer Research Program Fiscal Year 1997 New Investigator Award and the 2003 Consortium Award "A Synergy Consortium Targeting the Lethal Phenotypes of Prostate Cancer" directed by Dr. Jonathan Simons, Dr. Dong and his colleagues at Emory University searched for candidate tumor suppressor genes on chromosome 16q. Dr. Dong's research team narrowed the region of deletion to a small 861 kb region, at 16q22, and subsequently identified ATBF1 as a candidate for the tumor suppressor gene. ATBF1 is a transcription factor and homeodomain protein that negatively regulates the Myb oncoprotein and the alpha-fetoprotein oncogene. The researchers found that ATBF1 mRNA expression was reduced in prostate cancers compared to normal prostate tissue. The investigators identified 22 unique somatic mutations in ATBF1, many of which impair ATBF1 function, and showed that one or more of these mutations was present in over 36% of the tumors tested. Further evidence for a tumor suppressor role for ATBF1 was the inhibition of prostate cell proliferation by ATBF1. These findings suggest that loss of ATBF1 function, through either deletion or mutation, might increase susceptibility to prostate cancer. Therefore, ATBF1 could be a useful new biomarker, and its further study could lead to a prospective target for the development of novel therapeutics.
Sun X, Frierson HF, Chen C, Li C, Ran Q, Otto KB, Cantarel BL, Vessella RL, Gao AC, Petros J, Miura Y, Simons JW, Dong JT. 2005. Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer. Nature Genetics 37(4):407-412.
Nkx3.1 is a prostate tumor suppressor gene that is inactivated through haploinsufficiency and failure of the Nkx3.1 protein to accumulate to functional levels. Dr. Charles Bieberich of the University of Maryland is studying the mechanisms causing low levels of Nkx3.1 protein in prostate tumors. With funding from a Department of Defense Prostate Cancer Research Program Fiscal Year 2002 Idea Development Award, Dr. Bieberich tested his hypothesis that the failure of Nkx3.1 to accumulate to a functional level is due to rapid turnover of the protein resulting from altered regulation of modifications that mark NKX3.1 for proteolysis. Dr. Bieberich's research team discovered that the Casein Kinase 2 alpha subunit (CK2 a') phosphorylated Nkx3.1. Interestingly, CK2 is a regulator of cell differentiation, proliferation, and death, as well as of transcription factor activity. CK2 phosphorylation of Nkx3.1 on residues Thr89 and Thr93 stabilized Nkx3.1 and protected it from proteosomal degradation. Pharmacological inhibition of CK2 activity resulted in sharp decreases of Nkx3.1 mRNA and protein; treatment with proteasome inhibitors reversed this effect. Dr. Bieberich's group found that Nkx3.1 protein was marked for proteasomal destruction by polyubiquitination of Nkx3.1 protein mediated by the ubiquitin-proteasome system. These findings suggest that modulating CK2 activity or designing stable isoforms of Nkx3.1 with modified Thr89 and Thr93 residues could provide novel strategies for restoring Nkx3.1 function in prostate tumors.
While Part 2 in the Nkx3.1 series showed the importance of maintaining proper levels of Nkx3.1 to prevent prostate tumors and suggested potential new therapeutic strategies, Part 3 will focus on exploring the potential of Nkx3.1 as both a diagnostic and therapeutic target. Exciting new findings of Nkx3.1 alterations in human tumors will be featured.
Li X, Guan B, Maghami S, and Bieberich CJ. 2006. NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells. Molecular and Cellular Biology, 8:3008-3017.
Part 1 in the Nkx3.1 Series: Nkx3.1: A Homeobox Gene with Key Roles in Prostate Development and Cancer
Posted July 28, 2006
Cory Abate-Shen, Ph.D., University of Medicine and Dentistry of New Jersey; Michael Shen, Ph.D., University of Medicine and Dentistry of New Jersey; Xuesong Ouyang, Ph.D., University of Medicine and Dentistry of New Jersey
The Nkx3.1 tumor suppressor is a homeobox gene that is a central regulator of normal differentiation and development of the prostate gland. The Nkx3.1 gene shows tissue-specific expression in the male urogenital system, and loss of function of Nkx3.1 is an initiating event in prostate carcinogenesis. Prostate cancer researchers, led by Dr. Abate-Shen, are seeking to better understand the normal cellular functions of Nkx3.1 in order to understand why disruption of Nkx3.1 leads to prostate cancer.
