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Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Pharmacogenomics, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Interviews with Scientific Leaders, Medical and Population Genetics, Metabolomics, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Scientist: Career considerations, Stem Cells for Regenerative Medicine, Technology Transfer: Biotech and Pharmaceutical, tagged Aviva Lev-Ari, Cancer - General, Clinical trial, DNA, DNA Sequencing, Full genome sequencing, genetics, Genomic, Personalized medicine, University of Texas MD Anderson Cancer Center on January 13, 2013| 13 Comments »

Author & Curator: Aviva Lev-Ari, PhD, RN

Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

How to Tailor Cancer Therapy to the particular Genetics of a patient’s Cancer

THIS IS A SERIES OF FOUR POINTS OF VIEW IN SUPPORT OF the Paradigm Shift in Human Genomics

‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

Part 1:

Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine

Part 2:

LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment

http://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-drug-selection-in-cancer-personalized-treatment-part-2/

Part 3:

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research

http://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-research-part-3/

Part 4:

The Consumer Market for Personal DNA Sequencing

http://pharmaceuticalintelligence.com/2013/01/13/consumer-market-for-personal-dna-sequencing-part-4/

 

Part 1:

Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine

 

In Part 1, we will address the following FIVE DIRECTIONS in Genomics Research

• ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

• Sequencing DNA from individual cells vs “humans as a whole.” Sequencing DNA from individual cells is changing the way that researchers think of humans as a whole.

• Promising Research Directions By Watson, 1/10/2013

• Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper

• Molecular Analysis of the different Stages of  Cancer Progression for Targeting Therapy

First:

Predictive Biomarkers and Personalized Medicine

No to Sequencing Patient’s DNA, No to Sequencing Patient’s Tumor, Yes to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

 

MD Anderson Research

targeted agents matched with tumor molecular aberrations.

Molecular analysis

Patients whose tumors had an aberration were treated with matched targeted therapy, compared with those of consecutive patients who were not treated with matched targeted therapy

Results

40.2% – 1 or more aberration.

In 1 aberration , matched tx higher response rate  27% vs 5%

Longer time ot treatment failure  TTF 5.2 vs. 2.2

Longer survival  13.4 vs. 9 months

Pt. w/1 mutation (molecular aberrationMatched targeted therapy associated with longer TTF vs. prior systemic therapy 5.2 vs. 3.1

matched therapy was an independent factor predicting response superior to TTF

Conclusion

Not randomized study, and patients had diverse tumor types and a median of 5 prior therapies,  results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials

Clin Cancer Res. 2012 Nov 15;18(22):6373-83. doi: 10.1158/1078-0432.CCR-12-1627. Epub 2012 Sep 10.

Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.

Tsimberidou AM, Iskander NG, Hong DS, Wheler JJ, Falchook GS, Fu S, Piha-Paul S, Naing A, Janku F, Luthra R, Ye Y, Wen S, Berry D, Kurzrock R.

Source

Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. atsimber@mdanderson.org

http://www.ncbi.nlm.nih.gov/pubmed?term=22966018

 

Opinion by Dr. Pierluigi Scalia, 1/11/2013.

The fact of using nanotechnology in order to target and treat abnormal cancer cells and tissues adds a powerful weapon towards eradicating the disease in the foreseeable future. However, focusing on weapons when we still have not found a reliable way to build that personalized “shooting target” (Cancer Fingerprinting) still constitutes, in my opinion, the single most relevant barrier to the adoption of Personalized treatments.

http://pharmaceuticalintelligence.com/2013/01/09/nanotechnology-personalized-medicine-and-dna-sequencing/

Ritu Saxena’s interview

http://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

Other studies supporting this perspective

 

p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias

 

Chromosome aberrations in solid tumors

 

Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis

 

Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors

 

Clonal analysis of delayed karyotypic abnormalities and gene mutations in radiation-induced genetic instability.

 

Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgVH status and …

 

Detection of aberrations of the p53 alleles and the gene transcript in human tumor cell lines by single-strand conformation polymorphism analysis

 

Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma

 

VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

 

Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status

 

… nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations

 

Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations

[DOC] Pax 6 Gene Research and the Pancreas

 

Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies

Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p.

Cytogenetic analysis of soft tissue sarcomas: recurrent chromosome abnormalities in malignant peripheral nerve sheath tumors (MPNST)

Radiation-induced genomic instability: delayed cytogenetic aberrations and apoptosis in primary human bone marrow cells

SOURCES

Search:

Gene Mutation Aberration & Analysis of Gene Abnormalities

http://scholar.google.com/scholar?start=20&q=Gene+Mutation+Aberration+%26+Analysis+of+Gene+Abnormalities&hl=en&as_sdt=0,22&as_vis=1

Second:

Sequencing DNA from individual cells vs “humans as a whole.”

Sequencing DNA from individual cells is changing the way that researchers think of humans as a whole.

The ability to sequence single cells meant that researchers could take another approach. Working with a team at the Chinese sequencing powerhouse BGI, Auton sequenced nearly 200 sperm cells and was able to estimate the recombination rate for the man who had donated them. The work is not yet published, but Auton says that the group found an average of 24.5 recombination events per sperm cell, which is in line with estimates from indirect experiments2. Stephen Quake, a bioengineer at Stanford University in California, has performed similar experiments in 100 sperm cells and identified several places in the genome in which recombination is more likely to occur. The location of these recombination ‘hotspots’ could help population biologists to map the position of genetic variants associated with disease.

Quake also sequenced half a dozen of those 100 sperm in greater depth, and was able to determine the rate at which new mutations arise: about 30 mutations per billion bases per generation3, which is slightly higher than what others have found. “It’s basically the population biology of a sperm sample,” Quake says, and it will allow researchers to study meiosis and recombination in greater detail.

SOURCES:

http://www.nature.com/news/genomics-the-single-life-1.11710#/genome

Nature 491, 27–29 (01 November 2012) doi:10.1038/491027a

http://pharmaceuticalintelligence.com/2012/11/05/every-sperm-is-sacred-sequencing-dna-from-individual-cells-vs-humans-as-a-whole/

 

Third:

Promising Research Directions By Watson, 1/10/2013

The main reason drugs that target genetic glitches are not cures is that cancer cells have a work-around. If one biochemical pathway to growth and proliferation is blocked by a drug — the cancer cells activate a different, equally effective pathway.

Watson advocates a different approach: targeting features that all cancer cells, especially those in metastatic cancers, have in common.

A protein in cells called Myc. It controls more than 1,000 other molecules inside cells, including many involved in cancer. Studies suggest that turning off Myc causes cancer cells to self-destruct in a process called apoptosis.

cancer biologist Hans-Guido Wendel of Sloan-Kettering. “Blocking production of Myc is an interesting line of investigation. I think there’s promise in that.”

Personalized medicine” that targets a patient’s specific cancer-causing mutation

Watson wrote, may be “the inherently conservative nature of today’s cancer research establishments.”

http://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-of-dna-wcrick-41953/

 

Opinion by Dr. Stephen Willliams, 1/11/2013

Kudos to both Watson and Weinstein for stating we really need to delve into tumor biology to determine functional pathways (like metabolism) which are a common feature of the malignant state ( also see my posting on differentiation therapy).

http://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-of-dna-wcrick-41953/

http://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

Fourth:

Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper

Figure’s SOURCE:

Figure brought to my attention by Dr. Tilda Barlyia, 1/10/2013

http://blogs.nature.com/spoonful/2012/12/metabolic-gatekeeper-provides-new-target-for-disrupting-cancer-metabolism.html

Author: Yevgeniy Grigoryev

In the 1920s, the German physiologist Otto Warburgproposed that cancer cells generate energy in ways that are distinct from normal cells. Healthy cells mainly metabolize sugar via respiration in the mitochondria, switching only to glycolysis in the cytoplasm when oxygen levels are low. In contrast, cancer cells rely on glycolysis all the time, even under oxygen-rich scenarios. This shift in how energy is produced—the so-called ‘Warburg effect’, as the observation came to be known—is now recognized as a primary driver of tumor formation, but a mechanistic explanation for the phenomenon has remained elusive.

Now, researchers have implicated a chromatin regulator known as SIRT6 as a key mediator of the switch to glycolysis in cancer cells, a finding that could lead to new therapeutic modalities. “This work is very significant for the cancer field,” says Andrei Seluanov, a cancer biologist at the University of Rochester in New York State who studies SIRT6 but was not involved in the latest study. “It establishes the role ofSIRT6 as a tumor suppressor and shows that SIRT6 loss leads to tumor formation in mice and humans.”

SIRT6 encodes one of seven mammalian proteins called sirtuins, a group of histone deacetylases that play a role in regulating metabolism, lifespan and aging. SIRT1—which is activated by resveratrol, a molecule found in the skin of red grapes—is perhaps the best known sirtuin, but several of the others are now the focus of active investigation as therapeutic targets for a range of conditions, from metabolic syndrome tocancer. Just last month, for example, a paper in Nature Medicine demonstrated that SIRT6 plays an important role in heart disease.

