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Posts Tagged ‘Benign prostatic hyperplasia’


Reporter: Aviva Lev-Ari, PhD, RN

Dr. Lev-Ari was Director @ SRI International in the mid 1980s.

Denong Wang

Distinguished Scientist and Senior Program Director, Tumor Glycomics Laboratory, Center for Cancer and Metabolism
Denong Wang

Denong Wang, Ph.D., is an SRI distinguished scientist and senior program director of the Tumor Glycome Laboratoryin the Center for Cancer and Metabolism in SRI Biosciences. Wang’s long-term research interest is in the carbohydrate moieties that are critical for self/non-self recognition and induction of antibody responses.

Wang’s team has established multiple platforms of carbohydrate microarrays and introduced these glycomics tools to explore the structural and antigenic diversities of the glycome. The main research focus of his lab is in the immunogenic sugar moieties. In the past few years, his group has contributed to the identification of immunologically potent glycan markers of SARS-CoV, Bacillus anthracis exosporium, and a number of human cancers.

Wang received his Ph.D. in immunology and glycobiology with the late Professor Elvin A. Kabat at Columbia University in 1993. After that, he entered the developing field of post-genomics research. Before joining SRI in 2010, he served as head of the Functional Genomics Division at Columbia University’s Genome Center from 1998 to 2003 and was director of Stanford University’s Tumor Glycome Laboratory from 2007 to 2010.

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A Blood Test to Identify Aggressive Prostate Cancer

By Denong Wang at 9:15 AM PDT, Wed May 8, 2013

tumor glycomicsProstate cancer is the second most common cancer in American men, killing nearly 30,000 per year. In 2004, I attended a conference where one of the nation’s leading researchers in the field declared that the gold-standard test for this disease was not successful at identifying dangerous invasive tumors. That triggered my interest in how to address the challenge of developing a blood test to detect the deadly form of prostate cancer.

After nearly a decade, my collaborators and I have found the first marker that specifically identifies the approximately six to eight percent of prostate cancers that are considered “aggressive,” meaning they will migrate to other parts of the body, at which point they are very difficult to treat. Although we have confirmed this marker, there is much to be done before a clinical application can be developed.

If further study confirms that the test is clinically reliable, it can provide a much-needed tool to differentiate between aggressive cancer and the majority of cases, which are slow-growing tumors with a low probability of migrating to other parts of the body (and thus don’t require special treatment, such as radical prostatectomy).

The current standard test looks at elevated blood prostate-specific antigen (PSA) levels, known as the PSA test. Dr. Thomas Stamey, an emeritus faculty member and urologist at the Stanford University School of Medicine, published his original findings in 1987 linking elevated blood PSA levels to prostate cancer. In 2004, Dr. Stamey declared that the PSA test was no longer useful for the diagnosis of prostate cancer. Rather, an elevated PSA level is now known to reflect the volume increase of a prostate, which could either be associated with a harmless increase in prostate size called benign prostatic hyperplasia (BPH), or be caused by cancer.

I began collaborating with Dr. Stamey and his Stanford colleague Dr. Donna Peehl to look for a new prostate cancer marker, hopefully one that would indicate the presence of aggressive prostate cancer through a blood test.  This is a very active area of research, with scientists exploring the idea from (1) a genomics perspective, (2) a proteomics perspective, and (3) a glycomics perspective, the latter of which entails using carbohydrate-based markers to identify cancer. My focus is the third area, where we are concentrating on how the immune system recognizes changes in the carbohydrates found on the surface of cancer cells compared with those on the surface of normal cells.  

SRI’s Tumor Glycome Laboratory has discovered a marker that appears to be associated with aggressive prostate cancer. The marker is an antibody that is produced against a carbohydrate molecule on the surface of aggressive prostate cancer cells, and is expressed in increasing levels that correlate with cancer severity. We call it a “cryptic” biomarker, since it only becomes an immunological target if something goes awry in the cell, such as a viral infection or the malignant transformation of normal cells to cancer.

This biomarker has the potential, with further development, to be used as a test to help diagnose aggressive prostate cancer. It is rewarding to have reached this point in our understanding of prostate cancer and toward a diagnostic test that ultimately could save lives.

Our research findings were published last year in the Journal of Proteomics & Bioinformatics (5:090-095, DOI:10.4172/jpb.1000218). Our latest study, published in Drug Development Research, lays the foundation for predicting which prostate cancer patients may develop more aggressive forms of the disease and directs the future design of more effective treatments [14(2):65-80, DOI: 10.1002/ddr.21063].