Dr. Abate-Shen, Dr. Shen, and Dr. Ouyang of the University of Medicine and Dentistry of New Jersey are studying the functions of Nkx3.1 in prostate cell growth and development with funds from a Department of Defense (DOD) Prostate Cancer Research Program (PCRP) Fiscal Year 1997 (FY97) New Investigator Award, FY99 Idea Development Award, and FY02 Postdoctoral Traineeship Award. The research team developed heterozygous (+/-) and homozygous null (-/-) mouse models of Nkx3.1. The homozygous null mice showed defects in prostate ductal morphogenesis, altered production of prostatic secretory proteins, and altered cellular differentiation. Both the homozygous null and heterozygous mice exhibited prostatic epithelial hyperplasia and dysplasia. Upon aging, the homozygous null strains of Nkx3.1 mutant mice developed prostatic intraepithelial neoplasia (PIN), the presumed precursor of human prostate cancer. Therefore, the Nkx3.1 mutant mouse model is useful for studying early stages of prostate carcinogenesis. The researchers performed gene expression profiling of mutant and wild-type mice and found that the mutant mice showed deregulated expression of several antioxidant and prooxidant enzymes. The formation of PIN in the mutant mice was associated with increased oxidative damage of DNA. Progression to adenocarcinoma correlated with further deregulation of antioxidants and increased oxidative damage to DNA and protein. The research team also studied the cooperativity of Nkx3.1 with other genes in mouse models of carcinogenesis. Loss of function of Nkx3.1 cooperated with loss of function of the Pten suppressor gene, and this cooperativity resulted in the synergistic activation of Akt. The Nkx3.1:Pten mutant mice developed invasive adenocarcinoma, which was accompanied by metastases to lymph nodes. Hence, this mouse model is useful for studying advanced prostate cancer. Finally, the investigators created a triple mutant (Nkx3.1, Pten, and p27kip1) mouse model and showed that prostate epithelium was sensitive to the gene dosage of p27kip1 and cyclin D1. These models could provide vital information about the function of Nkx3.1 at various stages of prostate carcinogenesis.
While Part 1 in the Nkx3.1 highlight series showed the importance of the presence of functional Nkx3.1 for normal growth and development of the prostate, Part 2 will highlight the significance of maintaining proper levels of Nkx3.1 to prevent prostate tumors and will suggest potential new therapeutic strategies.
Ouyang X, DeWeese TL, Nelson WG, and Abate-Shen C. 2005. Loss-of-function of Nkx3.1 promotes increased oxidative damage in prostate carcinogenesis. Cancer Research 65(15):6773-6779.
Gao H, Ouyang X, Banach-Petrosky W, Borowsky AD, Lin Y, Kim M, Lee H, Shih WJ, Cardiff RD, Shen MM, and Abate-Shen C. 2004. A critical role for p27kip1 gene dosage in a mouse model of prostate carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 101(49):17204-17209.
Shen MM and Abate-Shen C. 2003. Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Developmental Dynamics 228(4):767-778.
Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD, Desai N, Gregg JP, Borowsky AD, Cardiff RD, and Shen MM. 2003. Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer Research 63(14):3886-3890.
Kim MJ, Bhatia-Gaur R, Banach-Petrosky WA, Desai N, Wang Y, Hayward SW, Cunha GR, Cardiff RD, Shen MM, and Abate-Shen C 2002. Nkx3.1 mutant mice recapitulate early stages of prostate carcinogenesis. Cancer Research 62(11):2999-3004.
Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons R, Shen MM, and Abate-Shen C. 2002. Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 99(5):2884-2889.
Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai N, Young P, Norton CR, Gridley T, Cardiff RD, Cunha GR, Abate-Shen C, and Shen MM. 1999. Roles for Nkx3.1 in prostate development and cancer. Genes and Development 1999 13(8):966-977.
African American men have a 60% greater incidence of prostate cancer and a twofold higher mortality rate than Caucasian men. These numbers can be further translated into African American men having one of the highest prostate cancer incidence rates in the world. The reason for this significant health disparity is unknown, but Dr. Matthew Freedman of Massachusetts General Hospital believes this disparity is due, in part, to genetic factors.
With funding from the Department of Defense Prostate Cancer Research Program Fiscal Year 2001 Health Disparity Training - Prostate Scholar Award, Dr. Freedman is attempting to identify risk factors for prostate cancer in African Americans through the use of large-scale genomic approaches. Dr. Freedman and his research team first assessed the impact of population stratification on genetic association studies. Population stratification occurs when allele frequencies differ between cases and controls due to ancestry rather than association of genes with disease and can result in false-positive associations of genes with disease. Dr. Freedman's team found that stratification existed in several case-control studies and determined methods for measuring and controlling for the amount of stratification in a study. Follow-up studies have supported their conclusion that population stratification is a real (but manageable) issue in association studies.
The research team also analyzed the role of high priority candidate genes (androgen receptor [AR] and insulin-like growth factor 1 [IGFI]) in prostate cancer risk in large case-control association studies. Previous studies showed inconsistent conclusions for the role of genetic variants of androgen receptor in prostate cancer risk, possibly due to small sample size and analysis of limited regions of the androgen receptor gene. In contrast, Dr. Freedman's team analyzed both coding and noncoding regions of the androgen receptor gene in blood samples from a large, multiethnic cohort. They found no evidence of an association between genetic variants of the androgen receptor and prostate cancer risk. The investigators then examined the IGF-1 locus in the same cohort. This study was the first comprehensive evaluation of the relationship between genetic variants in IGF-1 and prostate cancer risk. They found two SNPs that were strongly associated with prostate cancer risk, a risk that was consistent across all ethnic groups tested (African Americans, Native Hawaiians, Japanese, Latinos, and Caucasians). Dr. Freedman is now using a new genome wide approach termed admixture mapping to search for risk loci in sporadic prostate cancer in an African American population. This approach could identify multiple gene variants that contribute to increased risk of prostate cancer in African Americans, thereby leading to more effective screening, prevention, and treatment strategies.
Cheng I, Stram DO, Penney KL, Pike M, Le Marchand L, Kolonel LN, Hirschhorn J, Altshuler D, Henderson BE, and Freedman ML. 2006. Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. Journal of the National Cancer Institute 98(2):123-134.
Campbell CD, Ogburn EL, Lunetta KL, Lyon HN, Freedman ML, Groop LC, Altshuler D, Ardlie KG, and Hirschhorn JN. 2005. Demonstrating stratification in a European American population. Nature Genetics 37(8):868-872.
Freedman ML, Pearce CL, Penney KL, Hirschhorn JN, Kolonel LN, Henderson BE, and Altshuler D. 2005. Systematic evaluation of genetic variation at the androgen receptor locus and risk of prostate cancer in a multiethnic cohort study. American Journal of Human Genetics 76(1):82-90.
Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato CN, Pato MT, Petryshen TL, Kolonel LN, Lander ES, Sklar P, Henderson B, Hirschhorn JN, and Altshuler D. 2004. Assessing the impact of population stratification on genetic association studies. Nature Genetics 36(4):388-393.
