Archive for the ‘Personalized and Precision Medicine & Genomic Research’ Category

Opens Exome Service for Rare Diseases & Advanced Cancer @Mayo Clinic’s OncoSpire

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, tagged Cancer Genetics, DNA Sequencing, Mayo Clinic, Prostate cancer on May 29, 2013| 2 Comments »

Opens Exome Service for Rare Diseases & Advanced Cancer @Mayo Clinic’s OncoSpire

Reporter: Aviva Lev-Ari, PhD, RN

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Mayo Launches OncoSpire with Cancer Genetics; Opens Exome Service for Rare Diseases, Advanced Cancer

May 29, 2013

 

By Monica Heger

The Mayo Clinic is continuing its push into clinical sequencing with several new initiatives. Recently, it announced that it has teamed up with Cancer Genetics to form a commercial entity dedicated to developing products to better diagnose cancer, guide treatment, and predict outcomes. Additionally, the center has now opened a whole-exome sequencing service for patients with unknown diseases or advanced cancer, Gianrico Farrugia, who heads Mayo’s Center for Individualized Medicine, told Clinical Sequencing News.

It has also launched a clinical trial involving next-gen sequencing of patients with castration-resistant prostate cancer, called Prostate Cancer Medically Optimized Genome-Enhanced Therapy, or PROMOTE. The goal is to use sequencing technologies to identify treatment options for prostate cancer patients.

In addition, in April, it launched its first next-generation sequencing panel for hereditary colorectal cancer, and it has around 26 additional panels in the pipeline, Farrugia said.

OncoSpire Genomics

The Mayo/Cancer Genetics entity, dubbed OncoSpire Genomics, will be based in Rochester, Minn. It will focus on cancer biomarker discovery, around which tests can be developed to diagnose cancer, guide treatment, predict drug response and resistance, and predict outcomes.

“We felt that this was an opportunity for us to create a new company that would allow Mayo’s expertise to be partnered with outside resources to accelerate the process of bringing new biomarkers out for our patients,” Farrugia said.

The venture will leverage Mayo Clinic’s clinical expertise and next-generation sequencing resources with Cancer Genetics’ “commercial acumen” and operating capital, Panna Sharma, Cancer Genetics’ CEO, told CSN.

Initially, OncoSpire will focus on hematological and urogenital cancers. A board composed of both Mayo and Cancer Genetics employees will choose the projects, which will be carried out by Mayo staff, Farrugia said. The Mayo has one of the “best clinically annotated biobanks,” he said, and “the ability to use that is key.”

The initial board of governors consists of six members, three Mayo Clinic appointees and three Cancer Genetics appointees. Farrugia is on the board along with Scott Beck, administrator of the Mayo’s Center for Individualized Medicine, and Kathy Bates, director of business development for Mayo’s Medical Laboratories. The three representatives from Cancer Genetics are Sharma, Founder and Chairman of the Board Raju Chaganti, and John Pappajohn, a member of the firm’s board of directors.

Sequencing will initially be done at Mayo, but Farrugia said that the team has not yet decided if that will be its long-term plan.

Sharma added that more details about the products and commercial timeline would be provided at an analyst day conference that will be held in Rochester in the next month or two.

WES Service

Separately, the Mayo has launched a whole-exome sequencing service for patients with unknown diseases and advanced cancer.

For this service, Mayo has been contracting sequencing to Baylor College of Medicine and Foundation Medicine, but plans to do more in-house sequencing by the end of year when its pipeline is CLIA certified. The center is working with Silicon Valley Biosystems to develop that clinical sequencing pipeline (CSN 1/23/2013).

The exome service has been available since September, said Farrugia, but Mayo has only recently begun advertising for it. Around 30 to 35 patients have gone through the pipeline thus far.

The diagnostic rate is about 40 percent for the cancer patients and slightly higher for the diagnostic odyssey patients, said Farrugia, but those “numbers are too small to attach too much significance to them,” he said.

The Mayo Clinic works with patients’ insurance companies to obtain reimbursement for the services, which often will include targeted sequencing as well as whole-exome sequencing, and the average out-of-pocket expense ranges between $7,000 and $11,000, depending on the patient’s condition and what the service entails, said Farrugia.

For instance, the service for cancer patients can include obtaining a new tissue sample, sequencing both normal and tumor samples, and sometimes doing both targeted sequencing for a quicker turnaround and exome sequencing, Farrugia said.

As such, the total price charged for the cancer service can be much higher than what is charged for patients with a rare disease, sometimes approaching $30,000, Farrugia said, although prices vary.

Because of all these variables, Farrugia said there isn’t a list price for the service. “We’re really tailoring it to the patient and what we think they can best benefit from,” he said.

Turnaround time is still too long, he said, about one to two months, which he said will be reduced when the center’s clinical sequencing pipeline becomes CLIA certified and more can be done in-house.

Additionally, every patient that receives clinical sequencing also has the option of participating in research, said Farrugia. If the patient consents to research sequencing, that is done at the Mayo Clinic, while the clinical sequencing is outsourced. However, he said that is a temporary model until Mayo’s clinical exome pipeline is CLIA certified and has New York state approval.

The center also offers patients a choice in terms of which incidental findings to receive from the sequencing. Typically, patients with advanced cancer just want to hear about anything that’s actionable, while the conversation with patients and families with diagnostic odysseys is longer and more complicated, he said.

Like other labs offering clinical sequencing, Mayo has decided to diverge from recommendations recently published by the American College of Medical Genetics and Genomics, which say that providers should always return pathogenic variants from a list of 57 genes related to 24 disorders (CSN 5/8/2013).

The recommendations, which were released in March, have sparked a debate in the field as to how best to deal with incidental findings, and a number of groups have written publications both in support of and disagreeing with the recommendations (CSN 5/22/2013).

Farrugia said that Mayo has also written a formal response to ACMG, which he said would be published in an upcoming journal, detailing where it agrees and where it disagrees with the recommendations.

Monica Heger tracks trends in next-generation sequencing for research and clinical applications for GenomeWeb’s In Sequenceand Clinical Sequencing News. E-mail Monica Heger or follow her GenomeWeb Twitter accounts at @InSequence and@ClinSeqNews.

Related Stories

• People in the News: Gianrico Farrugia, Scott Beck, Kathy Bates, Panna Sharma, Raju Chaganti, More
  May 29, 2013 / Clinical Sequencing News
• Mayo Clinic Taps SV Bio to Combine Clinical Interpretation Pipeline with Patient Sequencing
  January 23, 2013 / Clinical Sequencing News
• Looking to Adopt NGS in ‘Day-to-Day’ Care, Mayo Clinic Taps Complete Genomics to Boost Capacity
  February 15, 2012 / Clinical Sequencing News
• Cancer Sequencing Takes off in 2011 Amid Debate on Benefits of Targeted vs. Comprehensive Approaches
  January 11, 2012 / Clinical Sequencing News
• Exome Sequencing of Metastatic Melanoma IDs Mutations in Pathway with Clinical Significance
  April 19, 2011 / Clinical Sequencing News

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Personalized Medicine and Colon Cancer

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Nutrition and Phytochemistry, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged BRAF, CIMP, CIN, colon cancer (CC), Colorectal cancer (CRC), dMMR, DNA methylation, gene expression profiles (GEPs), Immunoregulation, KRAS, Methylation, MSI, TP53, Wnt on May 25, 2013| 4 Comments »

Personalized Medicine and Colon Cancer

Author: Tilda Barliya, PhD

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According to Dr. Neil Risch a leading expert in statistical genetics and the director of the UCSF Institute for Human Genetics,  “Personalized medicine, in which a suite of molecules measured in a patient’s lab tests can inform decisions about preventing or treating diseases, is becoming a reality” (7).

Colorectal cancer (CRC) is the third most common cancer and the fourth-leading cause of cancer death worldwide despite advances in screening, diagnosis, and treatment. Staging is the only prognostic classification used in clinical practice to select patients for adjuvant chemotherapy. However, pathological staging fails to predict recurrence accurately in many patients undergoing curative surgery for localized CRC (1,2). Most of the patients who are not eligible for surgery need adjuvant chemotherapy in order to avoid relapse or to increase survival. Unfortunately, only a small portion of them shows an objective response to chemotherapy, becoming problematic to correctly predict patients’ clinical outcome (3).

CRC patients are normally being tested for several known biomarkers which falls into 4 main categories (5):

1. Chromosomal Instability (CIN)
2. Microsatellite Instability (MSI)
3. CpG Island methylator phynotype (CIMP)
4. Global DNA hypomethylation

In the past few years many studies have exploited microarray technology to investigate gene expression profiles (GEPs) in CRC, but no established signature has been found that is useful for clinical practice, especially for predicting prognosis.  Only a subset of CRC patients with MSI tumors have been shown to have better prognosis and probably respond differently to adjuvant chemotherapy compared to microsatellite stable (MSS) cancer patients (6).

Pritchard & Grady have summarized the selected biomarkers that have been evaluated in colon cancer patients (10).

Table 1

Selected Biomarkers That Have Been Evaluated in Colorectal Cancer

Biomarker	Molecular Lesion	Frequency in CRC	Prediction	Prognosis	Diagnosis
KRAS	Codon 12/13 activating mutations; rarely codon 61, 117,146	40%	Yes	Possible	–
BRAF	V600E activating mutation	10%	Probable	Probable	Lynch Syndrome
PIK3CA	Helical and kinase domain mutations	20%	Possible	Possible	–
PTEN	Loss of protein by IHC	30%	Possible	–	–
Microsatellite Instability (MSI)	Defined as >30% unstable loci in the NCI consensus panel or >40% unstable loci in a panel of mononucleotide microsatellite repeats9	15%	Probable	Yes	Lynch Syndrome
Chromosome Instability (CIN)	Aneuploidy	70%	Probable	Yes	–
18qLOH	Deletion of the long arm of chromosome 18	50%	Probable	Probable	–
CpG Island Methylator Phenotype (CIMP)	Methylation of at least three loci from a selected panel of five markers	15%	+/−	+/−	–
Vimentin (VIM)	Methylation	75%	–	–	Early Detection
TGFBR2	Inactivating Mutations	30%	–	–	–
TP53 Mutations	Inactivating Mutations	50%	–	–	–
APC Mutations	Inactivating Mutations	70%	–	–	FAP
CTNNB1 (β-Catenin)	Activating Mutations	2%	–	–	–
Mismatch Repair Genes	Loss of protein by IHC; methylation; inactivating mutations	1–15%	–	–	Lynch Syndrome

CRC- colorectal cancer; IHC- immunohistochemistry; FAP- Familial Adenomatous Polyposis

Examples for the great need of personalized medicine tailored according to the patients’ genetics is clearly seen with two specific drugs for CRC:  Cetuximab and panitumumab are two antibodies that were developed to treat colon cancer. However, at first it seemed as if they were a failure because they did not work in many patients. Then, it was discovered that if a cancer cell has a specific genetic mutation, known as K-ras, these drugs do not work.  This is an excellent example of using individual tumor genetics to predict whether or not treatment will work (8).