Anti‐Oligomannose Antibodies as Potential Serum Biomarkers of Aggressive Prostate Cancer

Abstract

This study bridges a carbohydrate microarray discovery and a large‐scale serological validation of anti‐oligomannose antibodies as novel serum biomarkers of aggressive prostate cancer (PCa). Experimentally, a Man9‐cluster‐specific enzyme‐linked immunosorbent assay was established to enable sensitive detection of anti‐Man9 antibodies in human sera. A large‐cohort of men with PCa or benign prostatic hyperplasia (BPH) whose sera were banked at Stanford University was characterized using this assay. Subjects included patients with 100% Gleason grade 3 cancer (n = 84), with Gleason grades 4 and/or 5 cancer (n = 204), and BPH controls (n = 135). Radical prostatectomy Gleason grades and biochemical (PSA) recurrence served as key parameters for serum biomarker evaluation. It was found that IgGMan9 and IgMMan9 were widely present in the sera of men with BPH, as well as those with cancer. However, these antibody reactivities were significantly increased in the subjects with the largest volumes of high grade cancer. Detection of serum IgGMan9 and IgMMan9 significantly predicted the clinical outcome of PCa post‐radical prostatectomy. Given these results, we suggest that IgGMan9 and IgMMan9 are novel serum biomarkers for monitoring aggressive progression of PCa. The potential of oligomannosyl antigens as targets for PCa subtyping and targeted immunotherapy is yet to be explored.

Authors: Denong Wang, Laila Dafik, Rosalie Nolley, Wei Huang, Russell D. Wolfinger, Lai‐Xi Wang, Donna M. Peehl
Journal: Drug Development Research
Year: 2013
Pages: n/a
DOI: 10.1002/ddr.21063
Publication date: 11-02-2013

Proteomics & Bioinformatics

N-glycan Cryptic Antigens as Active Immunological Targets in Prostate

Cancer Patients

Denong Wang*

Tumor Glycomics Laboratory, Center for Cancer Research, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA

*Corresponding author: Dr. Denong Wang, Tumor Glycomics Laboratory,

Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo

Park, CA 94025, USA, Tel: +1 650 859-2789; Fax: +1 650 859-3153; E-mail:

denong.wang@sri.com

Received March 07, 2012; Accepted April 13, 2012; Published April 30, 2012

Citation: Wang D (2012) N-glycan Cryptic Antigens as Active Immunological

Targets in Prostate Cancer Patients. J Proteomics Bioinform 5: 090-095.

doi:10.4172/jpb.1000218

Copyright: © 2012 Wang D.

Abstract

Although tumor-associated abnormal glycosylation has been recognized for decades, information regarding host recognition of the evolving tumor glycome remains elusive. We report here a carbohydrate microarray analysis of a number of tumor-associated carbohydrates for their serum antibody reactivities and potential immunogenicity in humans. These are the precursors, cores and internal sequences of N-glycans. They are usually masked by other sugar moieties and belong to a class of glyco-antigens that are normally “cryptic”. However, viral expression of these carbohydrates may trigger host immune responses. For examples, HIV-1 and SARS-CoV display Man9 clusters and tri- or multi-antennary type II (Galβ1→4GlcNAc) chains (Tri/m-II), respectively; viral neutralizing antibodies often target these sugar moieties. We asked, therefore, whether prostate tumor expression of corresponding carbohydrates triggers antibody responses in vivo. Using carbohydrate microarrays, we analyzed a panel of human sera, including 17 samples from prostate cancer patients and 12 from men with Benign Prostatic Hyperplasia (BPH).

We observed that IgG antibodies targeting the Man9- or Tri-/m-II-autoantigens are readily detectable in the sera of men with BPH, as well as those with cancer. Importantly, these antibody activities were selectively increased in prostate cancer patients. Thus, human immune systems actively recognize these N-glycan cryptic carbohydrates and produce targeting antibodies. This finding shads a light on a class of previously less studied immunological targets of human cancers. Identifying the diagnostic, prognostic and therapeutic values of these targets will require further investigation.

http://www.omicsonline.org/0974-276X/JPB-05-090.pdf

 

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Author, Curator: Tilda Barliya, PhD

Prostate cancer  is common and a frequent cause of cancer death. In the United States, prostate cancer is the most commonly diagnosed visceral cancer. In 2012, there were expected to be about 242,000 new prostate cancer diagnoses and about 28,000 prostate cancer deaths. Prostate cancer is second only to nonmelanoma skin cancer and lung cancer as the leading cause of cancer and cancer death, respectively, in US men. Worldwide, in 2008 there were estimated to be 903,000 new cases of prostate cancer and 258,000 prostate cancer deaths making it the second most commonly diagnosed cancer in men and the sixth leading cause of male cancer death (1).