Erythrocyte Cell Surface Protein May Hold Link to Increased Mortality from Prostate Cancer in the African American Population
Posted April 10, 2006
Alex Lentsch, Ph.D., University of Cincinnati College of Medicine, Cincinnati, Ohio
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among men in the United States. African American men have a 60% greater incidence of prostate cancer and a twofold higher mortality rate than Caucasian men. The reason for this disparity has long been unknown. Incidentally, approximately 70% of African Americans and more than 95% of Africans in malaria-endemic regions lack expression of a blood group antigen on their erythrocytes. This antigen, called Duffy antigen/receptor for chemokines (DARC), is required for malaria infection, and its lack of expression on erythrocytes is a genetic mechanism of protection against malaria in this population. Interestingly, DARC also binds to and clears a subgroup of CXC chemokines that are angiogenic and known to be involved in the development of tumor vasculature and tumor growth.
Given the importance of angiogenic chemokines in the development of tumor vascular networks and the chemokine binding properties of DARC, Dr. Alex Lentsch of the University of Cincinnati College of Medicine hypothesized that there may be a link between the lack of DARC expression on erythrocytes and the greater incidence and mortality of prostate cancer in the African American population. With funding from a Department of Defense Prostate Cancer Research Program Fiscal Year 2001 New Investigator Award, Dr. Lentsch and his colleagues used a transgenic model of prostate cancer with DARC-deficient mice to test the hypothesis that lack of DARC expression on erythrocytes contributes to increased prostate tumor growth. In vitro, erythrocytes from wild-type mice but not DARC-deficient mice cleared angiogenic CXC chemokines produced by prostate cancer cells in culture and reduced the ability of prostate tumor cell secretions to induce endothelial cell chemotaxis, a process that facilitates angiogenesis. In vivo, the onset of prostate cancer was similar in DARC-bearing and DARC-deficient mice, but the tumors from the latter group had higher intra-tumor concentrations of angiogenic chemokines, increased tumor vessel density, and greatly augmented prostate tumor growth. The data suggest that the lack of erythroid DARC, as occurs in the majority of African Americans, may be a contributing factor to the increased mortality from prostate cancer in this population.
Shen H, Schuster R, Stringer KF, Waltz SE, and Lentsch AB. 2006. The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. The FASEB Journal 20:59-64.
Lentsch AB. 2002. The Duffy antigen/receptor for chemokines (DARC) and prostate cancer. A role as clear as black and white? The FASEB Journal 16:1093-1095.
Activating T Cells to Annihilate Prostate Cancer Cells
Posted March 29, 2006
Douglas McNeel, University of Wisconsin, Madison, Wisconsin; Laura Johnson, University of Wisconsin, Madison, Wisconsin; and David Peace, University of Illinois at Chicago, Chicago, Illinois
Dr. Douglas McNeel and Dr. Laura Johnson of the University of Wisconsin and Dr. David Peace of the University of Illinois at Chicago believe the immune system holds the key to curing prostate cancer. They each plan to exploit a cellular mechanism that invokes immune system attack of prostate cancer cells. When healthy prostate cells become malignant, proteins not ordinarily expressed by prostate cells are produced. Presentation of these abnormal protein fragments on the malignant cells' surface can signal the body's T lymphocytes (both "helper T cells" and "killer T cells") to destroy those cancer cells. Both research groups have focused on identifying proteins capable of activating a patient's T cells to target prostate cancer cells expressing the abnormal protein fragments. Dr. McNeel and Dr. Johnson's strategy is to develop a DNA vaccine encoding prostatic acid phosphatase (PAP), while Dr. Peace's approach is to develop a vaccine based on peptides derived from prostate-specific antigen (PSA).
With funding from a Department of Defense (DOD) Prostate Cancer Research Program (PCRP) Fiscal Year (FY) 1999 Postdoctoral Traineeship Award to Dr. McNeel and a FY 2003 Postdoctoral Traineeship Award to Dr. Johnson, the University of Wisconsin team showed that T cell-proliferative responses specific for PAP could be detected in patients with prostate cancer. The research team tested the safety and immunological efficacy of a DNA vaccine encoding PAP in a rodent model. No toxicities were observed, and the vaccine elicited PAP-specific helper T cells. A DOD PCRP FY 2005 Clinical Trial Award granted to Dr. McNeel supports a Phase I clinical trial to determine the safety and efficacy of this vaccine in patients with stage D0 prostate cancer.