According to Marisa L et al, however, the molecular classification of CC currently used, which is based on a few common DNA markers as mentioned above (MSI, CpG island methylator phenotype [CIMP], chromosomal instability [CIN], and BRAF and KRAS mutations), needs to be refined.

Genetic Expression Profiles (GEP)

CRC is composed of distinct molecular entities that may develop through multiple pathways on the basis of different molecular features, as a consequence, there may be several prognostic signatures for CRC, each corresponding to a different entity. GEP studies have recently identified at least three distinct molecular subtypes of CC (4). Dr. Marisa Laetitia and her colleagues from the Boige’s lab however, have conducted a very thorough study and identifies 6 distinct clusters for CC patients. Herein, we’ll describe the majority of this study and their results.

Study  Design:

Marisa L et al (1) performed a consensus unsupervised analysis (using an Affymertix chip) of the GEP on tumor tissue sample from 750 patients with stage I to IV CC. Patients were staged according to the American Joint Committee on Cancer tumor node metastasis (TNM) staging system. Of the 750 tumor samples of the CIT cohort, 566 fulfilled RNA quality requirements for GEP analysis. The 566 samples were split into a discovery set (n = 443) and a validation set (n = 123).

Several known mutations were used as internal controls, including:

• The seven most frequent mutations in codons 12 and 13 of KRAS .
• The BRAF c.1799T>A (p.V600E)
• TP53mutations (exons 4–9)
• MSI was analyzed using a panel of five different microsatellite loci from the Bethesda reference panel
• CIMP status was determined using a panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1)

Results:

The results revealed six clusters of samples based on the most variant probe sets. The consensus matrix showed that C2, C3, C4, and C6 appeared as well-individualized clusters, whereas there was more classification overlap between C1 and C5. In other words:

• Tumors classified as C1, C5, and C6 were more frequently CIN+, CIMP−, TP53– mutant, and distal (p<0.001), without any other molecular or clinicopathological features able to discriminate these three clusters clearly.
• Tumors classified as C2, C4, and C3 were more frequently CIMP+ (59%, 34%, and 18%, respectively, versus <5% in other clusters) and proximal.
• C2 was enriched for dMMR (68%) and BRAF- mutant tumors (40%).
• C3 was enriched for KRAS- mutant tumors (87%).

Note: No association between clusters and TNM stage (histopathology) was found, except enrichment for metastatic (31%) tumors in C4.

Figure: These signaling pathways associated with the molecular subtype (by cluster)

Marisa L et al. Signaling pathways associated with each molecular subtype

These clusters fall into several signaling pathways:

• up-regulated immune system and cell growth pathways were found in C2, the subtype enriched for dMMR tumors
• C4 and C6 both showed down-regulation of cell growth and death pathways and up-regulation of the epithelial–mesenchymal transition/motility pathways. displaying “stem cell phenotype–like” GEPs (91%)
• Most signaling pathways were down-regulated in C1 and C3.
• In C1, cell communication and immune pathways were down-regulated.
• In C5, cell communication, Wnt, and metabolism pathways were up-regulated.

These results are further summarized in table 2:

Marisa L et al. Gene Expression Classification of Colon Cancer into Molecular Subtypes

The authors have identified six robust molecular subtypes of CC individualized by distinct clinicobiological characteristics (as summarized in table 2).

This classification successfully identified the dMMR tumor subtype, and also individualized five other distinct subtypes among pMMR tumors, including three CIN+ CIMP− subtypes representing slightly more than half of the tumors. As expected, mutation of BRAF was associated with the dMMR subtype, but was also frequent in the C4 CIMP+ poor prognosis subtype. TP53– andKRAS-mutant tumors were found in all the subtypes; nevertheless, the C3 subtype, highly enriched in KRAS-mutant CC, was individualized and validated, suggesting a specific role of this mutation in this particular subgroup of CC.

Current Treatments for colon cancer- Table 3 (11) .

Constant S et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Exploratory analysis of each subtype GEP with previously published supervised signatures and relevant deregulated signaling pathways improved the biological relevance of the classification.

The biological relevance of our subtypes was highlighted by significant differences in prognosis. In our unsupervised hierarchical clustering, patients whose tumors were classified as C4 or C6 had poorer RFS than the other patients.

Prognostic analyses based solely on common DNA alterations can distinguish between risk groups, but are still inadequate, as most CCs are pMMR CIMP− BRAFwt.

The markers BRAF-mutant, CIMP+, and dMMR may be useful for classifying a small proportion of cases, but are uninformative for a large number of patients.

Unfortunately, 5 of the 9 anti-CRC drugs approved by the FDA today are basic cytotoxic chemotherapeutics that attack cancer cells at a very fundamental level (i.e. the cell division machinery) without specific targets, resulting in poor effectiveness and strong side-effects (Table 3) (11).

An example for side effects induction mechanisms have also been reported in CRC for the BRAF(V600E) inhibitor Vemurafenib that triggers paradoxical EGFR activation (12).

Summary:

The authors of this study “report a new classification of CC into six robust molecular subtypes that arise through distinct biological pathways and represent novel prognostic subgroups. Our study clearly demonstrates that these gene signatures reflect the molecular heterogeneity of CC. This classification therefore provides a basis for the rational design of robust prognostic signatures for stage II–III CC and for identifying specific, potentially targetable markers for the different subtypes”.

These results further underline the urgent need to expand the standard therapy options by turning to more focused therapeutic strategies: a targeted therapy-for specific subtype profile.. Accordingly, the expansion and the development of new path of therapy, like drugs specifically targeting the self-renewal of intestinal cancer stem cells – a tumor cell population from which CRC is supposed to relapse, remains relevant.

Therefore, the complexity of these results supports the arrival of a personalized medicine, where a careful profiling of tumors will be useful to stratify patient population in order to test drugs sensitivity and combination with the ultimate goal to make treatments safer and more effective.

References:

1. Marisa L,  de Reyniès A, Alex Duval A,  Selves J, Pierre Gaub M, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Fléjou JF…Boige V. Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value. PLoS Med May 2013 10(5): e1001453. doi:10.1371. http://www.plosmedicine.org/article/info%3Adoi/10.1371/journal.pmed.1001453

2. Villamil BP, Lopez AR, Prieto SH, Campos GL, Calles A, Lopez- Asenjo JA, Sanz Ortega J, Perez CF, Sastre J, Alfonso R, Caldes T, Sanchez FM and Rubio ED. Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer 2012, 12:260.  http://www.biomedcentral.com/1471-2407/12/260/

3. Diaz-Rubio E, Tabernero J, Gomez-Espana A, Massuti B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, et al.: Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 2007, 25(27):4224-4230. http://jco.ascopubs.org/content/25/27/4224.long

4. Salazar R, Roepman P, Capella G, Moreno V, Simon I, et al. (2011) Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 29: 17–24. http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&doptcmdl=Citation&defaultField=Title%20Word&term=Salazar%5Bauthor%5D%20AND%20Gene%20expression%20signature%20to%20improve%20prognosis%20prediction%20of%20stage%20II%20and%20III%20colorectal%20cancer

5.  By: Global Genome Knowledge. Colorectal Cancer- Personalized Medicine, Now a Clinical Reality.  http://www.srlworld.com/innersense/Voice-135-Colorectal-Cancer-Sept-2012-IS.pdf

6. Popat S, Hubner R and Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005 Jan 20;23(3):609-618. http://www.ncbi.nlm.nih.gov/pubmed/15659508

7. By: Jeffrey Norris. Value of Genomics and Personalized Medicine Is Wrongly Downplayed.http://www.ucsf.edu/news/2012/04/11864/value-genomics-and-personalized-medicine-wrongly-downplayed

8. By: James C Salwitz. The Future is now: Personalized Medicine. http://www.cancer.org/cancer/news/expertvoices/post/2012/04/18/the-future-is-now-personalized-medicine.aspx

9. Jeffrey A. Meyerhardt., and Robert J. Mayer. Systemic Therapy for Colorectal Cancer. N Engl J Med 2005;352:476-487. http://www.med.upenn.edu/gastro/documents/NEJMchemotherapycolorectalcancer.pdf

10. Pritchard CC and Grady WM. Colorectal Cancer Molecular Biology Moves Into Clinical Practice. Gut. Jan 2011 60(1): 116-129.  Gut. 2011 January; 60(1): 116–129. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006043/

11. Constant S, Huang S, Wiszniewski L andMas C. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies.  Pharmacology, Toxicology and Pharmaceutical Science » “Drug Discovery”, book edited by Hany A. El-Shemy, ISBN 978-953-51-0906-8.  http://www.intechopen.com/books/drug-discovery/colon-cancer-current-treatments-and-preclinical-models-for-the-discovery-and-development-of-new-ther

12. Prahallad, C. Sun, S. Huang, F. Di Nicolantonio, R. Salazar, D. Zecchin, R. L. Beijersbergen, A. Bardelli, R. Bernards, 2012 Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature Jan 2012 483 (7387): 100-103. http://www.nature.com/nature/journal/v483/n7387/full/nature10868.html

Other related articles on this Open Access Online Scientific Journal include the following:

*. By Tilda Barliya PhD. Colon Cancer. http://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

**. By: Tilda Barliya PhD. CD47: Target Therapy for Cancer. http://pharmaceuticalintelligence.com/2013/05/07/cd47-target-therapy-for-cancer/

I. By: Aviva Lev-Ari, PhD, RN. Cancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. http://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. http://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.D. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. http://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.D. In Focus: Targeting of Cancer Stem Cells. http://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. http://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. http://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. http://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

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The Implications of a Newly Discovered CYP2J2 Gene Polymorphism Associated with Coronary Vascular Disease in the Uygur Chinese Population

Posted in Biological Networks, Gene Regulation and Evolution, Genome Biology, Genomic Testing: Methodology for Diagnosis, International Global Work in Pharmaceutical, Medical and Population Genetics, Nitric Oxide in Health and Disease, Nutrigenomics, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, tagged Acute coronary syndrome, Aviva Lev-Ari, Cardiovascular disease, China, Coronary artery disease, Coronary disease, Larry H. Bernstein, Polymorphism (biology) on May 24, 2013| 3 Comments »

The Implications of a Newly Discovered  CYP2J2 Gene Polymorphism  Associated with Coronary Vascular Disease in the Uygur Chinese Population

Author, Curator: Larry H Bernstein, MD, FCAP

This is an interesting genomic study of the relationship of genetic polymorphism in the Chinese Uygur population that highlights the difficulty in CVD genomics, and casts a promising light on difficulties over

1.  possibly no more than 8 genetic signatures to account for all of human CVD conditions

2.  genetic signatures may no be equally distributed over studied populations

3.  genetic signatures may be more pronounced in different populations

4.  there is little predictable validity in such studies over large assimilated populations (such as African-Americans

5.  the best genomic evidence for meaningful associations does appear to tie in with endothelial metabolism

6.  the greatest difficulty in all studies is the small dose of information provided by an such linkage

7.  there has been too little information provided in studies of the effect of dietary factors on the affected population, which would entail nutrigenomics.