Prostate cancer survival is related to many factors, especially the extent of tumor at the time of diagnosis. The five-year relative survival among men with cancer confined to the prostate (localized) or with just regional spread is 100 percent compared with 31.9 percent among those diagnosed with distant metastases . While men with advanced stage disease may benefit from palliative treatment, their tumors are generally not curable

Prostate-specific antigen (PSA) testing revolutionized prostate cancer screening. Although PSA was originally introduced as a tumor marker to detect cancer recurrence or disease progression following treatment, it became widely adopted for cancer screening by the early 1990s. Subsequently, professional societies issued guidelines supporting prostate cancer screening with PSA. PSA testing led to a dramatic increase in the incidence of prostate cancer, the majority of these newly-diagnosed cancers were clinically localized which led to an increase in radical prostatectomy and radiation therapy, aggressive treatments intended to cure these early-stage cancers (2). However, PSA is also elevated in a number of benign conditions, particularly benign prostatic hyperplasia (BPH) and prostatitis

So what is PSA?

PROSTATE SPECIFIC ANTIGEN (PSA) — PSA is a glycoprotein produced by prostate epithelial cells. PSA levels may be elevated in men with prostate cancer because PSA production is increased and because tissue barriers between the prostate gland lumen and the capillary are disrupted, releasing more PSA into the serum.

A research team led by Prof. Langer and Prof. Farokhzad from MIT and and Brigham and Women’s Hospital in Boston have developed a nanotechnology strategies adopted for the management of prostate cancer. In particular, the combination of targeted and controlled-release polymer nanotechnologies has recently resulted in the clinical development of BIND-14, a promising targeted Docetaxel-loaded nanoprototype, which can be validated for use in the prostate cancer therapy and entered clinical trials in January 2011

The BIND-014 nanoparticles have three components: one that carries the drug (docetaxel), one that targets PSMA, and one that helps evade macrophages and other immune-system cells.

Clinical results

The Phase I clinical trial involved 17 patients with advanced or metastatic tumors who had already gone through traditional chemotherapy. In Phase I trials, researchers evaluate a potential drug’s safety and study its effects in the body. To determine safe dosages, patients were given escalating doses of the nanoparticles. So far, doses of BIND-014 have reached the amount of docetaxel usually given without nanoparticles, with no new side effects. The known side effects of docetaxel have also been milder.

In the 48 hours after treatment, the researchers found that docetaxel concentration in the patients’ blood was 100 times higher with the nanoparticles as compared to docetaxel administered in its conventional form. Higher blood concentration of BIND-014 facilitated tumor targeting resulting in tumor shrinkage in patients, in some cases with doses of BIND-014 that correspond to as low as 20 percent of the amount of docetaxel normally given. The nanoparticles were also effective in cancers in which docetaxel usually has little activity, including cervical cancer and cancer of the bile ducts.

Summary:

Early detection of prostate cancer increased dramatically the five-year survival of patients. “This study demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionizing how complex diseases such as cancer are treated”. The Phase I clinical trial is still ongoing and continued dose escalation is underway; BIND Biosciences is now planning Phase II trials, which will further investigate the treatment’s effectiveness in a larger number of patients.

REFERENCES

1. Richard M Hoffman. Screening for prostate cancer. http://www.uptodate.com/contents/screening-for-prostate-cancer

2. http://web.mit.edu/newsoffice/2012/cancer-particle-0404.html

3. http://www.bindbio.com/content/pages/news/news_detail.jsp/q/news-id/70

4. State of the art in oncologic imaging of Prostate

https://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/

 

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Reported by: Dr. Venkat S. Karra, Ph.D.

 

NEW EVIDENCE FOR POLYOMAVIRUS BK ROLE IN PROSTATE CANCER

 

Prostate cancer is the leading cause of cancer morbidity and the third greatest cause of cancer death among men in developed countries.

English: Two-panel drawing shows normal male r...

English: Two-panel drawing shows normal male reproductive and urinary anatomy and benign prostatic hyperplasia (BPH). Panel on the left shows the normal prostate and flow of urine from the bladder through the urethra. Panel on the right shows an enlarged prostate pressing on the bladder and urethra, blocking the flow of urine. (Photo credit: Wikipedia)

A major question in cancer research has been whether virus infection plays a role in cancers of the genitourinary tract.

Now there seem to be a new evidence suggesting human polyomavirus BK is involved in maintaining and enhancing an environment suitable for prostate cancer growth. The research results were published in the August Journal of Virology, and the authors hope that these findings could lead to preventive and/or therapeutic prostate cancer vaccines.

(G. Sais, S. Wyler, T. Hudolin, I. Banzola, C. Mengus, L. Bubendorf, P.J. Wild, H.H. Hirsch, T. Sulser, G.C. Spagnoli, and M. Provanzano, 2012. Differential patterns of large tumor antigen-specific immune responsiveness in patients with BK polyomavirus-positive prostate cancer or benign prostatic hyperplasia. J. Virol. 86:8461-8471.)

Download a copy of the article at: http://bit.ly/asm0812b

 

 

 

 

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