Funds from DOD PCRP FY 1997 and FY 2000 Idea Development Awards have allowed Dr. Peace to concentrate on identifying immunogenic peptides from PSA, which is expressed at high levels in many prostate tumors. Dr. Peace has identified a peptide fragment from PSA, called PSA146-154 peptide, that elicits an immune response in T cell lines derived from patients with advanced hormone-refractory prostate cancer. With proof-of-concept in hand, Dr. Peace initiated a clinical trial using either intradermal vaccination with PSA146-154 peptide or intravenous administration of autologous dendritic cells pulsed with PSA146-154 peptide. Overall, specific T cell immunity was induced in 50 percent of patients with locally advanced and hormone-sensitive metastatic prostate cancer. However, the intradermal vaccination appeared to be more effective than intravenous administration in the groups of patients tested.
Utilizing the power of the immune system offers new potential for conquering prostate cancer. The complementary research approaches to activate the immune system by Dr. McNeel, Dr. Johnson, and Dr. Peace could lead to novel vaccines against prostate cancer.
Publications for Douglas McNeel and Laura Johnson:
Johnson LE, Frye TP, Arnot AR, Marquette C, Couture LA, Gendron-Fitzpatrick A, and McNeel DG. 2006. Safety and immunological efficacy of a prostate cancer plasmid DNA vaccine encoding prostatic acid phosphatase (PAP). Vaccine 24(3):293-303.
Zlotocha S, Staab MJ, Horvath D, Straus J, Dobratz J, Oliver K, Wasielewski S, Alberti D, Liu G, Wilding G, Eickhoff J, and McNeel DG. 2005. A phase I study of a DNA vaccine targeting prostatic acid phosphatase in patients with stage D0 prostate cancer. Clinical Genitourinary Cancer 4(3):215-218.
McNeel DG, Nguyen LD, and Disis ML. 2001. Identification of T helper epitopes from prostatic acid phosphatase. Cancer Research 61(13):5161-5167.
McNeel DG, Nguyen LD, Ellis WJ, Higano CS, Lange PH, Disis ML. 2001. Naturally occurring prostate cancer antigen-specific T cell responses of a Th1 phenotype can be detected in patients with prostate cancer. Prostate 47(3):222-229.
Publications for David Peace:
Perambakam S, Hallmeyer S, Reddy S, Mahmud N, Bressler L, DeChristopher P, Mahmud D, Nunez R, Sosman JA, and Peace DJ. 2005. Induction of specific T cell immunity in patients with prostate cancer by vaccination with PSA146-154 peptide. Cancer Immunology and Immunotherapy Nov 10:1-10 (e-published ahead of print).
Perambakam S, Srivastava R, and Peace DJ. 2005. Distinct cytokine patterns exist in peripheral blood mononuclear cell cultures of patients with prostate cancer. Clinical Immunology 117: 94-99.
Perambakam S, Xue BH, Sosman JA, and Peace DJ. 2002. Induction of Tc2 cells with specificity for prostate-specific antigen from patients with hormone-refractory prostate cancer. Cancer Immunology and Immunotherapy 51(5):263-270.