8.  there is an association between certain distinct CVD’s and later development of coronary heart disease (CHD).

This study concepts, methods and difficulties were recently reviewed in the following articles:

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Aviva Lev-Ari, PhD, RN and Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/03/07/genomics-genetics-of-cardiovascular-disease-diagnoses-a-literature-survey-of-ahas-circulation-cardiovascular-genetics-32010-32013/

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

Aviva Lev-Ari, PhD, RN and Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus

Justin D. Pearlman, MD, PhD, and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/05/11/arterial-elasticity-in-quest-for-a-drug-stabilizer-isolated-systolic-hypertension-caused-by-arterial-stiffening-ineffectively-treated-by-vasodilatation-antihypertensives/

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/08/24/vascular-medicine-and-biology-classification-of-fast-acting-therapy-for-patients-at-high-risk-for-macrovascular-events-macrovascular-disease-therapeutic-potential-of-cepcs/

Endothelial Function and Cardiovascular Disease

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/25/endothelial-function-and-cardiovascular-disease/

Reversal of Cardiac Mitochondrial Dysfunction

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

A Novel Polymorphism of the CYP2J2 Gene is Associated with Coronary Artery Disease in Uygur Population in China

Qing Zhu, Zhenyan Fu, Yitong Ma, Hong Yang, Ding Huang, Xiang Xie, Fen Liu, Yingying Zheng, Erdenbat Cha

PII: S0009-9120(13)00174-4    Available online 15 May 2013

http://dx.doi.org/10.1016/j.clinbiochem.2013.05.003

Reference: CLB 8375

To appear in: Clinical Biochemistry

Received date: 17 February 2013

Revised date: 13 April 2013

Accepted date: 3 May 2013

Background: Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs).

• The EETs are potent endogenous vasodilators and
• inhibitors of vascular inflammation.

The aim of the present study was to assess the association between the human CYP2J2 gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China.

We use two independent case-control studies:

1. a Han population (206 CAD patients and 262 control subjects) and
2. a Uygur population (336 CAD patients and 448 control subjects).

All CAD patients  and controls were genotyped for the same three single nucleotide polymorphisms (SNPs)

1. rs890293
2. rs11572223
3. rs2280275

of CYP2J2 gene by a Real-time PCR instrument.

Results: In the Uygur population, for total, the distribution of SNP3 (rs2280275) genotypes showed a significant difference between CAD and control participants (P=0.048).

For total and men, the distribution of SNP3 (rs2280275) alleles and the dominant model (CC vs CT + TT)

• showed a significant difference between CAD and control participants (for allele: P=0.014 and P=0.035, respectively; for dominant model: P=0.014 and P=0.034, respectively).

The significant difference in dominant model was retained after adjustment for covariates (OR: 0.279, 95% confidence interval [CI]: 0.176-0.440, P=0.001; OR: 0.240, 95% CI: 0.128-0.457, P=0.001, respectively).

Conclusions: The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China.

Highlights:

1. We used two independent case-control studies: one was in a Han population and the other was in a Uygur population.

2. The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China.

3. Polymorphism of the CYP2J2 gene can affect the synthesis of epoxyeicosatrienoic acids (EETs).

Reviewer Observations:

This article describes the association between CYP2J2 polymorphism(SNP1, SNP2 and SNP3) and coronary artery disease (CAD) in two populations of China (Han and Uygur).
Results show that

1. the frequency of T allele of rs2280275 (SNP3 of the CYP2J2) is higher in CAD patients than in control subjects and
2. that CC genotype of rs 2280275 is significantly lower in CAD patients than in control subjects.
3. “T allele of rs2280275 was significantly higher in CAD patients than in control participants. CC genotype of rs2280275 was significantly lower in CAD patients than in control participants.”;
4. It appears that CC is the homozygous and dominant state of this SNP3 sequence in a pairing-combination.
5. The effect of decreased CHD is seen only in the CC double combination, in men and not women. The difference between men and women with CAD is in LDL.

For Uygur population,

(1) after adjusting major confounding factors such as Glu、LDL、EH、DM and smoking, the effect of decreased CAD is seen only in the CC double combination, in men and not women.

(2) for men, the LDL level is higher in CAD than in control, for women, there isn’t a difference of LDL level between CAD and control.

(3) for men, the distribution of T and C allele is different between CAD and control (p=0.035), and not in women (p=0.118).

The T allele of SNP3 is increased in CAD. So the C allele is important, and a CT pair is neutral. Neither SNP1 or SNP2, or presumably both have lower incidence.

I might conjecture that having(heterozygous rs2280275), a C & a T, and eating a lot of fish and/or flax seed would show a difference

• because of the intimal enzymatic conversion of arachidonic acid to EETs.

Arachidonic acid is a derivative of linoleic acid,an n-6 PUFA, while linolenic acid is an omega-3 PUFA. Substantial documentation of the effect of EETs is given. The anti-inflammatory advantage of an n-3 PUFA is also known.
It appears that the intimal conversion results in an omega-3 product.  In addition, the EET activates eNOS, so that there is endothelial NO produced.

The studies of both Spiecker and Ping Yin Liu showed the polymorphism of CYP2J2 (rs890293, SNP1) has relation with CAD. However, in this study, the authors found there was no association between the polymorphism of CYP2J2 (rs890293, SNP1) and CAD in Han population and Uygur population. We found (rs 2280275, SNP3) has association with CAD.

• “The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China”

All participants had a differential diagnosis for chest pain encountered in the Cardiac Catheterization Laboratory of First Affiliated Hospital of Xinjiang Medical University. We recruited randomly CAD group and control group, subjects with valvular disease were excluded, control subjects were not healthy individuals, some of them have hypertension, some of them have DM, some of them have hyperlipidemia, which means control group expose to the same risk factors of CAD while the results of coronary angiogram is normal. All control subjects underwent a coronary angiogram and have no coronary artery stenosis.

The analysis was a logistic regression analysis, we used the major variables of CAD to analysis and found the CC genotype was the dependent useful factor after adjusting for major confounding factors such as Glu、LDL、EH、DM and smoking.

Schematic of EET interactions with cardiovascularion channels.

A: In the cardiac myocyte, EETs activate sarcolemmal or mitochondrial KATP channels.

B: In the vasculature, EETs activate endothelial small-(SKCa) or intermediate (IKCa)–conductance calcium-activated channels to cause hyperpolarization, which can be transmitted to the vascular smooth muscle via myoendothelial gap junctions. EETs also activate TRPV4 channels to activate Ca2+influx. In the vascular smooth muscle, EETs activate large conductance, calcium-activated (BK-Ca) channels through a G protein-Coupled event.

C: In platelets, EETs activate BK-Ca channels.calcium-activated (BK-Ca) channels through a G-protein-coupled event. C, In platelets, EETs activate BK-Ca channels.

Association of the ADRA2A polymorphisms with the risk of type 2 diabetes: A meta-analysis

Xi Chen, Lei Liu, Wentao He, Yu Lu, Delin Ma, Tingting Du, Qian Liu, Cai Chen, Xuefeng Yu

Clinical Biochemistry 2013;  46 (9): 722–726   http://dx.doi.org/10.1016/j.clinbiochem.2013.02.004

Results from the published studies on the association of ADRA2A (adrenoceptor alpha 2A) variants with type 2 diabetes (T2D) are conflicting and call for further assessment. The aim of this meta-analysis was to quantitatively summarize the effects of the two recently reported ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 on T2D risk.

Results

Twelve studies with 40,828 subjects from seven eligible papers were included in the meta-analysis. Overall, the present meta-analysis failed to support a positive association between ADRA2A SNPs (rs553668 and rs10885122) and susceptibility to T2D (OR = 1.05, p = 0.17, 95% CI: 0.98, 1.12; and OR = 1.06, p = 0.11, 95% CI: 0.99, 1.13; respectively).

However, in the subgroup analysis by ethnicity, the significant association between rs553668 and the risk of T2D was obtained in Europeans under the recessive genetic model (OR = 1.36, p = 0.02, 95% CI: 1.05, 1.76).

Conclusion

The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P < 0.05) but not in Asians. The results from our case-control study and meta-analyses might be explained by genetic heterogeneity in the susceptibility of CHD and ethnic differences between Asians and Caucasians.

http://ars.els-cdn.com/content/image/1-s2.0-S0009912013000404-gr1.jpg

http://ars.els-cdn.com/content/image/1-s2.0-S0009912013000404-gr2.jpg

Association between PCSK9 and LDLR gene polymorphisms with coronary heart disease: Case-control study and meta-analysis

Lina Zhang, Fang Yuan, Panpan Liu, Lijuan Fei, Yi Huang, Limin Xu, et al.

Clinical Biochemistry 2013; 46 (9): 727–732

► Association of rs11206510 and rs1122608 with CHD in 813 Chinese participants.

► The first association test of rs1122608 with the risk of CHD in Han Chinese.

► Meta-analyses were performed for rs11206510 and rs1122608.

► The two SNPs were associated with CHD in Caucasians but not in Asians.

Objective

To explore the association of rs11206510 (PCSK9 gene) and rs1122608 (LDLR gene) polymorphisms with coronary heart disease (CHD) in Han Chinese.

Methods

A total of 813 participants (290 CHD cases, 193 non-CHD controls and 330 healthy controls) were recruited in the case-control study. DNA genotyping was performed on the SEQUENOM® Mass–ARRAY iPLEX® platform. χ2-test was used to compare the genotype distribution and allele frequencies. Two meta-analyses were performed to establish the association between the two polymorphisms with CHD.