Six years ago, a team led by Raul Mostoslavsky, a molecular biologist at the Massachusetts General Hospital Cancer Center in Boston, first showed that SIRT6 protects mice from DNA damage and had anti-aging properties. In 2010, the same team established SIRT6 as a critical regulator of glycolysis. Now,reporting today in Cell, Mostoslavsky and his colleagues have shown that SIRT6 function is lost in cancer cells—thus, definitively establishing SIRT6 as a potent tumor suppressor.

In the latest study, the researchers showed that mouse embryonic cells genetically engineered to lackSIRT6 proliferated much faster than normal cells, growing from 5,000 cells to 200,000 cells in three days. In contrast, SIRT6-expressiong cells grew at less than half that rate over the same time period. When injected into adult mice, these SIRT6-deficient cells also rapidly formed tumors, but this tumor growth was reversed when the scientists put SIRT6 back into the cells.

“Our study provides a proof-of-concept that inhibiting glycolysis in SIRT6-deficient cells and tumors could provide a potential therapeutic approach to combat cancer,” says Mostoslavsky. “Additionally, SIRT6 may be a valuable prognostic biomarker for cancer detection.”

Currently, there are no approved anti-glycolytic drugs against cancer. However, the latest findings indicate that pharmacologically elevating SIRT6 levels might help keep tumor growth at bay. And there’s preliminary data to suggest that the work will translate from the bench to the clinic: looking at a range of cancers from human patients, Mostoslavsky’s team showed that the higher the level of SIRT6 the better the prognosis and the longer the survival times.

SOURCE:

http://blogs.nature.com/spoonful/2012/12/metabolic-gatekeeper-provides-new-target-for-disrupting-cancer-metabolism.html

Fifth:

Molecular Analysis of the different Stages of  Cancer Progression: The Example of Breast Cancer 

Figure’s SOURCE:

The molecular pathology of breast cancer progression

Alessandro Bombonati1 and Dennis C Sgroi1,2* Journal of Pathology, J Pathol 2011; 223: 307–317

Published online 16 November 2010 in Wiley Online Library

(wileyonlinelibrary.com) DOI: 10.1002/path.2808

http://onlinelibrary.wiley.com/store/10.1002/path.2808/asset/2808_ftp.pdf;jsessionid=26C2C424E6948A5FAF3CBADBA385184A.d02t04v=1&t=hi26qzd4&s=a8a4aadb3fc6d448080c0ef3c67415b8277145aa

Post by Dr. Tilda Barlyia and Comments on   “The Molecular Pathology of Breast Cancer Progression”

http://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/

Conclusion

The Paradigm Shift in Human Genomics will follow the following FIVE DIRECTIONS:

• No to Sequencing Patient’s DNA, No to Sequencing Patient’s Tumor, Yes to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities
• Sequencing DNA from individual cells vs “humans as a whole.” Sequencing DNA from individual cells is changing the way that researchers think of humans as a whole.

• Promising Research Directions By Watson, 1/10/2013

• Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper

• Molecular Analysis of the different Stages of  Cancer Progression for Targeting Therapy

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PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Posted in Bio Instrumentation in Experimental Life Sciences Research, CABG, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Coagulation Therapy and Internal Bleeding, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Interviews with Scientific Leaders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, PCI, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Stents & Tools, Systemic Inflammatory Response Related Disorders, tagged Conventional PCI, Dade-Behring, fibrinogen, MICHAEL WARD, myocardial infarction, University of California San Francisco on January 10, 2013| 12 Comments »

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #13: PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity. Published on 1/10/2013

WordCloud Image Produced by Adam Tubman

 

Q&A Session between Dr. Michael Ward and Dr. Larry Bernstein presented for in our Research Category on 

Interviews with Scientific Leaders

Primary research:

Ang L, et al “Elevated plasma fibrinogen rather than residual platelet reactivity after clopidogrel pre-treatment is associated with an increased ischemic risk during elective percutaneous coronary intervention” J Am Coll Cardiol2013; 61: 23-34.

 

Question by DR. MICHAEL WARD

How ironic that an old diagnostic parameter should
reappear in the limelight of diagnostic predictors.

Of course, decades ago, doctors asked for “sed rates”, seeking to know if red cells, thought to be bound to fibrinogen, settled faster in a patient compared to a control subject’s blood. Fibrinogen has always been a diagnostic number in evaluating inflammatory results.

However, the diagnostic world, like the worlds of pharmaceuticals, medical devices, biologics, and other industries, always seek the ‘new kid on the block’ to differentiate themselves from the rest of the pack in the
marketplace.

So there was a binge (and still is) to seek new and exotic blood proteins that are surrogate markers for specific diagnoses or prognoses.

That is the irony, that in this case at least, fibrinogen has come full circle. Biology works in mysterious ways.

Answer by Dr. Larry Bernstein, MD, FCAP

Dear Dr. M.  Ward:

Doctors asked for “sed rates”, seeking to know if red cells, thought to be bound to fibrinogen, settled faster in a patient compared to a control
subject’s blood. Fibrinogen has always been a diagnostic number in evaluating inflammatory results.

You are quite right that physicians used “sed rates” as a measure of inflammation, and more in Lupus Erythematosis, Rheumatoid Arthritis, Nephritides, Systemic Sclerosis, and so forth.  The “sed rate” was not a part of the thinking about CVD, and PCI didn’t exist.  Recently, MI post-PCI has been defined as a type (NSTEMI?).

Yes. In principle, the sed rate is related to fibrinogen and red-cell aggregation.  I am not prepared to accept that a platelet count over 400,000 would make no contribution, even if many of the PCI related infarcts are within a range of 150-300,000.  I don’t know how much power there is in the discussion.  The role of tissue factor (plaque), and of platelets in hemostasis is undeniable.

The industry does look for every opportunity to seize on promising biomarkers.  The coagulation assays developed at Dade-Behring (Dade, Dupont Division; then Dade) were far better and more explanatory that the “sed rate”.  The sed rate measurement requires that you set up graduated tubes to watch the rate of sedimentation.  It is not a walkaway procedure.  Industry has been so good at introducing automation that led to high volume efficiency, that this led to the only part of hospital operations that had good accounting measures.  The long trip to reducing personnel, but of course the profiles were a piece of cake.  I continually reorganized to carve out services for immunology and toxicology, which took longer to get automated.

The only use for sed rate now is for Temporal Thrombosis (?).

In the early days Yale NH Hospital had some 5 Perkin Elmer HPLCs to measure calcium.  Electrophoretic separation of isoenzymes was not helpful for managing patients.  The procedure was run batchwise once a day.  I was the first in CT to be running the immunoassay three times a day on the Roche COBAS Bio CFA., and Dupont put it on the ‘aca’.  A med tech could run it at 3 am  at Detroit Receiving, Bellevue, or Cook County, when the phone didn’t stop ringing for STAT results.

Physicians had expectations too.  So we had the progression from AST, LDH, and CK to isoenzyme MBCK, and then there were the cancer biomarkers – CEA, CA-125, PSA, with much to be discussed.

 

Q&A is derived from the following Article in

MedPage Today

Published: January 07, 2013

Fibrinogen Level Tied to Poorer PCI Outcomes

By Todd Neale, Senior Staff Writer, MedPage Today

Published: January 07, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

An elevated serum fibrinogen level predicted worse short-term ischemic outcomes among patients undergoing elective percutaneous coronary intervention after pretreatment with clopidogrel, researchers found.

Significantly higher levels of fibrinogen were seen in patients with periprocedural myocardial infarction (MI) defined by either creatine kinase-myocardial band (CK-MB) or troponin (P<0.02 for both), according to Ehtisham Mahmud, MD, of the University of California, San Diego, and colleagues.

Those relationships remained consistent after adjustment for several factors, including platelet function, which was not itself associated with periprocedural MI, the researchers reported in the Jan. 8 issue of the Journal of the American College of Cardiology.

“The results of the current study suggest that an elevated fibrinogen level…is related to significant platelet cross-linking and thrombus formation independent of residual P2Y12 receptor-mediated platelet activity during clopidogrel therapy,” they wrote.

Higher risk of ischemic cardiovascular events has been observed with both high platelet reactivity after thienopyridine treatment and elevated serum fibrinogen.

“As an acute phase reactant involved in the final common pathway of the coagulation cascade and essential component of platelet cross-linking in thrombus formation, fibrinogen possesses a clear biological mechanism for its adverse cardiovascular effects,” Mahmud and colleagues wrote.

In fact, high levels of serum fibrinogen have been shown to contribute to high platelet reactivity during clopidogrel treatment, resulting in uncertainty about whether insufficient platelet inhibition and elevated fibrinogen levels are independent or interactive risk factors for ischemic events.

To explore the issue, the researchers looked at data from 189 patients undergoing elective PCI who were pretreated with clopidogrel, defined as 75 mg daily for at least 7 days or a 600-mg bolus at least 12 hours before study enrollment. The mean age of the patients was 63.8 and most (74.1%) were male.

Nearly two-thirds (63%) had undergone a previous PCI, and 18% had undergone revascularization with coronary artery bypass grafting (CABG).

Baseline platelet function was measured using the VerifyNow P2Y12 assay. Markers of ischemic myocardial injury, including troponin and CK-MB, were measured every 8 hours after PCI until hospital discharge.