Links for Dr. McNeel and Dr. Johnson:
Links for Dr. Peace:
Conventional chemotherapy is often unable to elicit a sustained response in patients with advanced prostate cancer. One mechanism by which tumors acquire this resistance to chemotherapy is through over-expression of the survival factor BCL-2. Dr. Robert DiPaola of the University of Medicine and Dentistry of New Jersey and colleagues performed in vitro experiments, which suggested that a combination of 13-cis retinoic acid and alpha interferon could enable cells to overcome resistance to chemotherapeutic drugs by downregulating the expression of BCL-2. Dr. DiPaola hypothesized that 13-cis retinoic acid and alpha interferon supplementation would enhance the efficacy of the conventional chemotherapy regimen of taxotere/estramustine. Using funding from a Department of Defense Prostate Cancer Research Program Fiscal Year 2001 Prostate Cancer Clinical Trial Award, Dr. DiPaola and colleagues used these four compounds (abbreviated R.I.T.E.) to perform a combined phase I/II study in patients with hormone-refractory prostate cancer (HRPC). Patients (the majority of whom did not respond to previous chemotherapy treatment) received retinoic acid (1 mg/kg, days 1 through 4) and alpha interferon (six million units/m2, days 1 through 4), estramustine (280 mg, three times a day, days 1 through 5) and increasing doses of taxotere (0, 40, 50, 60 mg/m2) on day 2. The regimen was repeated every 21 days. Peripheral blood mononuclear cells were obtained prior to therapy and on days 2 through 4 of the first cycle of therapy to assess the effect on BCL-2 by immunoblot. The therapy was well-tolerated, with fatigue, hypophosphotemia, and nausea being the predominant side effects. During phase I clinical trials, BCL-2 and prostate-specific antigen (PSA) levels were decreased. Phase II clinical trials are under way (for more information, see http://www.clinicaltrials.gov/ct/show/NCT00176527?order=9).
Stein MN, Todd MB, Morton RA, Doyle-Lindrud S, Goodin S, Shah A, Shih W, Garikapaty V, Dvorzhinski D, and DiPaola RS. 2005. A completed phase I trial of 13-cis retinoic acid, alpha interferon, docetaxel, and estramustine (R.I.T.E.) for the treatment of hormone refractory prostate cancer (HRPC) and other advanced malignancies and effect on BCL-2 expression. American Society of Clinical Oncology (ASCO) Annual Meeting, Abstract No. 4740.
Thalasila A, Poplin E, Shih J, Dvorzhinski D, Capanna T, Doyle-Lindrud S, Beers S, Goodin S, Rubin E, DiPaola RS. 2003. A phase I trial of weekly paclitaxel, 13-cis-retinoic acid, and interferon alpha in patients with prostate cancer and other advanced malignancies. Cancer Chemotherapy and Pharmacology 52(2):119-124.
Breakthroughs in medical imaging technologies have produced instrumentation capable of capturing images of human anatomical structures at unprecedented levels of detail. These imaging technologies are used routinely for the diagnosis and treatment of prostate cancer. In their short clinical history, they have improved the efficacy of a number of different prostate cancer treatment modalities. The next challenge for improving image-guided prostate cancer therapies involves the integration of structural/anatomical details with real-time, functional data from two or more different imaging techniques. Image registration is an emerging field of study that is focused on providing these composite images. Professor Baowei Fei of Case Western Reserve University envisions developing a minimally invasive prostate cancer treatment based on image registration methods. Dr. Fei and his colleagues are particularly interested in interventional magnetic resonance imaging (iMRI) to guide biopsy needles for diagnosis and treatment. With funding from a Department of Defense Prostate Cancer Research Program Fiscal Year 2001 Postdoctoral Traineeship Award, Dr. Fei has created novel image registration techniques to combine multiple imaging modalities for early detection and image-guided therapies for prostate cancer. In particular, he is exploring a novel aspect of image registration to combine iMRI before-and-after treatment images to monitor radiofrequency (RF) thermal ablation of prostate cancer. This will provide the detailed information necessary to determine whether the treatment was adequate. Due to its small size and elastic properties, the prostate represents a particularly challenging target for image registration as it is easily deformable by patient motion and changes in bladder shape. Dr. Fei recently developed a "non-rigid" registration method for prostate therapy by RF. The registration method features hundreds of control points as part of the algorithm to account for tissue deformation. The control points are then optimized to assure accurate tumor localization. The control points, when combined with thin plate spline warping, rectify prostate deformation in the registered image. This "non-rigid" approach represents a significant improvement over "rigid" attempts to register the prostate. This tool will undoubtedly improve prostate therapy by RF thermal ablation treatment. Its utility may improve dosage planning for both external beam and brachytherapy treatments of prostate cancer.