Results

No significant associations between the two SNPs and the risk of CHD were observed in the present study. The meta-analysis of rs11206510 of PCSK9 gene comprises 11 case-control studies with a total of 69,054 participants. Significant heterogeneity was observed in Caucasian population in subgroup analysis of the association studies of rs11206510 with CHD (P = 0.003, I2 = 67.2%). The meta-analysis of LDLR gene rs1122608 polymorphism comprises 7 case-control studies with a total of 20,456 participants and the heterogeneity of seven studies was minimal (P = 0.148, I2 = 36.7%).

Conclusion

The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P < 0.05) but not in Asians.

http://ars.els-cdn.com/content/image/1-s2.0-S0009912013000404-gr1.jpg

http://ars.els-cdn.com/content/image/1-s2.0-S0009912013000404-gr2.jpg

The effect of hyperhomocysteinemia on aortic distensibility in healthy individuals

I Eleftheriadou, P Grigoropoulou, I Moyssakis, A Kokkinos. et al.

Nutrition 18 Feb 2013; 29 (6): 876-880, PII: S0899-9007(13)00015-4

http://dx.doi.org/10.1016/j.nut.2012.12.026

Elevated plasma homocysteine (HCY) levels have been associated with increased risk for cardiovascular disease. Aortic distensibility and aortic pulse wave velocity (PWV) are indices of aortic elasticity. The aim of the present study was to determine the effect of acute methionine-induced HHCY on aortic distensibility and PWV in healthy individuals and the effect of acute HHCY on myocardial performance of the left ventricle (Tei index).

Thirty healthy volunteers were included in this crossover study. Aortic distensibility and Tei index were determined non-invasively by ultrasonography at baseline and 3 h after methionine or water consumption, while PWV was measured by applanation tonometry at baseline and every 1 h for the same time interval.

Oral methionine induced an increase in total plasma HCY concentrations (P < 0.001), whereas HCY concentrations did not change after water consumption. Aortic distensibility decreased 3 h after methionine load (P < 0.001) and Tei index increased (P < 0.001), suggesting worsening compared with baseline values. Water consumption had no effect on aortic distensibility or Tei index values. PWV values did not change after either methionine or water consumption.

Acute methionine-induced HHCY reduces aortic distensibility and worsens myocardial performance in healthy individuals. Further research is warranted to examine in the long term the direct effects of HHCY on cardiovascular function and the indirect effects on structural remodeling.

Related articles

• Observations on Finding the Genetic Links (pharmaceuticalintelligence.com)
• CHAPTER 5. Mitochondria and Cardiovascular Disease (pharmaceuticalintelligence.com)
• Bioengineering of Vascular and Tissue Models (pharmaceuticalintelligence.com)
• Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems (pharmaceuticalintelligence.com)
• Contributions to vascular biology – Elazer Edelman Lab (pharmaceuticalintelligence.com)
• Cardiovascular Diseases: Decision Support Systems for Disease Management Decision Making (pharmaceuticalintelligence.com)
• Increased Cardiovascular Risk: Intestinal Microbial Metabolism (pharmaceuticalintelligence.com)
• Stents, biologically active implants and vascular repair (pharmaceuticalintelligence.com)

Micrograph of an artery that supplies the heart with significant atherosclerosis and marked luminal narrowing. Tissue has been stained using Masson’s trichrome. (Photo credit: Wikipedia)

Estimated propability of death or non-fatal myocardial-infarction over one year corresponding ti selectet values of the individual scores. Ordinate: individual score, abscissa: Propability of death or non-fatal myocardial infarction in 1 year (in %) (Photo credit: Wikipedia)

 

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Cardio-Metabolic Drug Targets, Inaugural, September 25 – 26, 2013, Westin Waterfront | Boston, Massachusetts

Posted in Atherogenic Processes & Pathology, Cardiovascular Pharmacogenomics, Chemical Biology and its relations to Metabolic Disease, Frontiers in Cardiology and Cardiovascular Disorders, Genomic Testing: Methodology for Diagnosis, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Health Economics and Outcomes Research, Interviews with Scientific Leaders, Liver & Digestive Diseases Research, Medical and Population Genetics, Metabolomics, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged Basal metabolic rate, Biotechnology and Pharmaceuticals, Business, Drug development, Metabolism, Pharmaceutical Sciences, Weight loss on May 23, 2013| Leave a Comment »

Cardio-Metabolic Drug Targets, Inaugural, September 25 – 26, 2013, Westin Waterfront | Boston, Massachusetts  

 

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #57:Cardio-Metabolic Drug Targets, Inaugural, September 25 – 26, 2013, Westin Waterfront | Boston, Massachusetts. Published on 5/23/2013

WordCloud Image Produced by Adam Tubman

                                 

ABOUT THIS CONFERENCE

Cardiovascular disease, diabetes, obesity and dyslipidemia, though traditionally treated as separate entities, are often conditions that appear together in individuals because of defects in underlying metabolic processes. Researchers are therefore now seeking compounds that target biological points of intersection of these related diseases in the hopes of ‘killing more birds with one stone.’ Or they are approaching drug development of a compound for a specific disease with a greater awareness of the backdrop of related conditions.

Join fellow biomedical researchers from academia and industry at our day and a half conference, Cardio-Metabolic Drug Targets to discuss the impact of this paradigm change in the way drugs are discovered and developed in the cardio-metabolic arena and to stay abreast of the latest targets and drug development candidates in the pipeline.

SUGGESTED EVENT PACKAGE:

September 23: Allosteric Modulators of GPCRs Short Course 
September 24 – 25: Novel Strategies for Kinase Inhibitors Conference
September 25: Setting Up Effective Functional Screens Using 3D Cell Cultures Dinner Short Course
September 25 – 26: Cardio-Metabolic Drug Targets Conference

Scientific Advisory Board:

Jerome J. Schentag, Pharm.D., Professor of Pharmaceutical Sciences, University at Buffalo

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

Preliminary Agenda

BEYOND STATINS: NEW APPROACHES FOR REGULATING LIPID METABOLISM AND ATHEROSCLEROSIS

Macrophage ABC Transporters: Novel Targets to Promote Atherosclerotic Plaque Regression by Inducing Reverse Cholesterol Transport (RCT) Mechanism

Eralp “Al” Bellibas, M.D., Senior Director, Head, Clinical Pharmacology, The Medicines Company

Targeting PCSK9 for Hypercholesterolemia and Atherosclerosis

Hong Liang, Ph.D., Associate Research Fellow, Rinat Research Unit, Pfizer

Novel Treatment for Dyslipidemia: Liver-Directed Thyroid Hormone Receptor-ß Agonist

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

CARDIO-METABOLIC THERAPEUTIC CANDIDATES

Oral Mimetics of RYGB and GLP-1 in Metabolic Syndromes

Jerome J. Schentag, Pharm.D., Professor of Pharmaceutical Sciences, University at Buffalo

FGF21-Mimetic Antibodies for Type 2 Diabetes

Jun Sonoda, Ph.D., Group Leader, Scientist, Molecular Biology, Genentech

NEW CARDIO-METABOLIC TARGETS

Blockade of Delta-Like Ligand 4 (Dll4)-Notch Signaling Reduces Macrophage Activation and Attenuates Atherosclerotic Vascular Diseases and Metabolic Disorders

Masanori Aikawa, Ph.D., Assistant Professor, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical

Modulating Glycerolipid Metabolism in Myeloid Cells for Cardiometabolic Benefit

Suneil K. Koliwad, M.D., Ph.D., Assistant Professor, Diabetes Center/Department of Medicine, University of California San Francisco

AMPK as a Target in Lipid and Carbohydrate Metabolism

Ajit Srivastava, Ph.D., Adjunct Professor, Pharmacology, Drexel University; Independent Consultant, Integrated Pharma Solutions, LLC

 http://www.discoveryontarget.com/Cardio-Drug-Targets

Inaugural n September 25 – 26, 2013

Cardio-Metabolic Drug Targets

Targeting One, Treating More

»»Suggested Event Package

September 23: Allosteric Modulators of GPCRs Short Course 4

September 24-25: Novel Strategies for Kinase Inhibitors

Conference

September 25: Setting Up Effective Functional Screens Using 3D

Cell Cultures Dinner Short Course 9

September 25-26: Cardio-Metabolic Drug Targets Conference

Wednesday, September 25

11:50 am Registration

BEYOND STATINS: NEW APPRO ACHES FOR

REGULATING LIPID METABOLISM AND

ATHERO SCLERO SIS

1:30 pm Chairperson’s Opening Remarks

1:40 PLENARY KEYNOTE PRESENTATION: Towards a Patient-

Based Drug Discovery

Stuart L. Schreiber, Ph.D., Director, Chemical Biology and Founding Member, Broad

Institute of Harvard and MIT; Howard Hughes Medical Institute Investigator; Morris

Loeb Professor of Chemistry and Chemical Biology, Harvard University

3:10 Refreshment Break in the Exhibit Hall with Poster Viewing

4:00 FEATURED SPEAKER: Atherosclerosis and Cardio-

Metabolism Research Overview: Promising Targets

Margrit Schwarz, Ph.D., MBA, formerly Director of Research, Dyslipidemia and

Atherosclerosis, Amgen; currently President, MS Consulting, LLC

4:30 Sponsored Presentations (Opportunities Available)

5:00 Novel Treatment for Dyslipidemia: Liver-Directed Thyroid

Hormone Receptor-ß Agonist

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

5:30 Modulating Glycerolipid Metabolism in Myeloid Cells for

Cardiometabolic Benefit

Suneil K. Koliwad, MD., Ph.D. Assistant Professor, Diabetes Center/Department

of Medicine, University of California San Francisco (UCSF)

6:00 Targeting PCSK9 for Hypercholesterolemia and

Atherosclerosis

Hong Liang, Ph.D., Associate Research Fellow, Rinat Research Unit, Pfizer

6:30 Close of Day

Thursday, September 26

7:30 am Registration

NEW ARTHERO /LIPID/CARDIO-METABOLIC

DRUG TARGETS

8:00 Breakfast Interactive Breakout Discussion Groups

9:05 Chairperson’s Opening Remarks

9:10 ApoE derived ABCA1 agonists for the Treatment of

Cardiovascular Disease

Jan Johansson, M.D., Ph.D., CEO, Artery Therapeutics, Inc.

9:40 Blockade of Delta-Like Ligand 4 (Dll4)-Notch Signaling

Reduces Macrophage Activation and Attenuates Atherosclerotic

Vascular Diseases and Metabolic Disorders

Masanori Aikawa, Ph.D., Assistant Professor, Department of Medicine,

Brigham and Women’s Hospital and Harvard Medical

10:10 Coffee Break in the Exhibit Hall with Poster Viewing

10:55 AMPK as a Target in Lipid and Carbohydrate Metabolism

Ajit Srivastava, Ph.D., Adjunct Professor, Department of Pharmacology, Drexel

University; Independent Consultant, Integrated Pharma Solutions, LLC

11:25 Macrophage ABC Transporters: Novel Targets to Promote

Atherosclerotic Plaque Regression by Inducing Reverse

Cholesterol Transport (RCT) Mechanism

Eralp “Al” Bellibas, M.D., Senior Director, Head, Clinical Pharmacology, The

Medicines Company

11:55 Targeting Ubiquitin Signaling Mediated Disease Pathology

of LDL Receptors

Udo Maier, Ph.D., Head of Target Discovery Research, Boehringer Ingelheim

Pharma

12:25 pm Sponsored Presentation (Opportunity Available)

12:55 Luncheon Presentation (Sponsorship Opportunity Available) or

Lunch on Your Own

Cardio-Metab olic Mimetics

2:25 Chairperson’s Opening Remarks

2:30 Oral Mimetics of RYGB and GLP-1 in Metabolic Syndromes

Jerome J. Schentag, PharmD, Professor of Pharmaceutical Sciences, University

at Buffalo

3:00 FGF21-Mimetic Antibodies for Type 2 Diabetes

Jun Sonoda, Ph.D., Group Leader, Scientist, Molecular Biology, Genentech

3:30 Ice Cream Refreshment Break in the Exhibit Hall with Poster

Viewing

gpCrS IN METABOLIC DISEASES

4:00 Targeting the Ghrelin Receptor with an Oral, Macrocyclic

Agonist

Helmut Thomas, Ph.D., Senior Vice President, Research and Preclinical

Development, Tranzyme Pharma

4:30 Presentation to be Announced

5:00 Lactate Receptor, GPR81/HCA1, as a Novel Target for

Metabolic Disorders

Changlu Liu, Ph.D., Scientific Director, Janssen Fellow, Head of Molecular

Innovation, Neuroscience, Janssen Research & Development, LLC

5:30 Targeting GPR55 in Cancer and Diabetes

Marco Falasca, Ph.D., Professor of Molecular Pharmacology, Queen Mary

University of London

6:00 Close of Conference

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In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, tagged Cancer - General, Conditions and Diseases, evidence based medicine, Prostate cancer, Prostate cancer screening, Prostate-specific antigen, PSA on May 23, 2013| 1 Comment »

In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Larry H. Bernstein, MD, FCAP, Author and Curator
Dror Nir, PhD, Curator
Aviva Lec-Ari, PhD, RN, Curator

• 

There have been two important articles in the last several days giving perspectives on the current and evolving status of current and evolving diagnosis of prostate cancer (PCA) by experts Dror Nir, PhD and Aviva Lev-Ari, PhD, RN, Editor-in-Chief, http://Pharmaceuticalintelligence.com

The first article reviews the recent published update on PCA screening and diagnosis, as determined by review of the literature by an Expert Panel, in order to determine what is the current validated Evidence-Based Medicine Practice Guideline for American Urological Surgeons.

The method of review is rigorously laid out and follows the accepted standard for publication.  The emphasis in the study lies in the reliance on prostate specific abtigen (PSA), which has undergone an evolutioary improvement sine 1999, although substantiation of a benefit could not be trusted until almost a decade later.   The problem the is notable is the absence of discussion of improvements in cancer imaging that has also evolved in that time period, and continues to evolve with molecular probes.

Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Author-Writer: Dror Nir, PhD

http://pharmaceuticalintelligence.com/2013/05/21/early-detection-of-prostate-cancer-aua-guideline/

When reviewing the DETECTION OF PROSTATE CANCER section on the AUA website , The first thing that catches one’s attention is the image below; clearly showing two “guys” exploring with interest what could be a CT or MRI image….

But, if you bother to read the review underneath this image regarding EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE produced by an independent group that was commissioned by the AUA to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening; Panel Members: H. Ballentine Carter, Peter C. Albertsen, Michael J. Barry, Ruth Etzioni, Stephen J. Freedland, Kirsten Lynn Greene, Lars Holmberg, Philip Kantoff, Badrinath R. Konety, Mohammad Hassan Murad, David F. Penson and Anthony L. Zietman – You are bound to be left with a strong feeling that something is wrong!

“The AUA commissioned an independent group to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening. The protocol of the systematic review was developed a priori by the expert panel. The search strategy was developed and executed by reference librarians and methodologists and spanned across multiple databases including Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials and Scopus. Controlled vocabulary supplemented with keywords was used to search for the relevant concepts of prostate cancer, screening and detection. The search focused on DRE, serum biomarkers (PSA, PSA Isoforms, PSA kinetics, free PSA, complexed PSA, proPSA, prostate health index, PSA velocity, PSA doubling time), urine biomarkers (PCA3, TMPRSS2:ERG fusion), imaging (TRUS, MRI, MRS, MR-TRUS fusion), genetics (SNPs), shared-decision making and prostate biopsy. The expert panel manually identified additional references that met the same search criteria”

While reading through the document, I was looking for the findings related to the roll of imaging in prostate cancer screening; see highlighted above. The only thing I found: “With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests.”

This must mean that: Notwithstanding hundreds of men-years and tens of millions of dollars which were invested in studies aiming to assess the contribution of imaging to prostate cancer management, no convincing evidence to include imaging in the screening progress was found by a group of top-experts in a thorough and rigorously managed literature survey! And it actually  lead the AUA to declare that “Nothing new in the last 20 years”…..

My interpretation of this: It says-it-all on the quality of the clinical studies that were conducted during these years, aiming to develop an improved prostate cancer workflow based on imaging. I hope that whoever reads this post will agree that this is a point worth considering!

For those who do not want to bother reading the whole AUA guidelines document here is a peer reviewed summary:

“Early Detection of Prostate Cancer: AUA Guideline; Carter HB, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, Holmberg L, Kantoff P, Konety BR, Murad MH, Penson DF, Zietman AL; Journal of Urology (May 2013)”

It says:

“A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age<40; 40 to 54; 55 to 69; ≥70).

RESULTS: With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and over treatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening.

Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics

Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/05/21/prostate-cancer-molecular-diagnostic-market-the-players-are-sri-intl-genomic-health-wcleveland-clinic-myriad-genetics-wucsf-genomedx-and-biotheranostics/

On February 6, 2013 we reported that DR. MARK RUBIN, LEADING PROSTATE CANCER AND GENOMICS EXPERT, TO LEAD CUTTING-EDGE CENTER FOR TARGETED, INDIVIDUALIZED PATIENT CARE BASED ON EACH PATIENT’S GENETICS

Genomically Guided Treatment after CLIA Approval: to be offered by Weill Cornell Precision Medicine Institute

On May 16, 2013 we reported a major breakthrough in the Prostate Cancer Screening

A Blood Test to Identify Aggressive Prostate Cancer: a Discovery @ SRI International, Menlo Park, CA

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.

http://pharmaceuticalintelligence.com/2013/05/16/a-blood-test-to-identify-aggressive-prostate-cancer-a-discovery-sri-international-menlo-park-ca/

Prostate Cancer MDx Competition Heating Up; New Data from Genomic Health, Myriad

May 15, 2013  By Turna Ray

Life sciences companies are gearing up for battle to capture the profitable prostate cancer molecular diagnostic market.

Genomic Health and Myriad Genetics both made presentations to the investment community last week about their genomic tests that gauge a man’s risk of prostate cancer aggressiveness. As part of its annual investor day, Myriad discussed new data on its Prolaris test, which analyzes the expression level of 46 cell cycle progression genes and stratifies men’s risk of biochemical recurrence of prostate cancer. If the test reports low gene expression, then the patient is at low risk of disease progression, while high gene expression is associated with disease progression.

Meanwhile, around the same time last week, Genomic Health launched its Oncotype DX prostate cancer test and presented data from the first validation study involving the diagnostic. The Oncotype DX prostate cancer test analyzes the expression of 17 genes within four biological pathways to gauge prostate cancer aggressiveness. The test reports a genomic prostate score from 0 to 100; the lower the score the more certain a patient can be that they can avoid treatment and continue with active surveillance. Prostate cancer patients who are deemed to be at very low risk, low risk, or intermediate risk of progressing are eligible to be tested with the Oncotype Dx test. If, based on standard clinical measures, a person’s prostate cancer is considered high risk, then he is not a candidate for Genomic Health’s test.

These molecular tests are entering the market at a time when currently available tools aren’t specific enough to distinguish between men who have an aggressive form of prostate cancer and therefore, need invasive treatments, and those that are low risk and can do well with active surveillance. According to an NIH estimate, in 2010, the annual medical costs associated with prostate cancer in the US were $12 billion.

It is estimated that each year 23 million men undergo testing for prostate specific antigen, a protein produced by the prostate gland that increases when a man has prostate cancer. Additionally, one million men get a prostate biopsy annually, while 240,000 men end up with a diagnosis for prostate cancer, and around 30,000 die from the disease. Although most of the men diagnosed with prostate cancer end up receiving surgery or radiation treatment, as many as half of these men will probably not progress, and their disease isn’t life threatening.

While PSA testing has been shown to reduce prostate cancer deaths, a man’s PSA level may be increased for reasons other than cancer. As such, broadly screening men for PSA has been controversial in the healthcare community since the test isn’t specific enough to gauge which men are at low risk of developing aggressive prostate cancer and can forgo unnecessary treatments that can have significant side effects.

Both Myriad and Genomic Health are hoping their tests will further refine prostate cancer diagnosis and help doctors gain more confidence in determining which of their patients have aggressive disease and which are at low risk.

Myriad’s advantage

In this highly competitive space, Myriad has the first mover advantage, having launched Prolaris three years ago. The company has published four studies involving the test and conducted a number of trials analyzing around 3,000 patient samples.

Researchers from UCSF and Myriad recently published the fourth validation study in the Journal of Clinical Oncology, which analyzed samples from 400 men who had undergone a radical prostatectomy. In the published study, researchers reported that 100 percent of the men whom Prolaris deemed to be at “low risk” of progression did not experience a recurrence within the five years the study was ongoing. Meanwhile, 50 percent of those the test deemed to be a “high risk” did experience recurrence during that time (PGx Reporter 3/6/2013).