Periprocedural MI defined by troponin I or T occurred in 13.9% of patients. Those who had an MI had significantly higher levels of fibrinogen (363.1 versus 309.1 mg/dL, P=0.017).

The rate of CK-MB-defined periprocedural MI was 5.8%. Patients with that outcome also had elevated levels of fibrinogen (403.4 versus 313.5 mg/dL, P=0.007).

Both differences remained significant after multivariate adjustment that accounted for platelet function and other inflammatory markers.

The researchers found that a fibrinogen level of 345 mg/dL or higher — a cutoff identified as having optimal combined sensitivity and specificity for CK-MB-defined periprocedural MI — was associated with periprocedural MI defined by either troponin or CK-MB (P<0.04 for both).

Those relationships were stronger when systemic inflammation was low (C-reactive protein ≤0.5 mg/dL).

The platelet reactivity measurements were not associated with either definition of periprocedural MI, which is inconsistent with the findings from several smaller studies. The authors noted, however, that “the significance of these negative findings may be limited due to inadequate study power.”

In discussing the limitations of the study, the researchers pointed out that “the findings … do not provide insight into whether the relationship between high platelet reactivity and ischemic cardiovascular events demonstrated in previous studies is a direct one or mediated through the effect of serum fibrinogen.”

To get to the bottom of that, they wrote, “future studies relating platelet reactivity and adverse cardiac events should measure baseline fibrinogen.”

Mahmud has received clinical trial support from Accumetrics, Eli Lilly, and sanofi-aventis, and is on the speakers bureau for Medtronic. One of his co-authors is a consultant for Abbott Vascular, Boston Scientific, St. Jude Medical, Medtronic, and sanofi-aventis.

From the American Heart Association:

• ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention

Primary source: Journal of the American College of Cardiology
Source reference:
Ang L, et al “Elevated plasma fibrinogen rather than residual platelet reactivity after clopidogrel pre-treatment is associated with an increased ischemic risk during elective percutaneous coronary intervention” J Am Coll Cardiol2013; 61: 23-34.

---

Add Your Knowledge ™

Todd Neale

Senior Staff Writer

Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University.

SOURCE:

http://www.medpagetoday.com/Cardiology/PCI/36734?goback=%2Egde_2184987_membe

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The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cerebrovascular and Neurodegenerative Diseases, Coagulation Therapy and Internal Bleeding, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, PCI, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Stents & Tools, tagged ACS, Columbia University Medical Center, Harvard Medical School, myocardial infarction, ST elevation, TIMI on January 3, 2013| 17 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Acute Coronary Syndrome

Tool Identifies Risk in Stenting ACS Patients

By Todd Neale, Senior Staff Writer, MedPage Today

Published: November 19, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A new, easy-to-calculate risk score developed for patients with non-ST-segment elevation acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) had better prognostic accuracy than other widely used risk scores, researchers found.

The ACUITY-PCI risk score includes six variables — insulin-treated diabetes, renal insufficiency, baseline cardiac biomarker elevation or ST-segment deviation, presence of a bifurcation lesion, small vessel/diffuse coronary artery disease, and extent of coronary artery disease, according to Gregg Stone, MD, of Columbia University Medical Center in New York City, and colleagues.

The 1-year rate of death or MI significantly increased from 5.3% in the lowest risk tertile to 9.1% in the middle tertile to 19% in the highest tertile (P<0.001), the researchers reported in the November issue of JACC: Cardiovascular Interventions.

Discrimination and calibration were greater with the ACUITY-PCI score than with other established scores.

“Although the TIMI and the GRACE scores have been shown to be valuable prognostic tools at the time of hospital admission for selecting pharmacological strategies and identifying those patients most likely to benefit from an invasive strategy, they have not been optimized for patients undergoing PCI and, thus, have relatively poor prognostic power to further risk stratify acute coronary syndrome patients undergoing PCI,” Stone and colleagues wrote.

“The ACUITY-PCI score is therefore intended to supplement the TIMI and GRACE scores when an invasive strategy has been undertaken and PCI is being considered.”

The researchers created the risk score using data from 1,692 patients enrolled in the angiographic substudy of the ACUITY trial, which was a comparison of heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin (Angiomax) plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone in patients with ACS undergoing an early invasive strategy. They then validated the score using another 846 patients from the same study.

Multivariate analysis revealed six variables that were significantly associated with 1-year mortality and MI and were included in the score. The researchers assigned points based on the strength of the predictor:

• Insulin-treated diabetes (12 points)
• Renal insufficiency (12 points)
• Baseline cardiac biomarker elevation or ST-segment deviation (8 points)
• Bifurcation lesion (4 points)
• Small vessel/diffuse coronary artery disease (2 points)
• Extent of coronary artery disease (1 point for each 10 mm of disease)

The C-statistic for the risk score — a measure of discrimination — was 0.67 in the derivation cohort and 0.70 in the validation cohort. In the validation cohort, the chi-square statistic for calibration was 6.2 and the index of separation was 0.44.

All of those values were better than those seen for four other established risk scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX. In addition, the net reclassification improvement with the new score ranged from 9% to 38% and the integrated discrimination index varied from 1.9% to 2.7%.

The researchers noted that the ACUITY-PCI score also was a good predictor of 1-year definite or probable stent thrombosis, with a C-statistic of 0.72.

In another study in the same journal, George Dangas, MD, PhD, of Mount Sinai Medical Center in New York City, and colleagues — including Stone — reported on the development of a risk score specifically for stent thrombosis in patients with ACS undergoing PCI.

The study included 6,139 patients from the HORIZONS-AMI and ACUITY trials, which included those with ST-segment elevation MI (STEMI) in the former trial and those with non-STEMI and unstable angina in the latter. The researchers used 4,093 patients for the derivation cohort and 2,046 for the validation cohort.

The risk score included 10 variables that were significantly associated with the risk of Academic Research Consortium-defined definite or probable stent thrombosis at 1 year:

• Type of acute coronary syndrome (4 points for STEMI, 2 points for non-ST-segment elevation ACS with ST deviation, and 1 point for non-ST-segment elevation ACS without ST changes)
• Current smoking (1 point)
• Insulin-dependent diabetes (2 points)
• Prior PCI (1 point)
• Baseline platelet count (1 point for 250 to 400 K/µL and 2 points for more than 400 K/µL)
• Absence of pre-PCI heparin therapy (1 point)
• Aneurysmal/ulcerated lesion (2 points)
• Baseline TIMI flow grade 0/1 (1 point)
• Final TIMI flow grade less than 3 (1 point)
• Number of treated vessels (1 point for two vessels and 2 points for three vessels)

Scores from 1 to 6 are considered low risk, 7 to 9 are intermediate risk, and 10 or higher are high risk.

The rates of stent thrombosis at 1 year were 1.36%, 3.06%, and 9.18% across the three risk tertiles in the derivation cohort (P<0.001 for trend), with a similar trend seen in the validation cohort.

The C-statistics were 0.67 in the derivation cohort and 0.66 in the validation cohort. Performance was comparable for events occurring both early (within the first 30 days) and late (from 1 month to 1 year).

“We believe that the development and initial validation of this stent thrombosis risk score can be a useful tool for both clinical practice and future clinical investigation (future analyses of trials or registries), as it can be a simple way to risk stratify patients immediately following a procedure,” Dangas and colleagues wrote. “The risk score could also be used in the informed consent process to better inform patients of their individual risk of stent thrombosis.”

But Ron Waksman, MD, and Israel Barbash, MD, of MedStar Washington Hospital Center in Washington, D.C., noted some limitations of the tool, including the pooling of different types of patients, the exclusion of important variables associated with stent thrombosis risk, and the use of mostly first-generation drug-eluting stents in the trials.

“It is imperative that the user of such a prediction tool be aware of its capabilities and performance, as well as its limitations, in various clinical scenarios,” they wrote in an accompanying editorial.

“A newly developed risk score for stent thrombosis should be robust and should be tested across broad study populations, stents, and antiplatelet regimens. A new model should also be validated in a setting different from the one in which it was derived,” they wrote. “Unfortunately, this is not the case with the newly proposed model.”

“Until such an encompassing tool is developed and validated,” they wrote, “one should rely on the known stent thrombosis risk factors and tailor an appropriate treatment for each patient.”

The ACUITY trial was funded by The Medicines Company and Nycomed.

Stone has served as a consultant to Abbott Vascular, Boston Scientific, Medtronic, and The Medicines Company. His co-authors reported relationships with Abbott, Regado, Ortho McNeil, Janssen, Merck, Maya Medical, AstraZeneca, Sanofi/Bristol-Myers Squibb, Eli Lilly, and Daiichi Sankyo.

The HORIZONS-AMI trial was supported by the Cardiovascular Research Foundation, with grant support from Boston Scientific and The Medicines Company.