Fei B, Wang H, Muzic RF Jr, Flask CA, Wilson DL, Duerk JL, Oleinick NL. 2006. "Deformable and rigid registration of microPET and high-resolution MR images for photodynamic therapy of cancer in mice," Medical Physics, (In Press)
Fei B, Duerk JL, Sodee DB, and Wilson DL. 2005. Semiautomatic nonrigid registration for the prostate and pelvic MR volumes. Academic Radiology 12:815-824.
Fei B, Lee Z, Boll DT, Duerk JL, Sodee DB, Lewin JS, and Wilson DL. 2004. Registration and fusion of SPECT, high resolution MRI and interventional MRI for thermal ablation of prostate cancer. IEEE Transductions on Nuclear Science 51:177-183.
Fei B, Kemper C, and Wilson DL. 2003. A comparative study of warping and rigid body registration for the prostate and pelvic MR volumes. Computer Medical Imaging and Graphics 27:267-281.
Fei B, Duerk JL, Boll DT, Lewin JS, and Wilson DL. 2003. Slice to volume registration and its potential application to interventional MRI guided radiofrequency thermal ablation of prostate cancer. IEEE Transactions on Medical Imaging 22:515-525.
Fei B, Lee Z, Duerk JL, and Wilson DL. 2003. Image registration for interventional MRI guided procedures: similarity measurements, interpolation methods, and applications to the prostate. Lecture Notes in Computer Science 2717:321-329.
Fei B, Lee Z, Boll DT, Duerk JL, Lewin JS, and Wilson DL. 2003. Image registration and fusion for interventional MRI guided thermal ablation of prostate cancer. Lecture Notes in Computer Science 2879:364-372.
Fei B, Duerk JL, and Wilson DL. 2002. Automatic 3D registration for interventional MRI-guided treatment of prostate cancer. Computer Aided Surgery 7:257-267.
Dr. Arul Chinnaiyan and Dr. Rohit Mehra of the University of Michigan have discovered the first evidence that gene fusions play a widespread role in the development of prostate cancer. Gene fusions are commonly found in hematologic malignancies such as leukemias and lymphomas, but have not been implicated previously in the development of solid tumors. Supported in part by funding from a Department of Defense Prostate Cancer Research Program Fiscal Year 2002 Idea Development Award and a Fiscal Year 2004 Health Disparity Training - Prostate Scholar Award, the investigators employed a novel bioinformatics strategy to identify gene fusions in prostate cancers. Dr. Chinnaiyan and Dr. Mehra hypothesized that gene fusions would result in overexpression of oncogenes that could be detected in cDNA microarrays. Recognizing that these results would not be evident when microarray data were analyzed using conventional analytical approaches, the investigators developed a new analytical method called cancer outlier profile analysis (COPA). Using COPA, they identified two "outlier" genes that showed marked overexpression in a subset of cancers: ERG and ETV1. These genes encode ETS family transcription factors and are involved in oncogenic translocations in Ewing's sarcoma and myeloid leukemias. The research team found that either ERG or ETV1 was overexpressed in many prostate cancer samples, but not in benign prostate tissues. Further investigation revealed the mechanism leading to overexpression of ERG and ETV1: recurrent gene fusions of the prostate-specific androgen-regulated geneTMPRSS2 with ERG or ETV1 in approximately 80 percent of the prostate cancer tissue samples analyzed. Fusion of ERG and TMPRSS2 resulted in androgen regulation of ERG, suggesting that aberrant ERG expression may play a role in androgen sensitivity of prostate tumors. These findings have broad implications for prostate cancer diagnosis and treatment, as the fused genes may provide both a novel biomarker and a therapeutic target in the majority of prostate cancers. Furthermore, these findings suggest a paradigm shift in the cancer research field: potential recurrent chromosomal rearrangements can occur in epithelial cancers.
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, and Chinnaiyan AM. 2005. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310(5748):644-648.
Marx J. 2005. Fused genes may help explain the origins of prostate cancer. Science 310(5748): 603.