New competition

Like Myriad’s BRACAnalysis test, which comprises more than 80 percent of its product revenues, Genomic Health’s Oncotype DX breast cancer recurrence tests is bringing in the majority of its product revenues. However, the company believes that its newly launched Oncotype DX prostate cancer test stands to be its largest market opportunity to date.

Last week, researchers from University of California, San Francisco, presented data from the first validation study involving the Oncotype DX prostate cancer test. The study involved nearly 400 prostate cancer patients considered low or intermediate risk by standard methods such as Gleason score and showed that when the Oncotype DX score was used in conjunction with other measures, investigators identified more patients as having very low risk disease who were appropriate for active surveillance than when they diagnosed patients without the test score.

More than one third of patients classified as low risk by standard measures in the study were deemed to be “very low risk” by Oncotype DX and therefore could choose active surveillance. Meanwhile, 10 percent of patients in the study were found by clinical measures to be at very low risk or low risk, but the Oncotype DX test deemed them as having aggressive disease that needed treatment.

Matthew Cooperberg of UCSF, who presented data from this validation study at the American Urological Association’s annual meeting last week, highlighted this feature of the Oncotype DX prostate cancer test to investors during a conference call last week. He noted that the test not only gauges which low-risk patients can confidently remain with active surveillance, but it also finds those patients who didn’t receive an accurate risk assessment based on standard clinical measures. “It’s also equally important that we identify the man who frankly should not be on active surveillance, because they’re out there,” he said.

Genomic Health has aligned its test with guidelines from the National Comprehensive Cancer Network, which has expressed concern about over-diagnosis and over-treatment in prostate cancer patients. In 2010, NCCN guidelines established a new “very low risk” category for men with clinically insignificant prostate cancer and recommended that men who fall into this category and have a life expectancy of more than 20 years should only be followed with active surveillance. In 2011, NCCN made the active surveillance criteria more stringent for men in the “very low risk” category.

In order to develop the prostate cancer test, Genomic Health collaborated with the Cleveland Clinic on six feasibility studies and selected the gene expression panel after analyzing 700 genes on tissue samples from 700 patients. The commercial test analyzes the expression of 17 genes across four biological

I am quite surprised that nothing is said about the current status of  PSA for Pca, which is far advanced today, and it also needs attention.  We are in the old SUFI tale about the blind men who grasped the trunk, or the tail, etc., and called it the elephant.

Robustness of ProsVue™ linear slope for prognostic identification of patients at reduced risk for prostate cancer recurrence: Simulation studies on effects of analytical imprecision and sampling time variation

Mark J. Sarno, Charles S. Davis

Clinical Biochemistry  Nov 2012;  45 (16–17): 1479-1484

 

Highlights

► We simulate effects of analytical and sampling time variation on ProsVue slope.

 ► Classification switching is minimal in both stable disease and recurrence.

 ► We provide a framework for assessment of assays using rate of change principles

Objective

The ProsVue assay measures serum total prostate-specific antigen (PSA) over three time points post-radical prostatectomy and calculates rate of change expressed as linear slope. Slopes ≤ 2.0 pg/ml/month are associated with reduced risk for prostate cancer recurrence. However, an indicator based on measurement at multiple time points, calculation of slope, and relation of slope to a binary cutoff may be subject to effects of analytical imprecision and sampling time variation. We performed simulation studies to determine the presence and magnitude of such effects.

Design and methods

Using data from a two-site precision study and a multicenter clinical trial of 304 men, we performed simulation studies to assess whether analytical imprecision and sampling time variation can drive misclassifications or classification switching of patients with stable disease or recurrence.

Results

Analytical imprecision related to expected PSA values in a stable disease population results in ≤ 1.2% misclassifications. For populations with recurrent disease, an analysis taking into account correlation between sampling time points demonstrates that classification switching across the 2.0 pg/ml/month cutoff occurs at a rate ≤ 11%. In the narrow region of overlap between populations, classification switching maximizes at 12.3%. Lastly, sampling time variation across a wide range of scenarios results in 99.7% retention of proper classification for stable disease patients with linear slopes up to the 75th percentile of the distribution.

Conclusions

These results demonstrate the robustness of the ProsVue assay and the linear slope indicator. Further, these simulation studies provide a potential framework for evaluation of future assays that rely on the rate of change principle.

 

As the reviewer of this paper for Clinical Biochemistry, I have never encountered such a beautiful and rigorous evaluation that is described in the outline below:

 

Article Outline

1. Introduction

2. Materials and Methods

2.1. Source data

2.2. Simulation 1 – Effects of analytical imprecision in patients with stable disease

2.3. Simulations 2 and 3 – Effects of analytical imprecision in patients with PCa recurrence

2.4. Simulations 4 and 5 – Simulations in highest tertile of stable disease slopes and lowest tertile of recurrent slopes

2.5. Simulation 6 – Effects of sampling time variation

2.6. Software

3. Results

3.1. Source data for simulations

3.2. Simulation 1 – Effects of analytical imprecision in patients with stable disease

3.3. Simulations 2 and 3 – Effects of analytical imprecision in patients with PCa recurrence

3.4. Simulations 4 and 5 — Simulations in highest tertile of stable disease slopes and lowest tertile of recurrent slopes

3.5. Simulation 6 – Effects of sampling time variation

4. Discussion

5. Conclusions

References

 

This article is followed by another in the Urology journal.

NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy.

 

Moul JW, Lilja H, Semmes OJ, Lance RS, Vessella RL, Fleisher M, Mazzola C, Sarno MJ, Stevens B, Klem RE, McDermed JE, Triebell MT, Adams TH.

Division of Urologic Surgery and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina 27710, USA. judd.moul@duke.edu

Urology. 2012 Dec;80(6):1319-25. http://dx.doi.org/10.1016/j.urology.2012.06.080. Epub 2012 Oct 26.

OBJECTIVE:

To validate the hypothesis that men displaying serum prostate-specific antigen (PSA) slopes ≤ 2.0 pg/mL/mo after prostatectomy, measured using a new immuno-polymerase chain reaction diagnostic test (NADiA ProsVue), have a reduced risk of clinical recurrence as determined by positive biopsy, imaging findings, or death from prostate cancer.

MATERIALS AND METHODS:

From 4 clinical sites, we selected a cohort of 304 men who had been followed up for 17.6 years after prostatectomy for clinical recurrence. We assessed the prognostic value of a PSA slope cutpoint of 2.0 pg/mL/mo against established risk factors to identify men at low risk of clinical recurrence using uni- and multivariate Cox proportional hazards regression and Kaplan-Meier analyses.

RESULTS:

The univariate hazard ratio of a PSA slope >2.0 pg/mL/mo was 18.3 (95% confidence interval 10.6-31.8) compared with a slope ≤ 2.0 pg/mL/mo (P <.0001). The median disease-free survival interval was 4.8 years vs >10 years in the 2 groups (P <.0001). The multivariate hazard ratio for PSA slope with the covariates of preprostatectomy PSA, pathologic stage, and Gleason score was 9.8 (95% confidence interval 5.4-17.8), an 89.8% risk reduction for men with PSA slopes ≤ 2.0 pg/mL/mo (P <.0001). The Gleason score (<7 vs ≥ 7) was the only other significant predictor (hazard ratio 5.4, 95% confidence interval 2.1-13.8, P = .0004).

CONCLUSION:

Clinical recurrence after radical prostatectomy is difficult to predict using established risk factors. We have demonstrated that a NADiA ProsVue PSA slope of ≤ 2.0 pg/mL/mo after prostatectomy is prognostic for a reduced risk of prostate cancer recurrence and adds predictive power to the established risk factors.

Urology. 2012 Dec;80(6):1325-6; author reply 1326-7. http://dx.doi.org/10.1016/j.urology.2012.06.081. Epub 2012 Oct 26.      Collins S.

Editorial comment.

NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy. [Urology. 2012]

 

Why NADiA ProsVue?      IRIS INTERNATIONAL

http://www.irispermed.com/patients/why-nadia-prosvue

Some patients who had surgery to remove the prostate may be at higher risk for recurrence. Determining the risk of recurrence is critical for these patients and their physicians in order to make the most informed decision possible about future medical management.

Physicians use post-surgical risk assessment to review a variety of parameters to help determine if the patient might develop recurrent disease.  Risk factors may include:

• The size and proximity of the tumor at the time of surgery (whether it has grown through the prostate walls):

Through imaging tests, physicians can determine how far cancerous tissue may have spread, with indicators such as

• extracapsular extensions (ECE, beyond the prostatic capsule) and
• seminal vesicle invasion (SVI, presence in the walls of the vesicles surrounding the prostate).
• The presence of cancer cells at the edge of the removed tumor (known as positive margins) or in the lymph nodes outside the prostate.
• A high preoperative PSA level (> 20 ng/mL).
• The tumor’s Gleason Score (if it is at least 8 or higher).

However, current risk assessment relies on subjective and imprecise information. This uncertainty can have a dramatic impact on a patient’s personal experience after prostatectomy.

The newly available NADiA ProsVue test may help provide a more clear and accurate prediction of a patient’s true risk for clinical recurrence.
The NADiA ProsVue test measures

• the rate of change of PSA at extremely low levels over time, which can help quickly and accurately identify patients
• who are at reduced risk for clinical recurrence.

In conjunction with other information, NADiA ProsVue may allow some men to avoid unnecessary treatments and anxiety after prostatectomy.

NADiA ProsVue is an in-vitro diagnostic assay for determining

• rate of change of serum total prostate specific antigen (tPSA) over a period of time (slope, pg/mL per month).

The NADiA ProsVue assay is performed for patients having less than 0.1 ng/mL serum tPSA values (determined by standard-of-care assays that are FDA approved/cleared) in the first sample collected more than 6 weeks after radical prostatectomy.

What is NADiA?

NADiA stands for Nucleic Acid Detection immunoassay.  Immuno-PCR, first described by Sano and Cantor in 1992 involves combining protein antigen detection by immunoassay with the detection sensitivity and precision of real-time polymerase chain reaction (qPCR).  This amplified DNA-immunoassay approach is similar to that of an enzyme immunoassay, involving antibody binding reactions and intermediate washing steps.  The enzyme label is replaced by a strand of DNA and detected by exponential amplification using qPCR.

http://www.irispermed.com/images/pictures/thumbnails/thumb_NADiA_Technology1.jpg

 

NADiA employs a soluble (reporter) monoclonal antibody (MAb) labeled with an assay-specific double-stranded DNA sequence.

• The presence of this DNA label does not interfere with MAb binding, nor
• does the MAb interfere with DNA label amplification and detection.
• The second (capturing) MAb specific for another site on the target protein (antigen)
  is coated onto paramagnetic microparticles.

The reporter MAb-DNA conjugate is reacted with sample in a microtiter plate format to form a first immune complex with the target antigen. The immune complex is then captured onto paramagnetic particles coated with the second capture MAb, forming an insoluble sandwich immune complex. The microparticles are washed by several cycles of magnetic capture and re-suspension to remove excess reporter MAb-DNA conjugate.
The specifically bound DNA label is then detected by subjecting

• suspended particles to qPCR conditions and monitoring the generations of amplicon in real time.

What are possible clinical applications?

Proteins play a crucial role in all biological functions. Identifying and measuring the quantity of specific proteins is fundamental to understanding the cause and evolution of many human disease processes.
There are hundreds of thousands of proteins in the human body, but the vast majority are present at extremely low concentrations. For example, only ten (10) proteins make up 90% of the mass of plasma proteins found in human serum. Twelve (12) proteins make up another 9% of the mass. The remaining proteins comprise the final 1%. Advancing medicine through the study of proteins (known as proteomics) requires powerful and sensitive tools.
http://www.irispermed.com/images/pictures/Protein_Slide_2.png

NADiA combines the specificity of an immunoassay with the detection sensitivity of qPCR and can assist efforts to provide clinical insight into many human diseases.  Any disease process involving proteins below the detection limits of today’s enzyme immunoassays (EIA) is a potential target for NADiA.

NADiA ProsVue is the first of a line of assays designed to advance human healthcare in the areas of oncology and infectious disease.

http://www.irispermed.com/images/pictures/Major_Plasma_Proteins.jpg

 

510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION

DECISION SUMMARY

A. 510(k) Number:

k101185

B. Purpose for Submission:

New device

C. Measurand:

Total Prostate specific antigen (tPSA)

D. Type of Test:

Quantitative, Immuno-PCR (Polymerase Chain Reaction)

E. Applicant:

Iris Molecular Diagnostics

F. Proprietary and Established Names:

NADiA® ProsVue™

 

 Intended Use:

NADiA® ProsVue™ is an in-vitro diagnostic assay for determining rate of change of serum total prostate specific antigen over a period of time (slope, pg/mL per month). The NADiA® ProsVue™ assay is performed for patients having less than 0.1 ng/mL serum total PSA values (determined by standard-of-care assays that are FDA approved/cleared) in the first sample collected more than 6 weeks after radical prostatectomy. ProsVue™ slope is indicated for use as a prognostic marker in conjunction with clinical evaluation as an aid in identifying those patients at reduced risk for recurrence of prostate cancer for the eight year period following prostatectomy.

The NADiA® ProsVue™ assay is not intended for the diagnosis or for the monitoring of prostate cancer.

 †”Recurrence” is defined as clinical recurrence, not biochemical recurrence, and was documented by positive imaging, positive biopsy, or death due to prostate cancer.

U.S. FDA approves NADiA ProsVue prognostic test for prostate cancer

Posted on September 23, 2011 by Sitemaster

According to a media release issued

Moul et al. have now conducted a retrospective, multi-center clinical trial to further evaluate the potential prognostic value of ProsVue slope at a decision threshold of 2 pg/ml/month. (One nanogram or 1 ng = 1,000 picograms or 1,000 pg.)

The retrospective analysis was based on data from 392 prostate cancer patients who had been given radical prostatectomies between November 1991 and August 2001. To be eligible for this study, all of the following data had to be available from individual patients:

1. A first post-surgical PSA level of <100 pg/ml (i.e., <  0.1 ng/ml)
2. Full pathologic and radiographic data
3. Three frozen serum samples drawn between 6 weeks and 19.4 months post-surgery.
4. Patients were not eligible if they had received adjuvant radiotherapy and/or hormone therapy after surgery and prior to completion of the three post-surgical blood draws.

The results of this retrospective study showed that:

1. The average (median) PSA levels of the 392 patients was 6.3 ng/ml (range, 0 to 60.6 ng/ml)
2. The average (median) post-surgical Gleason score was 7.0 (range, 4 to 10).

73 patients had received neoadjuvant hormone therapy prior to their surgery.

The pathologic stages of the patients were

pT0-2, n = 228

pT3, n = 147

pT4, n = 17

116 patients had positive margins and 8 had positive lymph nodes.

The three post-surgical PSA values were based on serum drawn

• after median times of 4.9, 8.6, and 12.8 months and showed median values of 10.7, 23.0 and 50.7 pg/ml, respectively.

The sensitivity, specificity, PPV and NPV for a 2 pg/mL/month ProsVue slope were 75.0, 96.6, 81.4, and 95.2, respectively.

• At a median follow-up of 10.5 years, 14 patients had died of prostate cancer and 40 had died overall.

The authors conclude the the ProsVue test “provides information previously unknown” in patients in the first year post-surgery, and that a ProsVue slope of  ≤ 2 pg/mL/month in that first year is highly associated with a lack of evidence of progression in long-term follow-up.

In theory, the ProsVue test may have some clinical value in the identification of patients who do not need long-term oncologic follow-up and in predicting the need for adjuvant radiation therapy. However, additional prospective studies will be necessary before this can be confirmed, and the practical clinical value of such a test would depend on whether it is significantly more accurate that data currently available from ultrasensitive PSA testing.

Additional information is available in a media release from the developer of the ProsVue test (IRIS International). According to that media release, the developer has submitted data to the FDA requesting approval to market this test.

The centers involved in this study included Duke University, Memorial Sloan-Kettering Cancer Center, Eastern Virginia Medical Center, and the University of Washington — all of which are highly reputable institutions.

NADiA ProsVue results are calculated as the linear slope of three NADiA ProsVue total PSA test results obtained on three serum samples collected between six weeks and 20 months post-radical prostatectomy.

http://www.irispermed.com/images/pictures/NADiA_ProsVue_Timeline.jpg

 

by IRIS International, the U.S. Food & Drug Administration (FDA) has approved the company’s NADiA® ProsVue™ test as a prognostic marker that can “aid in identifying” men at reduced risk for recurrence of prostate cancer in the first 8 years after a prostatectomy

 

NADiA ProsVue: A prognostic test for identifying men at a reduced risk for prostate cancer recurrence following radical prostatectomy

J. Moul2, R. Lance1, J. Alter3, M. Sarno3, J. McDermed3
1 Eastern Virginia Medical School, Norfolk, USA
2 Duke Prostate Center, Durham, USA
3 Iris Molecular Diagnostics, Carlsbad, USA

Introduction: Clinical recurrence after radical prostatectomy (RP) is difficult to predict since established factors do not reliably stratify risk. We validated a pre-specified hypothesis that a post-RP NADiA® PSA slope cutpoint of ≤2.0 pg/mL/month (mo) identifies men at reduced risk of clinical recurrence as determined by positive biopsy, imaging or prostate cancer death. This study aimed to compare the prognostic strength of the ProsVue slope cutpoint vs. surgical margin status to identify men at very low risk of post-RP clinical recurrence.
Methods: From a cohort of 304 men, surgical margin data was available for 234 men. PSA was measured with a Nucleic Acid Detection Immunoassay (NADiA®) having a limit of quantification of 0.00065 ng (0.65 pg) per mL. Least-squares linear PSA slope (ProsVue™) was calculated using 3 serum samples drawn 1.5-20 mo post-RP. Recurrence risk using a 2.0 pg/mL/mo ProsVue cutpoint and surgical margin status were compared by two survival methods, univariate Cox proportional hazards regression analysis (table) and Kaplan-Meier plots (figure).
Results: ProsVue slope ≤2.0 pg/mL/mo was significantly associated with a reduced risk of clinical recurrence by univariate Cox analysis (HR 18.3, 95% CI, 10.6–31.8, P < 0.0001). A negative surgical margin was less significantly associated with a reduced risk of recurrence (HR 3.3, 95% CI 2.0–5.4). Median time to recurrence for men with ProsVue slope ≤2.0 pg/mL/mo and those with negative margins exceeded 17.6 years (yrs). However, median time to recurrence in men with ProsVue slope >2.0 pg/mL/mo was shorter compared to those with positive margins.

NADiA ProsVue Prostate-specific Antigen Slope Is an Independent Prognostic Marker for Identifying Men at Reduced Risk of Clinical Recurrence of Prostate Cancer After Radical Prostatectomy

Judd W. Moul, Hans Lilja, O. John Semmes, Raymond S. Lance, Robert L. Vessella, Martin Fleisher, Clarisse Mazzola, Mark J. Sarno, Barbara Stevens, Robert E. Klem, Jonathan E. McDermed, Melissa T. Triebell, Thomas H. Adams
Urology Dec 2012; 80(6): 1319-1327,

Objective
To validate the hypothesis that men displaying serum prostate-specific antigen (PSA) slopes ≤2.0 pg/mL/mo after prostatectomy, measured using a new immuno-polymerase chain reaction diagnostic test (NADiA ProsVue), have a reduced risk of clinical recurrence as determined by positive biopsy, imaging findings, or death from prostate cancer.
Materials and Methods
From 4 clinical sites, we selected a cohort of 304 men who had been followed up for 17.6 years after prostatectomy for clinical recurrence. We assessed the prognostic value of a PSA slope cutpoint of 2.0 pg/mL/mo against established risk factors to identify men at low risk of clinical recurrence using uni- and multivariate Cox proportional hazards regression and Kaplan-Meier analyses.
Results
The univariate hazard ratio of a PSA slope >2.0 pg/mL/mo was 18.3 (95% confidence interval 10.6-31.8) compared with a slope ≤2.0 pg/mL/mo (P <.0001). The median disease-free survival interval was 4.8 years vs >10 years in the 2 groups (P <.0001). The multivariate hazard ratio for PSA slope with the covariates of preprostatectomy PSA, pathologic stage, and Gleason score was 9.8 (95% confidence interval 5.4-17.8), an 89.8% risk reduction for men with PSA slopes ≤2.0 pg/mL/mo (P <.0001). The Gleason score (<7 vs ≥7) was the only other significant predictor (hazard ratio 5.4, 95% confidence interval 2.1-13.8, P = .0004).
Conclusion
Clinical recurrence after radical prostatectomy is difficult to predict using established risk factors. We have demonstrated that a NADiA ProsVue PSA slope of ≤2.0 pg/mL/mo after prostatectomy is prognostic for a reduced risk of prostate cancer recurrence and adds predictive power to the established risk factors.