Dangas has received speaker honoraria from AstraZeneca, Bristol-Myers Squibb, The Medicines Company, sanofi-aventis, and Abbott Vascular. His co-authors reported relationships with sanofi-aventis, The Medicines Company, Abbott Vascular, Bristol-Myers Squibb, Cordis, AstraZeneca, Daiichi Sankyo, Eli Lilly, Maquet, Roche, Boehringer Ingelheim, Liposcience, Merck, Pozen, Gilead Sciences, WebMD, the NIH, Pfizer, Johnson & Johnson, Schering-Plough, Merck Sharpe and Dohme, GlaxoSmithKline, Regado Biosciences, Boston Scientific, and Bristol-Myers Squibb/Sanofi.

Waksman and Barbash reported that they had no conflicts of interest.

From the American Heart Association:

• 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention

Primary source: JACC: Cardiovascular Interventions
Source reference:
Palmerini T, et al “A new score for risk stratification of patients with acute coronary syndromes undergoing percutaneous coronary intervention: the ACUITY-PCI (Acute Catheterization and Urgent Intervention Triage Strategy-Percutaneous Coronary Intervention) risk score” JACC Cardiovasc Interv 2012; 5: 1108-1116.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Dangas G, et al “Development and validation of a stent thrombosis risk score in patients with acute coronary syndromes” JACC Cardiovasc Interv 2012; 5: 1097-1105.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Waksman R, Barbash I “The appropriate use of risk scores” JACC Cardiovasc Interv 2012; 5: 1106-1107.

---

Todd Neale

Senior Staff Writer

Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University. He is based atMedPage Today headquarters in Little Falls, N.J.

SOURCE:

http://www.medpagetoday.com/Cardiology/AcuteCoronarySyndrome/36010

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Differentiation Therapy – Epigenetics Tackles Solid Tumors

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Molecular Genetics & Pharmaceutical, tagged Aviva Lev-Ari, Biology, breast cancer, Cancer - General, Chemotherapy, colon cancer, Conditions and Diseases, DNA, Epigenetics, health, Histone, Histone deacetylase, Histone deacetylase inhibitor, histone modification, medicine, ovarian cancer, Prostate cancer, research, solid tumors on January 3, 2013| 18 Comments »

Differentiation Therapy – Epigenetics Tackles Solid Tumors

Author-Writer: Stephen J. Williams, Ph.D.

Updated 4/27/2021

Word Cloud By Danielle Smolyar

Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation.  Differentiation therapy is a chemotherapeutic strategy directed at re-activating endogenous cellular differentiation programs in a tumor cell therefore driving the cancerous cell to a state closer resembling the normal or preneoplastic cell and therefore incurring loss of the tumorigenic phenotype.

This post will deal with:

• Agents such as histone deacetylase inhibitors (HDACi), retinoids, and PPARϒ agonists which have been shown to reactivate terminal differentiation programs in solid tumors
• Clinical trials in solid tumors
• Issues regarding the use of differentiation therapy in solid tumors

This post is a follow-up post to Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells

To put the need for alternate chemotherapeutic strategies in perspective, one is referred to the National Cancer Statistics from http://www.cancer.gov show that 33% of cancer patients, treated with standard cytolytic chemotherapy, will still die within five years (i.e. one in three will die within 5 years).  However the addition of the differentiation agent retinoic acid to standard chemotherapy regimen for treatment of acute promyelocytic leukemia (APML) had improved 5 year survival rates from a range of 50-80% up to near 90% complete remission rates while 75% become disease free, an astonishing success story.  For a review of APML please be referred to http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemia.  Briefly, APML is predominantly a result of the chromosomal translocation producing a fusion gene between the promyelocytic leukemia (PML) and RARα receptor genes.  The PML-RARα fusion protein recruits transcriptional repressors, histone deacetylases (HDACs), and DNA methyltransferases.  Treatment with pharmacologic doses of retinoic acid dissociates the PML-RARα from HDACs and results in degradation of PML-RARα, eventually resulting in the differentiation of the myeloid cells in APML.

Dr. Igor Matushansky of Columbia University believes such differentiation therapy could be useful in soft tissue sarcomas, due to the existence of a connective tissue (mesenchymal) stem cell,  in vitro methods which can differentiate these cells into mature tissues, and, from a gene clustering analysis his group had performed, correlation of expression signatures of each liposarcoma subtype throughout the adipocytic differentiation spectrum, including early differentiated to more mature differentiated cells(1).   A parallel study by Riester and colleagues had been able to classify breast tumors and liposarcomas along a phylogenetic tree showing solid tumors can be reclassified based on cell of origin via expression patterns(2).  In addition, other solid tumors, such as ovarian cancer are easily classified, based both on pathologic, histologic, and expression analysis into well and poorly differentiated tumors, correlating differentiation status with prognosis.

Compound Classes which have potential in

differentiation therapy for solid tumors

A. Histone Deacetylase Inhibitors (HDACi)

In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression.  Histone deacetylation leads to chromatin compaction and is associated with transcriptional repression of tumor suppressors, cell growth and differentiation.  Therefore, HDACi are promising anti-tumor agents as they may affect the cell cycle, inhibit proliferation, stimulate differentiation and induce apoptotic cell death (3). In a review by Kniptein and Gore, entinostat was found to be a well-tolerated HDACi that demonstrates promising therapeutic potential in both solid and hematologic malignancies(4). The path to the discovery of suberoylanilide hydroxamic acid (SAHA, vorinostat) began over three decades ago with our studies designed to understand why dimethylsulfoxide causes terminal differentiation of the virus-transformed cells, murine erythroleukemia cells. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in vivo at concentrations that have little or no toxic effects on normal cells (for references see (5). In fact, treatment of MCF-7 breast carcinoma cells with SAHA resulted in morphologic changes resembling epithelial mammary differentiation(6).

Figure.  Structures of some HDACi used in clinical trials for cancer (see section below)

Figure.  HDAC with SAHA

B. Retinoids

Vitamin A and retinoids play significant roles in basic physiological processes such as vision, reproduction, growth, development, hematopoiesis and immunity (7). Retinoids are the natural derivatives and synthetic analogs of vitamin A. They have been shown to prevent mammary carcinogenesis in rodents (8), to inhibit the growth of human cancer cells in vitro  (9,10) and be effective chemopreventive and chemotherapeutic agents in a variety of human epithelial and hematopoietic tumors (11-14).

Retinoids cannot be synthesized de novo by higher animals and consequently must be consumed in the diet. The two sources of retinoids are animal products that contain retinol and retinyl esters, and plant-derived carotenoids (provitamin A). b-carotene is the most potent vitamin A precursor and has been shown to be an active inhibitor of both tumor initiation and promotion (15).

A major function of retinol, relevant to cancer, is its function as an antioxidant. The antioxidant properties of vitamin A have been shown both in vitro and in vivo (16,17). Retinol deficiency causes oxidative damage to liver mitochondria in rats that can be reversed by vitamin A supplementation (18). A caveat to this is in vitro and in vivo evidence of chronic hypervitaminosis A inducing oxidative DNA damage, as well (19-21). Therefore, it is evident that maintaining the vitamin A concentration within a physiological range is critical to normal cell function because either a deficiency or an excess of vitamin A induces oxidative stress (22). Retinoic acids (RA) (all-trans, 9-cis and 13-cis) are the major biologically active retinoids and exert their effects by regulation of gene expression by binding two families of ligand-activated nuclear retinoid receptors (23). Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) regulate the transcription of a large number of target genes that contain retinoic acid response elements (RAREs) in their promoters. Many of these genes are involved in cancer (13,24) and differentiation (24-26).

Several lines of evidence suggest involvement of defects in retinol signaling in cancer, from the observation that a vitamin A-deficient (VAD) diet leads to an increase in the number of spontaneous and chemically induced tumors in animals (27-29) to the observation that RA itself can induce  differentiation and inhibit the growth of many tumor cells (30-32), as well as the identification that components of the RA signaling pathway are absent in cancer cells (33). Vitamin A and its metabolites have been proposed to have a dual effect in cancer prevention, as antioxidants (16,17,19,34) and differentiating agents (35-37). as it is well accepted that retinoid signaling is integral in maintaining the differentiated state of many cell types (13,38). Additionally, current rationale for chemoprevention with retinoids is based, in part, on the hypothesis that some tumors, may arise due to loss of normal somatic differentiation during tissue repair.

C. PPARϒ Agonists

Peroxisome proliferator-activated receptor ϒ (PPARϒ) is a member of the steroid hormone receptor superfamily that responds to changes in lipid and glucose homeostasis but has increasing roles in differentiation and tumorigenesis. The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity.  One of the first agents, developed in the early 80’s for treatment of hyperlipidemia and hperlipoproteinemia, was clofibrate.  All PPAR subtypes heterodimerize with the retinoid-x-receptor (RXR) and, upon binding of ATRA, activate target genes.

PPARϒ agonists have shown potential as a therapeutic in a variety of cancer types including bladder cancer (39), colon cancer(40),  breast cancer(41), prostate cancer(42).  There are numerous studies showing that PPARϒ agonists have anti-tumorigenic activity via anti-proliferative, pro-differentiation and anti-angiogenic mechanisms of action(43). For example, Papi et al. observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells(44) with concomitant upregulation of differentiation markers.

A great website for further information on PPAR is Dr. Jack Vanden Heuvel, Professor of Toxicology at Penn State University at http://ppar.cas.psu.edu/general_information.html.

D. Trabectedin

Trabectedin (ecteinascidin-743 (ET-743); Yondelis) is derived from the Caribbean tunicate Ecteinascidia turbinacta has antitumor activity by binding to the DNA minor groove thus disrupting binding of transcription factors and inhibiting DNA synthesis.  However, it has also been shown, in myxoid liposarcoma (MLS) cells, to cause dissociation of transcription factor TLS-CHOP from promoter sequences resulting in downregulation of target genes such as CHOP, PTX3 and FN1 and induces an adipogenic differentiation program by enhancing activation of CAAT/enhancer binding protein (C/EBP) family of genes.  In MLS, TLS-CHOP sequesters C/EBPβ resulting in block of differentiation programs while trabectedin disrupts this association freeing up C/EBPβ to act as transcriptional activator of genes related to differentiation.

Ongoing Cancer Clinical Trials with HDAC Inhibitors

The following is a listing of some clinical trials using histone deacetylase inhibitors in combination with approved chemotherapeutics in various tumors.  This data was taken from the New Medicine Oncology Knowledge Base ( at http://www.nmok.net).

Issues and Future of Differentiation-based Therapy

In the review by Filemon Dela Cruz and Igor Matushansky(1), the authors suggest that, like days of old of cytotoxic monotherapy, differentiation therapy would not evolve as a simplistic one-size-fits –all but mirror an extremely complicated process.  Therefore they suggest three theoretical mechanisms in which differentiation therapy may occur:

1. Cancer directed differentiation: differentiation pathways are activated without correcting the underlying oncogenic mechanisms which produced the initial differentiation block
2. Cancer reverted differentiation: correction of the underlying oncogenic mechanism results in restoration of endogenous differentiation pathways
3. Cancer diverted differentiation: cancer cell is redirected to an earlier stage of differentiation

Finally the authors suggest that “the potential for reversion of the malignant cancer phenotype to a more benign, or at the very least a lower grade of biological aggressiveness, may serve as a critical clinical and biologic transition of a uniformly fatal cancer into one more amenable to management or to treatment using conventional therapeutic approaches.”

References:

1.            Cruz, F. D., and Matushansky, I. (2012) Oncotarget 3, 559-567

2.            Riester, M., Stephan-Otto Attolini, C., Downey, R. J., Singer, S., and Michor, F. (2010) PLoS computational biology 6, e1000777

3.            Seidel, C., Schnekenburger, M., Dicato, M., and Diederich, M. (2012) Genes & nutrition 7, 357-367

4.            Knipstein, J., and Gore, L. (2011) Expert opinion on investigational drugs 20, 1455-1467

5.            Marks, P. A. (2007) Oncogene 26, 1351-1356

6.            Munster, P. N., Troso-Sandoval, T., Rosen, N., Rifkind, R., Marks, P. A., and Richon, V. M. (2001) Cancer research 61, 8492-8497

7.            Napoli, J. L. (1999) Biochim Biophys Acta 1440, 139-162

8.            Moon, R., Metha, R., and Rao, K. (1994) Retinoids and cancer in experimental animals. in The Retinoids: Biology, Chemistry, and Medicine (Sporn, M., Roberts, A., and Goodman, D. eds.), 2 Ed., Raven Press, New York. pp 573-596

9.            De Luca, L. M. (1991) Faseb J 5, 2924-2933

10.          Gudas, L. J. (1992) Cell Growth Differ 3, 655-662

11.          Degos, L., and Parkinson, D. (1995) Retinoids in Oncology, Springer-Verlag, Berlin

12.          Lotan, R. (1996) Faseb J 10, 1031-1039

13.          Zhang, D., Holmes, W. F., Wu, S., Soprano, D. R., and Soprano, K. J. (2000) J Cell Physiol 185, 1-20

14.          Fontana, J. A., and Rishi, A. K. (2002) Leukemia 16, 463-472

15.          Suda, D., Schwartz, J., and Shklar, G. (1986) Carcinogenesis 7, 711-715

16.          Ciaccio, M., Valenza, M., Tesoriere, L., Bongiorno, A., Albiero, R., and Livrea, M. A. (1993) Arch Biochem Biophys 302, 103-108

17.          Palacios, A., Piergiacomi, V. A., and Catala, A. (1996) Mol Cell Biochem 154, 77-82

18.          Barber, T., Borras, E., Torres, L., Garcia, C., Cabezuelo, F., Lloret, A., Pallardo, F. V., and Vina, J. R. (2000) Free Radic Biol Med 29, 1-7

19.          Borras, E., Zaragoza, R., Morante, M., Garcia, C., Gimeno, A., Lopez-Rodas, G., Barber, T., Miralles, V. J., Vina, J. R., and Torres, L. (2003) Eur J Biochem 270, 1493-1501

20.          Omenn, G. S., Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Glass, A., Keogh, J. P., Meyskens, F. L., Jr., Valanis, B., Williams, J. H., Jr., Barnhart, S., Cherniack, M. G., Brodkin, C. A., and Hammar, S. (1996) J Natl Cancer Inst 88, 1550-1559

21.          Murata, M., and Kawanishi, S. (2000) J Biol Chem 275, 2003-2008

22.          Schwartz, J. L. (1996) J Nutr 126, 1221S-1227S

23.          Chambon, P. (1996) Faseb J 10, 940-954

24.          Freemantle, S. J., Kerley, J. S., Olsen, S. L., Gross, R. H., and Spinella, M. J. (2002) Oncogene 21, 2880-2889

25.          Collins, S. J., Robertson, K. A., and Mueller, L. (1990) Mol Cell Biol 10, 2154-2163

26.          Grunt, T. W., Somay, C., Oeller, H., Dittrich, E., and Dittrich, C. (1992) J Cell Sci 103 ( Pt 2), 501-509

27.          Lasnitzki, I. (1955) Br J Cancer 9, 434-441

28.          Moore, T. (1965) Proc Nutr Soc 24, 129-135

29.          Saffiotti, U., Montesano, R., Sellakumar, A. R., and Borg, S. A. (1967) Cancer 20, 857-864

30.          Strickland, S., and Mahdavi, V. (1978) Cell 15, 393-403

31.          Breitman, T. R., Selonick, S. E., and Collins, S. J. (1980) Proc Natl Acad Sci U S A 77, 2936-2940

32.          Breitman, T. R., Collins, S. J., and Keene, B. R. (1981) Blood 57, 1000-1004

33.          Niles, R. M. (2000) Nutrition 16, 573-576

34.          Monagham, B., and Schmitt, F. (1932) J Biol Chem 96, 387-395

35.          Miller, W. H., Jr. (1998) Cancer 83, 1471-1482

36.          Miyauchi, J. (1999) Leuk Lymphoma 33, 267-280

37.          Reynolds, C. P. (2000) Curr Oncol Rep 2, 511-518

38.          Ortiz, M. A., Bayon, Y., Lopez-Hernandez, F. J., and Piedrafita, F. J. (2002) Drug Resist Updat 5, 162-175

39.          Mansure, J. J., Nassim, R., and Kassouf, W. (2009) Cancer biology & therapy 8, 6-15

40.          Osawa, E., Nakajima, A., Wada, K., Ishimine, S., Fujisawa, N., Kawamori, T., Matsuhashi, N., Kadowaki, T., Ochiai, M., Sekihara, H., and Nakagama, H. (2003) Gastroenterology 124, 361-367

41.          Stoll, B. A. (2002) Eur J Cancer Prev 11, 319-325

42.          Smith, M. R., and Kantoff, P. W. (2002) Investigational new drugs 20, 195-200

43.          Rumi, M. A., Ishihara, S., Kazumori, H., Kadowaki, Y., and Kinoshita, Y. (2004) Current medicinal chemistry. Anti-cancer agents 4, 465-477

44.          Papi, A., Guarnieri, T., Storci, G., Santini, D., Ceccarelli, C., Taffurelli, M., De Carolis, S., Avenia, N., Sanguinetti, A., Sidoni, A., Orlandi, M., and Bonafe, M. (2012) Cell death and differentiation 19, 1208-1219

Updated 4/27/2021

Epizyme’s EZH2 blocker boosts immuno-oncology response in prostate cancer models

Source: https://www.fiercebiotech.com/research/epizyme-s-ezh2-blocker-boosts-immuno-oncology-response-prostate-cancer-models

Inhibiting EZH2 either genetically or with a chemical inhibitor signaled the immune system to respond to PD-1 inhibition in prostate cancer. (NIH)

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The protein EZH2 has long been known as a major driver of prostate cancer because of its ability to inactivate genes that would normally suppress tumor growth. Now, a team at Cedars-Sinai Cancer has shown in preclinical models of the disease that blocking EZH2 reduces resistance to immune-boosting checkpoint inhibitors—and they did it with the help of Epizyme, which won FDA approval for the first EZH2 blocker last year.

The Cedars-Sinai team inhibited EZH2 in preclinical prostate cancer models, activating interferon-stimulated genes in the immune system. The interferons then boosted the immune response and reversed resistance to drugs that inhibit the checkpoint PD-1, they reported in the journal Nature Cancer.

By inhibiting EZH2 either genetically or with a chemical inhibitor donated by Epizyme, the researchers used a technique called “viral mimicry” to “reopen” parts of the genome that are typically inactive, they explained in a statement. That signaled the immune system to respond to PD-1 inhibition.

Checkpoint inhibitors have been approved to treat several cancer types, but they’ve been largely disappointing in prostate cancer. Hence several research groups have been exploring combination strategies. They include the University of Texas MD Anderson Cancer Center, which published research in 2019 showing early evidence that combining checkpoint inhibition with anti-TGF-beta drug could be effective in prostate cancer.

More recently, bispecific antibodies have shown early promise in prostate cancer. Last September, Amgen presented data from a phase 1 study of AMG 160, a bispecific targeting PSMA and CD3 on T cells. The company said that 68.6% of patients experienced a decline in PSA, and eight out of 15 patients evaluated showed stable disease.

Regeneron is also developing a bispecific antibody for prostate cancer, targeting PSMA and CD28. The drug is being tested as a solo therapy and in combination with Regeneron’s PD-1 inhibitor Libtayo in a phase 1/2 clinical trial enrolling men with metastatic castration-resistant prostate cancer.

As for Epizyme’s EZH2 inhibitor, Tazverik, its path to market hasn’t been perfectly smooth. An advisory committee to the FDA questioned its efficacy and safety in its initial indication, metastatic or locally advanced epithelioid sarcoma. Still, the company got the go-ahead to market the drug in adult patients with the rare cancer last January. Then the FDA added follicular lymphoma to the label in June. The drug’s takeoff has been slower than expected, however, largely because the pandemic has prevented face-to-face interactions between the sales force and physicians.

The company is currently testing Tazverik in several other cancer types, including as a combination with standard-of-care treatments in castration-resistant prostate cancer.

Other research papers on Cancer and Cancer Therapeutics were published on this Scientific Web site as follows:

Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Nanotechnology Tackles Brain Cancer

Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

Personalized medicine-based cure for cancer might not be far away

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Lung Cancer (NSCLC), drug administration and nanotechnology

Non-small Cell Lung Cancer drugs – where does the Future lie?

Cancer Innovations from across the Web

arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

mRNA interference with cancer expression

Search Results for ‘cancer’ on this web site

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

mRNA interference with cancer expression

Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Crucial role of Nitric Oxide in Cancer

Targeting Glucose Deprived Network Along with Targeted Cancer Therapy Can be a Possible Method of Treatment

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UPDATED: PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cell Biology, Signaling & Cell Circuits, Coagulation Therapy and Internal Bleeding, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Mitral Valve: Repair and Replacement, Origins of Cardiovascular Disease, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged Adverse effect, American Heart Association, AstraZeneca, Brilinta, Clopidogrel, European Commission, European Union, Food and Drug Administration, myocardial infarction, ST elevation, Ticagrelor on December 28, 2012| 3 Comments »

UPDATED: PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/1/2019

Extended DAPT with Brilinta: No Benefit for Stable CAD in T2D

Substudy in those with prior PCI might identify group where bleeding tradeoff is worthwhile

PARIS — Ticagrelor (Brilinta) as part of a dual antiplatelet therapy (DAPT) regimen didn’t improve net outcomes for stable coronary artery disease (CAD) among type 2 diabetes patients, except perhaps in the setting of percutaneous coronary intervention (PCI), the THEMIS trial showed.

Adding the potent antiplatelet agent to aspirin reduced cardiovascular (CV) death, myocardial infarction (MI), or stroke (7.7% vs 8.5%, HR 0.90, 95% CI 0.81-0.99), reported Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, at the European Society of Cardiology (ESC) congress and online in the New England Journal of Medicine.

But it also increased

• TIMI major bleeding (2.2% vs 1.0%, HR 2.32, 95% CI 1.82-2.94) and
• intracranial hemorrhage (0.7% vs 0.5%, HR 1.71, 95% CI 1.18- 2.48) over aspirin alone, albeit
• without more fatal bleeding (0.2% vs 0.1%, P=0.11).

The combined effect was neutral for the exploratory composite outcome of “irreversible harm” (death from any cause, MI, stroke, fatal bleeding, or intracranial hemorrhage 10.1% vs 10.8%, HR 0.93, 95% CI 0.86-1.02).

ESC session study discussant Colin Baigent, MD, of Oxford University in England, actually calculated 12 major bleeds for every eight events prevented.

“This is a consistent story: when we add an antiplatelet agent for risk reduction, we increase the risk of bleeding,” noted Richard Kovacs, MD, of Indiana University in Indianapolis and president of the American College of Cardiology.

THEMIS is the final part of a largely-disappointing PARTHENON development program for ticagrelor, he noted. “It hasn’t changed practice. …Will the main THEMIS trial change clinical practice? In my opinion, no.”

• Primary Source

  New England Journal of Medicine

  Source Reference: Steg PG, et al “Ticagrelor in Patients with Stable Coronary Disease and Diabetes” N Engl J Med 2019; DOI: 10.1056/NEJMoa1908077.

• Secondary Source

  New England Journal of Medicine

  Source Reference: Bates ER “Antiplatelet Therapy for Prevention of Cardiovascular Events in Patients with Type-2 Diabetes Mellitus” N Engl J Med 2019; DOI: 10.1056/NEJMe1910813.

• Additional Source

  The Lancet

  Source Reference: Bhatt DL, et al “Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial” Lancet 2019; DOI: 10.1016/S0140-6736(19)31887-2.

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/81925?xid=nl_mpt_ACC_Reporter_2019-09-01&eun=g5099207d2r

 

UPDATED on 10/4/2016

Soriot’s $3.5B Brilinta dream is dashed by yet another big trial flop for AstraZeneca

by john carroll
October 4, 2016 09:00 AM EDT
Updated: 09:33 AM

Brilinta, the drug failed to demonstrate a benefit over generic Plavix (clopidogrel) for peripheral artery disease. Back in March, the heart drug flopped in a large stroke study, unable to prove that it could beat aspirin. And Soriot can chalk up those expensive studies to proving Brilinta’s serious deficiencies.

“We don’t believe the goal of $3.5 billion is attainable. I think it would be unrealistic to believe that,” Ludovic Helfgott, head of AstraZeneca’s Brilinta business, told Reuters.

Brilinta brought in a total of $619 million last year after disappointing analysts repeatedly with lower-than-expected quarterly revenue.

Heart studies aren’t cheap. AstraZeneca recruited 13,500 patients for the EUCLID study, and it had enrolled close to that number for the earlier SOCRATES trial.

SOURCE

http://endpts.com/soriots-3-5b-brilinta-dream-is-dashed-by-yet-another-big-trial-flop-for-astrazeneca/?utm_medium=email&utm_campaign=75%20Dinner%20with%20Brent&utm_content=75%20Dinner%20with%20Brent+CID_8008d3b4f16d90576238cceef624d211&utm_source=ENDPOINTS%20emails&utm_term=Soriots%2035B%20Brilinta%20dream%20is%20dashed%20by%20yet%20another%20big%20trial%20flop%20for%20AstraZeneca

UPDATED on 9/4/2014

Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction

Gilles Montalescot, M.D., Ph.D., Arnoud W. van ‘t Hof, M.D., Ph.D., Frédéric Lapostolle, M.D., Ph.D., Johanne Silvain, M.D., Ph.D., Jens Flensted Lassen, M.D., Ph.D., Leonardo Bolognese, M.D., Warren J. Cantor, M.D., Ángel Cequier, M.D., Ph.D., Mohamed Chettibi, M.D., Ph.D., Shaun G. Goodman, M.D., Christopher J. Hammett, M.B., Ch.B., M.D., Kurt Huber, M.D., Magnus Janzon, M.D., Ph.D., Béla Merkely, M.D., Ph.D., Robert F. Storey, M.D., D.M., Uwe Zeymer, M.D., Olivier Stibbe, M.D., Patrick Ecollan, M.D., Wim M.J.M. Heutz, M.D., Eva Swahn, M.D., Ph.D., Jean-Philippe Collet, M.D., Ph.D., Frank F. Willems, M.D., Ph.D., Caroline Baradat, M.Sc., Muriel Licour, M.Sc., Anne Tsatsaris, M.D., Eric Vicaut, M.D., Ph.D., and Christian W. Hamm, M.D., Ph.D. for the ATLANTIC Investigators

September 1, 2014DOI: 10.1056/NEJMoa1407024

BACKGROUND

The direct-acting platelet P2Y₁₂ receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown.

Full Text of Background…

METHODS

We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours’ duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days.

Full Text of Methods…

RESULTS

The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used.

Full Text of Results…

CONCLUSIONS

Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion. (Funded by AstraZeneca; ATLANTIC ClinicalTrials.gov number, NCT01347580.)

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMoa1407024?query=TOC

 

 

UPDATED on 2/7/2014

PLATO Controversy Hits the Wall Street Journal

Michael O’Riordan

February 05, 2014

NEW YORK, NY – The controversy surrounding the PLATOtrial of ticagrelor (Brilinta, AstraZeneca) continues unabated, according to a story published in the Wall Street Journal. Specifically, a sealed complaint filed in US district court in the District of Columbia by a researcher contends that the cardiovascular events in the study “may have been manipulated” ^[1].

Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD), who has long been a thorn in the side of AstraZeneca and the PLATO investigators, filed the complaint under the False Claims Act, reports theWall Street Journal. The Journal notes that the US attorney’s office in Washington, DC, has contacted Serebruany and is currently investigating the clinical trial.As reported by heartwirein October 2013, the US Department of Justice issued a civil investigative demand from its civil division “seeking documents and information regarding PLATO.” AstraZeneca is complying with the request.

First reported by heart wirein 2009 , the PLATO trial was a positive study involving more 18 000 patients from 43 countries. PLATO investigators, led by Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden), showed that treating acute coronary syndrome patients with ticagrelor significantly reduced the rate of MI, stroke, and cardiovascular death compared with patients taking clopidogrel. Results were presented at the European Society of Cardiology 2009 Congress and reported in the New England Journal of Medicine.

PLATO has been dogged by questions, including prior to approval. In the sealed complaint, Serebruany takes issue with a number of things, many of which have been reported previously. He alleges that the

• number of clinical events among those taking clopidogrel was high compared with other studies, pointing out that the rate of all-cause death was 5.9% among clopidogrel-treated patients—nearly twice as high as earlier studies. In addition,
• the sealed complaint documents the geographic discrepancies in the trial, noting there was a trend toward worse outcomes with ticagrelor at North American sites.The complaint also alleges that
• an initial count of clinical events suggested the two drugs were equivalent, but adjudication by the Duke Clinical Research Institute attributed another 45 MIs to the clopidogrel group, which tipped the results in favor of ticagrelor. Other questions raised about the study include
• site monitoring and timing of clinical events. Serebruany also alleges that
• the trial may have unintentionally been unblinded because of the shape of clopidogrel’s “split capsules,” which would have enabled doctors and nurses to know which drug patients received.

AstraZeneca rebutted these issues, telling the Journal that it is cooperating with the government. It said it is confident in the integrity of the trial and noted the overall study showed the superiority of ticagrelor over clopidogrel. There is no evidence the trial was unblinded and researchers used the same standards when qualifying all clinical events, including MIs, they noted. In addition, the company said it is not possible to compare event rates with clopidogrel in PLATO with other studies because the patient populations differ.

The Journal reports that Serebruany became embroiled in the controversy when asked by the FDA‘s Dr Thomas Marciniak to advise the agency about the PLATO data in 2010. Marciniak, who led the FDA’s review of PLATO, called AstraZeneca’s submission on serious adverse events the “worst submission” he ever encountered. According to the submission, he noted, 12 patients reported their own deaths by telephone. Before approving ticagrelor, the FDA requested an additional analysis of PLATO, and it was eventually approved in the US in July 2011. Ticagrelor was approved in Europe in December 2010 and is authorized for use in more than 100 countries.

The Journal called Serebruany an expert in the antiplatelet field but said he is a “controversial figure,” partly because of his financial ties to industry and repeated criticisms of new drug approvals. Through HeartDrug Research, Serebruany has worked on prasugrel (Effient, Lily/Daiichi-Sankyo), a competing antiplatelet agent, but has also done work for AstraZeneca.

REFERENCE

Burton TM. Doctor challenges testing of AstraZeneca’s Brilinta. Wall Street Journal, February 2, 2014. Available here.

SOURCE

http://www.medscape.com/viewarticle/820236?nlid=47583_1984&src=wnl_edit_medn_card&uac=93761AJ&spon=2

UPDATED 3/28/2013

How AstraZeneca Will Use A Diagnostic To Market Its Blood Thinner

by Matthew Harper, Forbes Staff on 3/21/2013

Earlier today I wrote about how AstraZeneca is telling investors that its blood-thinner Brilinta, used to prevent second heart attacks, could be a multi-billion dollar drug, at least twice as big as Wall Street analysts expect. So far the drug has been a disappointment.

I wrote:

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

via Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug – Forbes.

But will the Food and Drug Administration allow Astra to tell doctors that? Stratification using troponin is not in Brilinta’s FDA-approved label, and off-label promotion is illegal. But Ferguson says that communications about troponin will be allowed because all patients with high troponin are patients who would be included in the FDA-approved indication. He confirms that use of troponin testing will be part of the new marketing plan for Brilinta.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/how-astrazeneca-will-use-a-diagnostic-to-market-its-blood-thinner/

Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug

by Matthew Herper, Forbes Staff on 3/21/2013

This morning in New York, new AstraZeneca chief executive Pascal Soriot is telling investors how he is going to turn around the company that has had the absolute worst track record in research and development among any big pharmaceutical firm. The plan is fairly wide-ranging and involves a lot of the steps one might expect:

• new layoffs (2,300 jobs);
• a re-focusing of research and development on three areas: heart disease and diabetes; oncology; and respiratory and inflammation;
• new R&D initiatives involving Moderna, a biotech company, and the Karolinska Instutet;
• moving the company’s headquarters to its R&D hub in Cambridge, U.K.;
• re-focusing on emerging markets, where AZ already gets $6 billion in sales, especially China.

But the short-term key to delivering on his promises today seems to come down to a single drug: Brilinta, the Plavix competitor thatAstraZeneca introduced in 2011 which has so far disappointed, generating  just $324 $89 million in global sales last year. This is a medicine to prevent heart attacks and strokes in patients who suffer acute coronary syndrome, the condition that occurs after a heart attack or serious heart-related chest pain. It works by preventing the formation of blood clots.

Plavix was the second biggest drug in the world, with $6 billion in annual sales, but it is now generic. The conventional wisdom is that it will be difficult to compete with cheap generics. Brilinta is actually trailing Effient, a similar medicine from Eli Lilly, in usage. Wall Street consensus currently sees Brilinta growing to become a moderate-sized drug in 2018, with $1.3 billion in annual sales. But AstraZeneca is saying that it thinks Brilinta can be a multi-billion dollar product. Astra has confirmed that this means Brilinta will have to surpass Effient. The newer drugs also cause more bleeding than Plavix.

What is the company’s argument? In his presentation today, Paul Hudson, Astra’s Executive Vice President, North America, said that the key would be focusing on one key fact: Brilinta reduced cardiovascular deaths by 21% compared to Plavix in a big clinical trial. That would mean that if everyone eligible for Brilinta got it, 100,000 lives would be saved.

But the reality is that doctors have been skeptical of that data because in the part of that trial that was run in North America, the benefit was less clear. AstraZeneca says that this may have been due to an interaction of Brilinta and aspirin and that, according to current cardiovascular guidelines, doctors should be prescribing less aspirin anyway.

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

A lot of what Astra will do in the short term on Brilinta will be blocking and tackling. It needs to pay bigger rebates to insurers to make sure that patients can get cheap access to the drug. (This is how discounts happen in the American insurance system: the patient pays a co-payment and the insurer pays full price for the drug, but then the drug maker gives the insurer money back to make the end cost cheaper.) It will also be doing a lot of medical marketing, involving its internal experts or paid, external doctors, to get the word out about the benefits of Brilinta.

Brilinta has other advantages (it stops acting quickly) and disadvantages (it must be given twice a day). But the other big question for expanding results is whether large clinical trials that are now ongoing will show that it works in a broader array of heart patients. Astra is starting a big trial to show Brilinta prevents strokes. These trials are risky and expensive, but there will be a big payoff if they work.

Astra has some other commercial levers to point to. It’s diabetes pill Onglyza, which is sold with Bristol-Myers Squibb, will have results in a big study of its efficacy in preventing heart disease before a similar study of Merck’s top-selling Januvia, which started first. Soriot has smart ideas about which drugs to advance into later testing. But Brilinta is going to be the biggest single indicator of whether Soriot’s new strategies are paying off.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/can-pascal-soriot-turn-around-astrazeneca-it-may-come-down-to-one-drug/

BRILINTA is an antiplatelet medication

Taking BRILINTA is a first step in the treatment your physician has chosen for you. At BRILINTA.com, you will find helpful information and useful learning tools to help you complete your course of BRILINTA therapy. Make sure you and your loved ones read through all of the sections.

What is BRILINTA?

BRILINTA is a type of prescription antiplatelet medication for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart. BRILINTA is used with aspirin to stop platelets from sticking together and forming a blood clot that could block blood flow to the heart and cause another, possibly fatal, heart attack. Platelets are small cells in the blood that help with normal blood clotting.

Take BRILINTA and aspirin exactly as instructed by your doctor: BRILINTA twice a day, plus one 81-mg aspirin tablet once a day. You should not take a dose of aspirin higher than 100 mg each day because it can affect how well BRILINTA works. Tell your doctor about any medicines you are taking that contain aspirin. Do not take any new medicines that contain aspirin.

Why BRILINTA?

BRILINTA used with aspirin lowers your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal. In fact, in a large clinical study BRILINTA was even better than Plavix^® (clopidogrel bisulfate) tablets at lowering your chances of having another heart attack.

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death.

Taking BRILINTA

Complete the
Course Program

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack or stroke, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. Instances of serious bleeding, such as internal bleeding, may require blood transfusions or surgery. While you take BRILINTA, you may bruise and bleed more easily and be more likely to have nosebleeds. Bleeding will also take longer than usual to stop.

Call your doctor right away if you have any signs or symptoms of bleeding while taking BRILINTA, including: severe, uncontrollable bleeding; pink, red, or brown urine; vomit that is bloody or looks like coffee grounds; red or black stool; or if you cough up blood or blood clots.

Do not stop taking BRILINTA without talking to the doctor who prescribes it for you. People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase. Tell all your doctors and dentists that you are taking BRILINTA. To decrease your risk of bleeding, your doctor may instruct you to stop taking BRILINTA 5 days before you have elective surgery. Your doctor should tell you when to start taking BRILINTA again, as soon as possible after surgery.

Take BRILINTA and aspirin exactly as instructed by your doctor. You should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works. Tell your doctor if you take other medicines that contain aspirin. Do not take new medicines that contain aspirin.

Do not take BRILINTA if you are bleeding now, especially from your stomach or intestine (ulcer), have a history of bleeding in the brain, or have severe liver problems.

BRILINTA can cause serious side effects, including bleeding and shortness of breath. Call your doctor if you have new or unexpected shortness of breath or any side effect that bothers you or that does not go away. Your doctor can decide what treatment is needed.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works.

Approved uses
BRILINTA is a prescription medicine for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart.

BRILINTA is used with aspirin to lower your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal.

Please read Prescribing Information, including Boxed WARNINGS.

Please read Medication Guide.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you are without prescription coverage and cannot afford your medication, AstraZeneca may be able to help. For more information, please visit www.AstraZeneca.com.

This product information is intended for US consumers only.

BRILINTA is a trademark of the AstraZeneca group of companies.

Plavix® is a registered trademark of sanofi-aventis.

©2012 AstraZeneca.706809-1789005 8/12

SOURCE:

http://www.brilinta.com/antiplatelet-prescription-medication.aspx#au

http://www1.astrazeneca-us.com/pi/brilinta.pdf

BRILINTA (ticagrelor)

Ticagrelor (trade name Brilinta in the US, Brilique and Possia in the EU) is a platelet aggregation inhibitor produced by AstraZeneca. The drug was approved for use in the European Union by the European Commission on December 3, 2010.^[1][2] The drug was approved by the US Food and Drug Administrationon July 20, 2011.^[3]

Indications

Ticagrelor is indicated for the prevention of thrombotic events (for example stroke or heart attack) in patients with acute coronary syndrome or myocardial infarction with ST elevation. The drug is combined with acetylsalicylic acid unless the latter is contraindicated.^[4] Treatment of acute coronary syndrome with ticagrelor as compared with clopidogrel significantly reduces the rate of death.^[5]

Contraindications

Contraindications for ticagrelor are: active pathological bleeding and a history of intracranial bleeding, as well as reduced liver function and combination with drugs that strongly influence activity of the liver enzymeCYP3A4, because the drug is metabolized via CYP3A4 and excreted via the liver.^[4]

Adverse effects

The most common side effects are shortness of breath (dyspnea, 14%)^[6] and various types of bleeding, such as hematoma, nosebleed, gastrointestinal, subcutaneous or dermal bleeding. Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.^[4]

Physical and chemical properties

Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity toadenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System.^[1]

Ticagrelor as a nucleoside analogue

The nucleoside adenosinefor comparison

Pharmacokinetics

Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring.^[7] It peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260 mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor’s plasma concentrations. Drug and metabolite are mainly excreted via bile and feces.

Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as ‘coloured’ and such with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.^[4]

Mechanism of action

Like the thienopyridines prasugrel, clopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y₁₂. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible.^[8] Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants).^[9][10][11]

Comparison with clopidogrel

The PLATO trial, funded by AstraZeneca, in mid-2009 found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084), higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding. Rates of major bleeding were not different. Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, P<0.001)^[5] The PLATO trial showed a statistically insignificant trend toward worse outcomes with ticagrelor versus clopidogrel among US patients in the study – who comprised 1800 of the total 18,624 patients. The HR actually reversed for the composite end point cardiovascular (death, MI, or stroke): 12.6% for patients given ticagrelor and 10.1% for patients given clopidogrel (HR = 1.27). Some believe the results could be due to differences in aspirin maintenance doses, which are higher in the United States.^[12] Others state that the central adjudicating committees found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelor arm, which improved the MI outcomes with ticagrelor. Without this adjudication the trials’ primary efficacy outcomes should not be significant^[13]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.^[14] This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur.^[4][15]

Interactions

Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, for example rifampicin and possibly St. John’s wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9.

The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxin, ciclosporin and other P-gp substrates. Ticagrelor and AR-C124910XX levels are not significantly influenced by P-gp inhibitors.^[4]

In the US a boxed warning states that use of ticagrelor with aspirin doses exceeding 100 mg/day decreases the effectiveness of the medication.^[16]

References

1. ^ ^a b “Assessment Report for Brilique”. European Medicines Agency. January 2011.
2. ^ European Public Assessment Report Possia
3. ^ “FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes”. FDA. 20 July 2011.
4. ^ ^{a b c d e f} Haberfeld, H, ed. (2010) (in German). Austria-Codex (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
5. ^ ^a b Wallentin, Lars; Becker, RC; Budaj, A; Cannon, CP; Emanuelsson, H; Held, C; Horrow, J; Husted, S et al. (August 30, 2009). “Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes”. NEJM 361 (11): 1045–57. doi:10.1056/NEJMoa0904327. PMID 19717846.
6. ^ Brilinta: Highlights of prescribing information
7. ^ Teng, R; Oliver, S; Hayes, MA; Butler, K (2010). “Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects”. Drug metabolism and disposition: the biological fate of chemicals 38 (9): 1514–21. doi:10.1124/dmd.110.032250. PMID 20551239.
8. ^ Birkeland, Kade; Parra, David; Rosenstein, Robert (2010). “Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor”. Journal of Blood Medicine 1: 197–219.
9. ^ H. Spreitzer (February 4, 2008). “Neue Wirkstoffe – AZD6140” (in German). Österreichische Apothekerzeitung (3/2008): 135.
10. ^ Owen, RT, Serradell, N, Bolos, J (2007). “AZD6140”. Drugs of the Future 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
11. ^ Tantry, Udaya S; Bliden, Kevin P (2010). “First Analysis of the Relation Between CYP2C19 Genotype and Pharmacodynamics in Patients Treated With Ticagrelor Versus Clopidogrel”. Circulation: Cardiovascular Genetics 3: 556–566. doi:10.1161/CIRCGENETICS.110.958561.
12. ^ Bernardo Lombo, José G Díez. Ticagrelor: the evidence for its clinical potential as an oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndromes Core Evid. 2011; 6: 31–42. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065559/
13. ^ Serebruany VL, Atar D. Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials—Common patterns in TRITON, RECORD, and PLATO? Thromb Haemost 2012; DOI: 10.1160/TH12-04-0251. http://www.theheart.org/article/1433145/print.do
14. ^ Miller, R (24 February 2010). “Is there too much excitement for ticagrelor?”. TheHeart.org.
15. ^ H. Spreitzer (17 January 2011). “Neue Wirkstoffe – Elinogrel” (in German). Österreichische Apothekerzeitung (2/2011): 10.
16. ^ July 20, 2011 AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval Larry Husten cardiobrief.org/2011/07/20/astrazeneca-ticagrelor-brilinta-gains-fda-approval/

SOURCE:

http://en.wikipedia.org/wiki/Ticagrelor

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• Recent Posts

  • Grok thinks like PhDs – Hybrid Model for Autonomous Update of Doctoral Dissertations with Original PhD Student Author editing and acceptance of Grok’s updated output. 3rd Joint article, a pilot study for Validation of an Autonomous Journal Articles Updating System (AJAUS) tested on Autonomous Update of Aviva Lev-Ari, PhD, RN Doctoral Thesis, UC, Berkeley, 1983. January 31, 2026
  • 2026 World Economic Forum, 1/19 – 1/23/2026, Davos, Switzerland, LPBI Group’s KOLs interpretation of AI in Health Videos January 24, 2026
  • Evolving LPBI Group’s Portfolio of Intellectual Properties (IP): From 2021 Vision to 2026 Reality January 12, 2026
  • Aviva Lev-Ari, PhD, RN – Biography ->> Grokepedia Entry January 11, 2026
  • List of Articles included in the Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter January 10, 2026
  • Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter January 10, 2026
  • Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com January 10, 2026
  • The youngest leader in AI in Health: Tanishq Mathew Abraham, Ph.D. (@iScienceLuvr) January 8, 2026
  • 2026 Grok Multimodal Causal Reasoning on Proprietary Cariovascular Corpus: From 2021 Wolfram NLP Baseline to Thousands of Novel Relationships – A Second Head-to-Head Validation of LPBI’s Domain-Aware Training Advantage January 6, 2026
  • Workflow for Dynamic Linkage and Transition between two Authoring Systems: LPBI Group’s WordPress.com Multi-Authors Authoring System and Microsoft PowerPoint product for Slide show presentation – Part 10.1 in Composition of Methods January 6, 2026

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