Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease
February 14, 2013 by 2012pharmaceutical
Curator: Aviva Lev-Ari, PhD, RN
Word Cloud By Danielle Smolyar
A new etiology for Prostate Cancer based on Integrative Genomic Analyses reveals difference in Pathomechanism between Early onset and and Non-Early onset was reported this week in Cancer Cell, Volume 23, Issue 2, 159-170, 11 February 2013
Early Onset: Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer
Median age of 47: EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG
Non Early onset:
Around 65 years of age at onset: elderly-onset PCAs displayed primarily non-androgen-associated structural rearrangement (SR) formations.
Treatment Comparison for Clinically Localized Primary Prostate Cancer Therapies
Treatment
|
Description
|
Selected Risks
|
Recovery
|
Selected Outcomes
|
HIFU – (high intensity focused ultrasound) |
Minimally invasive use of focused ultrasound waves
to ablate diseased tissue |
Incontinence: 0-10% 1-3
Impotence: 8-50%4,5
Rectal Injury: <3% 4-6 |
Catheter worn for
approximately 2-3 weeks; can
return to normal activities
within a few days |
55-95% biochemical
disease-free survival rate at 5 years; 55-98% negative biopsy1-9 |
Cryotherapy |
Minimally invasive
procedure using
controlled freeze and thaw cycles to destroy the prostate |
Incontinence: 3-10% 10
Impotence: 40-100% 10
Rectal Injury: 0-3% 10 |
2-3 hour procedure with possible overnight stay; return to normal activities within a few days |
50-92% biochemical
disease-free survival at 5 years; 87-98% negative biopsy 11,12 |
Radical Prostatectomy |
Surgery to remove
prostate, open or
laparoscopic |
Incontinence: 9-20% 13
Impotence: 4-85%13
Rectal Injury:0-5%14 |
2-3 day hospital stay, catheter for 2-3 weeks for open surgery; shorter
hospitalization and fewer postoperative complications for laparoscopic procedure |
68–98% biochemical
disease-free survival15,16 |
External Beam Radiation |
6-8 week treatment;
external machine
concentrating radiation
beams to the prostate |
Incontinence: 4-15% 17
Impotence: 41-62% 17
Rectal Injury: 15%17 |
Five treatments per week for 6-8 weeks, up to 2 months fatigue after full course of treatment |
55–86% biochemical
disease-free survival18-19 |
Brachytherapy |
Minimally invasive implants of radiation seeds in the prostate |
Incontinence: 3-18% 20
Impotence: 14-82% 20
Rectal Injury: 3%21 |
1-2 hour procedure with
possible overnight stay |
78–89% biochemical
disease-free survival22 |
Data presented are for clinically localized, low-high risk primary prostate cancer. The information provided in the chart is therapy and not device specific and may not include all potential risks, recovery and outcome information. For further information please see references.
The Sonablate® 500 is approved for investigational use within the U.S. and is being studied for the treatment of prostate cancer in clinical trials in the U.S. The FDA has made no decision as to the safety or efficacy of the Sonablate® 500 for the treatment of prostate cancer. Currently, the device is available for the treatment of prostate cancer outside the U.S. in more than 30 countries.
http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ
http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxByzdV
Prostate Cancer and Nanotecnology
Dr. T. Barlyia summaried:
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.
http://pharmaceuticalintelligence.com/2013/02/07/prostate-cancer-and-nanotecnology/
BIND-014 is a programmable nanomedicine that combines a targeting ligandand a therapeutic nanoparticle. BIND-014 contains docetaxel, a proven cancer drug which is approved in major cancer indications including breast, prostate and lung, encapsulated in FDA-approved biocompatible and biodegradable polymers. BIND-014 is targeted to prostate specific membrane antigen (PSMA), a cell surface antigen abundantly expressed on the surface of cancer cells and on new blood vessels that feed a wide array of solid tumors. In preclinical cancer models, BIND-014 was shown to deliver up to ten-fold more docetaxel to tumors than an equivalent dose of conventional docetaxel. The increased accumulation of docetaxel at the site of disease translated to marked improvements in antitumor activity and tolerability. BIND-014 is currently in Phase 1 human clinical testing in cancer patients with advanced or metastatic solid tumor cancers (NCT01300533). The early development of BIND-014 was funded in part by the National Cancer Institute and the U.S. National Institutes of Standards and Technology (NIST) under its Advanced Technology Program (ATP).
State of the art in oncologic imaging of Prostate
Dr. D. Nir summarizes:
In regards to treatment choice: “active surveillance, focal therapy, radical prostatectomy, and radiation therapy represent a range of treatments with varying degrees of invasiveness for men with different disease grades and stages. Active surveillance and focal therapy, which are relatively new options, are promising but are complicated by uncertainties in risk stratification that affect treatment decision-making, as well as by uncertainties regarding the definition of appropriate outcome measures. Biopsy, which leaves the possibility of under sampling, is not sufficient to resolve these uncertainties. Novel biomarkers and modern imaging are expected to play increasingly important roles in facilitating broader acceptance of both active surveillance and focal therapy. Further research, particularly involving prospective validation, is needed to facilitate standardization and establish the roles of advanced imaging tools in routine prostate cancer management.”
My summary: Prostate cancer is a disease managed by urologists, not radiologists. This disease’s multi-choice of pathways is “craving” for tissue characterization. Nothing could fit the urologist’s work-flow better than ultrasound-based tissue characterization!
Early Onset:
Median age of 47: EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG,
Non Early onset:
Around 65 years of age at onset: elderly-onset PCAs displayed primarily non-androgen-associated SRs.