Fifth–Generation Digital Immunoassay for Prostate Specific Antigen by Single Molecule Array Technology.

D.H. Wilson, D.W. Hanlon, G.K. Provuncher, L. Chang, L. Song, P.P. Patel, E.P. Ferrell, H. Lepor,A.W. Partin, D.W. Chan, L.J. Sokoll, C.D. Cheli, R.P. Thiel, D.R. Fournier, and D.C. Duffy
http://dx.doi.org/10.1373/clinchem.2011.169540

Measurement of prostate specific antigen (PSA) in prostate cancer patients following radical prostatectomy (RP) has been hindered by the limit of quantification of available assays. Because radical prostatectomy removes the tissue responsible for PSA production, postsurgical PSA is typically undetectable with current assay methods. Evidence suggests, however, that more sensitive determination of PSA status following RP could improve assessment of patient prognosis and response to treatment and better target secondary therapy for those who may benefit most. We developed an investigational digital immunoassay with a 2–logs–lower limit of quantification than current ultrasensitive third–generation PSA assays. We developed reagents for a bead–based ELISA for use with high–density arrays of femtolitervolume wells. Anti–PSA capture beads with immunocomplexes and associated enzyme labels were singulated within the wells of the arrays and interrogated for the presence of enzymatic product. We characterized analytical performance, compared its accuracy with a commercially available test, and analyzed longitudinal serum samples from a pilot study of 33 RP patients. The assay exhibited a functional sensitivity (20% interassay CV) <0.05 pg/mL, total imprecision <10% from 1 to 50 pg/mL, and excellent agreement with the comparator method. All RP samples were well within the assay measurement capability. PSA concentrations following surgery were found to be predictive of prostate cancer recurrence risk over 5 years. The robust 2–log improvement in limit of quantification relative to current ultrasensitive assays and the validated analytical performance of the assay allow for accurate assessment of PSA status after RP.

Related articles

• EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE
   Dror Nir, PhD
  http://pharmaceuticalintelligence.com/2013/05/21/early-detectio…-aua-guideline
• Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics
   Aviva Lev-Ari, PhD, RN
  http://pharmaceuticalintelligence.com/2013/05/21/prostate-cance…iotheranostics/

• EARLY DETECTION OF PROSTATE CANCER: American Urological Association (AUA) GUIDELINE (pharmaceuticalintelligence.com)
• From AUA2013: “Histoscanning”- aided template biopsies for patients with previous negative TRUS biopsies (pharmaceuticalintelligence.com)
• FDA Approves a New Drug for Prostate Cancer (cancerwhattodoorsay.wordpress.com)
• Clinical trial tests targeting prostate cancer treatment (sys-con.com)
• Routine PSA Tests No Longer Recommended – American Urological Association (medicalnewstoday.com)
• Clinical trial tests targeting prostate cancer treatment (hormonetherapymiami.wordpress.com)
• AUA Releases New Clinical Guideline On Prostate Cancer Screening (medicalnewstoday.com)

Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA Catalona W, Partin A, Slawin K, Brawer M, Flanigan R, Patel A, Richie J, deKernion J, Walsh P, Scardino P, Lange P, Subong E, Parson R, Gasior G, Loveland K, Southwick P (1998). “Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial”. JAMA 279 (19) : 1542–7. doi:10.1001/jama.279.19.1542. PMID 9605898. (Photo credit: Wikipedia)

English: Human prostate specific antigen (PSA/KLK3) with bound substrate from complex with antibody (PDB id: 2ZCK) (Photo credit: Wikipedia)

Table 1. Side-effects and effects on recovery of treatments for newly diagnosed prostate cancer. The Prostate Brachytherapy Advisory Group: http://www.prostatebrachytherapyinfo.net (Photo credit: Wikipedia)

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The Clinical Epigenome Conference (TCEC): June 26-27, 2013 | Hotel Kabuki | San Francisco, CA

Posted in Genome Biology, Genomic Testing: Methodology for Diagnosis, Interviews with Scientific Leaders, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Stem Cells for Regenerative Medicine, Technology Transfer: Biotech and Pharmaceutical, tagged Biology, DNA, DNA methylation, Ontario Cancer Institute, Salk Institute for Biological Studies, Stem cell, University of California on May 22, 2013| Leave a Comment »

The Clinical Epigenome Conference (TCEC): June 26-27, 2013 | Hotel Kabuki | San Francisco, CA

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #56: The Clinical Epigenome Conference (TCEC): June 26-27, 2013 | Hotel Kabuki | San Francisco, CA. Published on 5/22/2013

WordCloud Image Produced by Adam Tubman

 

Above the Genome – Underlying Disease

June 26-27, 2013 | Hotel Kabuki | San Francisco, CA | Visit website

FINAL AGENDA

http://www.clinicalgenomeconference.com/Clinical-Epigenome

KEYNOTE PRESENTATIONS

 

Adventures in Personal Medicine: Integrated Personal Omics Profiling for Following Healthy and Disease States

Michael Snyder, Ph.D., Professor and Chair, Genetics; Director, Stanford Center for Genomics and Personalized Medicine, Stanford University

 

Spontaneous and Therapy Induced Evolution of Tumor Genomes and Epigenomes

Joseph Costello, Ph.D., Professor in Residence, Department of Neurological Surgery; Director, Epigenetics Division, Cell Cycling and Signaling Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

THIS WEEK’S FEATURED TALKS

This is just a small sample of presentations that you’ll be able to hear at TCEC: The Clinical Epigenome Conference in San Francisco, CA next month.

Distinguishing between Driver and Passenger Epigenetic Modifications in Cancer

Daniel De Carvalho, Ph.D., Principal Investigator, Ontario Cancer Institute, University Health Network; Assistant Professor, Medical Biophysics, Faculty of Medicine, University of Toronto

Cancer cells typically exhibit aberrant DNA methylation patterns that can drive malignant transformation. Whether cancer cells are dependent on these abnormal epigenetic modifications remains elusive. We used experimental and bioinformatic approaches to unveil genomic regions that require DNA methylation for survival of cancer cells, suggesting these are key epigenetic events associated with tumorigenesis.

Family Proteins and 5-Hydroxymethylcytosine in Stem Cells, Development and Cancer

Yujiang Geno Shi, Ph.D., Associate Biochemist, Division of Endocrinology, Brigham and Women’s Hospital; Assistant Professor, Medicine, Harvard Medical School

Recent studies have shown that ten-eleven translocation (Tet) proteins can catalyze 5mC oxidation and generate 5mC derivatives, including 5-hydroxymethylcytosine (5hmC). Not only are Tet family proteins and 5hmC critical for the identity and normal function of embryonic stem cells and early embryonic process of development, but dysregulation of these newly identified epigenetic factors also plays a major role in cancer development. Here we report an essential role of Tet3 in animal development, and define 5hmC as a potential biomarker for tumor progression. These studies will significantly increase our current understanding of the biological functions of Tet proteins and 5hmC while providing mechanistic insight into the development of epigenetic therapeutics.

Defining the Epigenetic Landscape during Normal and Malignant Hematopoiesis

Lucy A. Godley, M.D., Ph.D., Associate Professor, Department of Medicine, Section of Hematology/Oncology, Cancer Research Center, The University of Chicago

Hematopoietic stem cell commitment and differentiation involves silencing of self-renewal genes and induction of a specific transcriptional program, which is controlled in part through dynamic changes in covalent cytosine modifications. We have studied how the abundance and distribution of these derivatized bases influences hematopoietic stem cell commitment during normal erythropoiesis as well as during leukemia development. The identification of recurrent mutations in several genes important in epigenetic pathways as well as mouse modeling suggest that the balance of covalent cytosine modifications is a key driver of normal blood cell development. I will also discuss how these findings impact our understanding of the activity of the ‘hypomethylating drugs’, now in common use for the treatment of myeloid malignancies.

DNA Methylation Alterations in Lung Adenocarcinoma

Ite A. Laird-Offringa, Ph.D., Associate Professor, Departments of Surgery, Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California

I will discuss our research on integrated genome-scale DNA methylation and mRNA expression data from microdissected lung adenocarcinoma and matched non-tumor lung. We have identified 164 hypermethylated genes showing concurrent downregulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis and detailed examination of individual genes suggests mechanistic contributions of several of these genes to lung adenocarcinoma development and/or progression. I will present information on a number of candidate epigenetic driver genes for lung adenocarcinoma.

Lessons from Surveying the DNA Methylation “Cityscape” of Lethal Metastatic Prostate Cancer

Srinivasan (Vasan) Yegnasubramanian, M.D., Ph.D., Assistant Professor, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine

Alterations in DNA methylation are a hallmark of human cancers, including prostate cancer. We carried out genome-scale analyses of DNA methylation alterations in multiple metastases from each of 13 men that died of metastatic prostate cancer and created DNA methylation cityscapes to visualize these complex data. These analyses revealed that each individual developed a unique DNA methylation signature that was largely maintained across all metastases within that individual. By analyzing their frequency, clonal maintenance, and correlation with expression, we nominated potential “driver” DNA methylation alterations that could be prioritized for development as epigenetic biomarkers and therapeutic targets.

DNA Methylation Detection using Nanopores

George Vasmatzis, Ph.D., Director, Biomarker Discovery Program, Center of Individualized Medicine; Consultant, Department of Molecular Medicine, Mayo Clinic and Foundation

I will discuss some of our latest work around integrating micro-fabrication and solid state technologies with biomarkers. In diagnostics, a biosensor that could look for subtle structural or sequence variations at the single molecule level would be extremely useful . Epigenetic modifications have been linked with cancer, and we have developed nanopore technology to detect the methylation profile of a single molecule. The challenges and the potential of such technology will be discussed.

 

CONFERENCE TOPICS INCLUDE:

Genetic & Epigenetic Interplay in Cancer 

Mechanisms in (De)Methylation Underlying 

Development of Disease 

The Predictive Power of Epigenetics: Diagnostic 

& Prognostic Utility 

The Clinical Genome Technology Showcase 

Trends in Analysis & Interpretation 

————————————————————————

DINNER SHORT COURSES*

Wednesday, June 26      View Details     Registration Information

5:30 – 8:30 pm

(SC3) Clinical Combination Economic Conundrums

 

5:30 – 8:30 pm

(SC4) Advances in Methylation Analysis

 

 

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