Integrative Genomic Analyses Reveal an Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer
Joachim Weischenfeldt,
Ronald Simon,
Lars Feuerbach,
Karin Schlangen,
Dieter Weichenhan,
Sarah Minner,
Daniela Wuttig,
Hans-Jörg Warnatz,
Henning Stehr,
Tobias Rausch,
Natalie Jäger,
Lei Gu,
Olga Bogatyrova,
Adrian M. Stütz,
Rainer Claus,
Jürgen Eils,
Roland Eils,
Clarissa Gerhäuser,
Po-Hsien Huang,
Barbara Hutter,
Rolf Kabbe,
Christian Lawerenz,
Sylwester Radomski,
Cynthia C. Bartholomae,
Maria Fälth,
Stephan Gade,
Manfred Schmidt,
Nina Amschler,
Thomas Haß,
Rami Galal,
Jovisa Gjoni,
Ruprecht Kuner,
Constance Baer,
Sawinee Masser,
Christof von Kalle,
Thomas Zichner,
Vladimir Benes,
Benjamin Raeder,
Malte Mader,
Vyacheslav Amstislavskiy,
Meryem Avci,
Hans Lehrach,
Dmitri Parkhomchuk,
Marc Sultan,
Lia Burkhardt,
Markus Graefen,
Hartwig Huland,
Martina Kluth,
Antje Krohn,
Hüseyin Sirma,
Laura Stumm,
Stefan Steurer,
Katharina Grupp,
Holger Sültmann,
Guido Sauter,
Christoph Plass,
Benedikt Brors,
Marie-Laure Yaspo,
Jan O. Korbel,
Thorsten SchlommSee Affiliations
- Genome sequencing revealed age-related genetic alterations in PCA
- Early-onset PCAs display a specific abundance of androgen-driven rearrangements
- These age-linked alterations coincide with activity levels of the androgen receptor
- This is an observation of age-specific DNA alterations in a common cancer
Summary
Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with “classical” (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions includingTMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic “androgen-type” pathomechanism in EO-PCA.
Early onset prostate cancer tumors tend to have a propensity for containing balanced structural rearrangements, particularly involving genes regulated by the androgen hormone, according to a study in Cancer Cell. As part of the International Cancer Genome Project’s Early-Onset Prostate Cancer project, researchers from Germany and the UK performed whole-genome sequencing on tumor and matched normal samples from 11 individuals who were surgically treated for prostate cancer at a median age of 47 years old. The tumors were also subjected to transcriptome and methylome sequencing.
When they compared sequences from these tumors with sequences from a previously described set of samples taken from seven individuals diagnosed with prostate cancer at around 65 years of age, investigators saw a rise in gene fusion-producing structural changes in the early onset samples.
Those fusions often affected ETS family genes and other genes prone to androgen-related regulation, researchers reported. In contrast, tumors from individuals whose prostate cancer appeared later in life were more apt to contain structural rearrangements affecting genes without any androgen ties.
Follow-up tests using samples from more than 10,000 other patients seemed to support this link between age at prostate cancer diagnosis and androgen receptor rearrangement, study authors said, pointing to a distinct, androgen-driven “pathomechanism” in early-onset forms of the disease.
SOURCE:
http://www.genomeweb.com//node/1191311?hq_e=el&hq_m=1498692&hq_l=5&hq_v=5f2bf80408
Cancer Cell, Volume 23, Issue 2, 159-170, 11 February 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.ccr.2013.01.002
http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxrkZbB
REFERENCES
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- Uchida T, Ohkusa H, Yamashita H, et al. Five years experience of transrectal high-intensity focused ultrasound using the Sonablate device in the treatment of localized prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2006;13:228-33.
- Muto S, Yoshii T, Saito K, Kamiyama Y, Ide H, Horie S. Focal therapy with high-intensity-focused ultrasound in the treatment of localized prostate cancer. Japanese journal of clinical oncology 2008;38:192-9.
- Ahmed HU, Zacharakis E, Dudderidge T, et al. High-intensity-focused ultrasound in the treatment of primary prostate cancer: the first UK series. British journal of cancer 2009;101:19-26.
- Inoue Y, Goto K, Hayashi T, Hayashi M. Transrectal high-intensity focused ultrasound for treatment of localized prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2011;18:358-62.
- Uchida T, Shoji S, Nakano M, et al. Transrectal high-intensity focused ultrasound for the treatment of localized prostate cancer: eight-year experience. International journal of urology : official journal of the Japanese Urological Association 2009;16:881-6.
- Sumitomo M, Hayashi M, Watanabe T, et al. Efficacy of short-term androgen deprivation with high-intensity focused ultrasound in the treatment of prostate cancer in Japan. Urology 2008;72:1335-40.
- Sumitomo M, Asakuma J, Yoshii H, et al. Anterior perirectal fat tissue thickness is a strong predictor of recurrence after high-intensity focused ultrasound for prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2010;17:776-82.
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http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxrkZbB
Other research papers related to the management of Prostate cancer were published on this One Access Online Scientific Journal
Prostate Cancer and Nanotecnology
http://pharmaceuticalintelligence.com/2013/02/07/prostate-cancer-and-nanotecnology/
State of the art in oncologic imaging of Prostate
http://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/
Genomically Guided Treatment after CLIA Approval: to be offered by Weill Cornell Precision Medicine Institute
http://pharmaceuticalintelligence.com/2013/02/06/genomically-guided-treatment-after-clia-approval-to-be-offered-by-weill-cornell-precision-medicine-institute/
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette