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Posts Tagged ‘University of Texas MD Anderson Cancer Center’


Author/Curator: Ritu Saxena, PhD

For several decades, research efforts have focused on targeting progression of cancer cells in primary tumors. Primary tumor cell targeting strategies include standard chemotherapy and immunotherapy and modulation of host microenvironment including tumor vasculature. However, cancer progression is comprised of both primary tumor growth and secondary metastasis (Langley RR and Fidler IJ. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev. 2007 May;28(3):297-321; http://www.ncbi.nlm.nih.gov/pubmed/17409287). Owing to the property of unilimited cell division, cells in primary tumor increase rapidly in number and density and are able to favorably influence their microenvironment. Metastasis, on the other hand, depends on the ability of cancer cells to disseminate, circulate, adapt to the harsh environment and seed in different organs to establish secondary tumors. Although tumor cells are shed into the circulation in large numbers since early stages of tumor formation, few tumor cells can survive and proceed to overt metastasis. (Husemann Y et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008 Jan;13(1):58-68; http://www.ncbi.nlm.nih.gov/pubmed/18167340). Tight vascular wall barriers, unfavorable conditions for survival in distant organs, and a rate-limiting acquisition of organ colonization functions are just some of the impediments to the formation of distant metastasis (Chiang AC and Massagué J. Molecular basis of metastasis. N Engl J Med. 2008 Dec 25;359(26):2814-23; http://www.ncbi.nlm.nih.gov/pubmed/19109576).

It has been hypothesized that metastasis is initiated by a subpopulation of circulating tumor cells (CTC) found in the blood of patients. Therefore, understanding the function of CTC and targeting the CTC is gaining attention as a possible therapeutic avenue in carcinoma treatment.

CTCs

Figure: Circulating tumor cells in the metastatic cascade

(Image source: Chaffer CL and Weinberg RA. Science 2011,331, pp. 1559-1564; http://www.ncbi.nlm.nih.gov/pubmed/21436443)

Isolation of CTC

Initial methods relied on the difference in physical properties of cells. When spun in a centrifuge, different cells in the blood sample settle in separate layers based on their byoyancy, and CTC are found in the white blood cell fraction. Because CTC are generally larger than white blood cells, a size-based filter could be used to separate the cell types (Vona G, et al, Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol, 2000 Jan;156(1):57-63; http://www.ncbi.nlm.nih.gov/pubmed/10623654).

Herbert A Fritsche, PhD, Professor and Chief, Clinical Chemistry, Department of Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, demonstrated that the CTC can be captured using antibody labeled magnetic beads, either in positive or negative selection schema. After the circulating tumor cells are isolated, they may be characterized by immunohistochemistry and counted.  Alternatively, these cells may be characterized by gene expression analysis using RT-PCR. One of the CTC detection methods, Veridex Inc, Cell Search Assay, has been cleared by the US FDA for use as a prognostic test in patients with metastatic cancers of the breast, prostate and colon. This technology relies on the expression of epithelial cellular adhesion molecular (EpCAM) by epithelial cells and the isolation of these cells by immunomagnetic capture using anti-EpCAM antibodies.  Enriched CTC are identified by immunofluorescence. Martin Fleisher, PhD, Chair, Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center discussed in a webinar at the biomarker symposia, Cambridge Healthtech Institute, that every new technology has shortcomings, and the reliance on cancer cells to express sufficient EpCAM to enable capture may affect the role of this technology in future clinical use. Heterogeneous downregulation of epithelial surface antigen in invasive tumor cells has been reported. Thus, alternative methods to detect CTC are being developed. These new methods include-

  1. Flow cytometry that sorts cells by size and surface antigen expression.
  2. CTC microchips that are designed to capture CTC as whole blood flows past EpCAM-coated mirco-posts.
  3. Enrichment by filtration using filters with a pore size of 7-8 µm, that permits smaller red blood cell, leukocytes, and platelets to pass, but captures CTC that have diameters of about 12-15 µm.

Better identification of CTC

Baccelli et al (2013) developed a xenograft assay and demonstrated that the primary human luminal breast cancer CTC contain metastasis-initiated cells (MICs) that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. It was observed that in a small cohort of patients with metastases, the number of CTC expressing markers EPCAM,CD44, CD47 and MET, but not of bulk EPCAM+ CTC, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer. The findings were published in the Nature Biotechnology journal recently (Baccelli I, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology 2013 31, 539–544; http://www.ncbi.nlm.nih.gov/pubmed/23609047).

CTC as prognostic and predictive factor for cancer progression

Martin Fleisher, PhD states “detecting CTC in peripheral blood of patients with cancer has become a clinically relevant and important prognostic biomarker and has been shown to be a predictive biomarker post-therapy. But, key to the use of CTC as a biomarker is the technology designed to enrich cancer cells from peripheral blood.”

Since CTC isolation methods started being established, correlation studies between the cells and a patient’s disease emerged. In 2004, investigators at the Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center (Houston, TX) discovered that the CTC were associated with disease progression and survival in metastatic breast cancer. The clinical trial recruited 177 patients with measurable metastatic breast cancer for levels of CTC both before the patients were to start a new line of treatment and at the first follow-up visit. The progression of the disease or the response to treatment was determined with the use of standard imaging studies at the participating centers. Patients in a training set with levels of CTC equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 CTC per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P<0.001) and shorter overall survival (10.1 months vs. >18 months, P<0.001). At the first follow-up visit after the initiation of therapy, this difference between the groups persisted (progression-free survival, 2.1 months vs. 7.0 months; P<0.001; overall survival, 8.2 months vs. >18 months; P<0.001), and the reduced proportion of patients (from 49 percent to 30 percent) in the group with an unfavorable prognosis suggested that there was a benefit from therapy.  Thus, the number of CTC was found to be an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer (Cristofanilli M, et al, Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004 Aug 19;351(8):781-91; http://www.ncbi.nlm.nih.gov/pubmed/15317891).

Similar results have been observed in other cancer types, including prostate and colorectal cancer. The Cell Search System developed by Veridex LLC (Huntingdon Valley, PA) enumerated CTC from 7.5 mL of venous blood and was used to compare the outcomes from three prospective multicenter studies investigating the use of CTC to monitor patients undergoing treatment for metastatic breast, colorectal, or prostate cancer. Evaluation of CTC at anytime during the course of disease allowed assessment of patient prognosis and is predictive of overall survival (Miller MC, et al. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J Oncol. 2010; http://www.ncbi.nlm.nih.gov/pubmed/20016752). In addition, the CTC test may permit the oncologist to make an early decision to discontinue first line therapy for metastatic breast cancer and pursue more aggressive alternative treatments.

Genetic analysis of CTC

Additional studies have analyzed the genetic mutations that the cells carry, comparing the mutations to those in a primary tumor or correlating the findings to a patient’s disease severity or spread. In one study, lung cancer patients whose CTC carried a mutation known to cause drug resistance had faster disease progression than those whose CTC lacked the mutation. The investigators analyzed the evolutionary aspect of cancer progression and studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers. Single disseminated cancer cells isolated from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients were analyzed by whole-genome screening which revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. Chromosome 17q12-21, the region comprising HER2, was identified as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Furthermore, survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death (Stoecklein NH, et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell. 2008 May;13(5):441-53; http://www.ncbi.nlm.nih.gov/pubmed/18455127).

The abovementioned studies indicate that CTC blood tests have been successfully used to track the severity of a cancer or efficacy of a treatment. In conclusion, the evolution of the CTC technology will be critical in the emerging area of targeted therapy.  With the development and use of new technologies, the links between the genomic information and CTC could be explored and established for targeted therapy.

Challenges in CTC research

  1. Potential clinical significance of CTC has been demonstrated as early detection, diagnostic, prognostic, predictive, surrogate, stratification, and pharmacodynamic biomarkers. Hong B and Zu Y (2013) discuss that “the role of CTC as a disease marker may be unique in different clinical conditions and should be carefully interpreted. A good example is the comparison between the prognostic and predictive biomarkers. Both biomarkers employ progression-free survival and overall survival for data interpretation; however, the prognostic biomarker is independent of specific drug treatment or therapy, and used for the determination of outcomes before treatment, while the predictive biomarker is related to a particular treatment to predict the response. Furthermore, inconsistent results are increasingly reported among the various CTC assay methods, specifically pertaining to results for the CTC detection rate, patient positivity rate, and the correlation between the presence of CTC and survival rate (Hong B and Zu Y. Detecting circulating tumor cells: current challenges and new trends. Source. Theranostics. 2013 Apr 23;3(6):377-94; http://www.ncbi.nlm.nih.gov/pubmed/23781285).
  2. Heterogeneity in CTC along with several other technical factors contribute to discordance, including the changes in methodology, lack of reference standard, spectrum and selection bias, operator variability and bias, sample size, blurred clinical impact with known clinical/pathologic data, use of diverse capture antibodies from different sources, lack of awareness of the pre-analytical phase, oversimplification of the cytopathology process, use of dichotomous decision criteria, etc (Sturgeon C. Limitations of assay techniques for tumor markers. In: (ed.) Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz MK. Tumor markers: physiology, pathobiology, technology, and clinical applications. Washington, DC: AACC Press. 2002:65-82; Gion M and Daidone MG. Circulating biomarkers from tumour bulk to tumour machinery: promises and pitfalls. Eur J Cancer. 2004;40(17):2613-2622; http://www.ncbi.nlm.nih.gov/pubmed/15541962). Therefore, employing a standard protocol is essential in order to minimize a lot of inconsistencies and technical errors.
  3. CTC in a small amount of blood sample might not represent the actual CTC count in the whole blood. In fact, it has been reported that the Cell Search system might undercount the number of CTC. Nagrath et al (2007) have demonstrated that the average CTC number per mL of whole blood is approximately 79-155 in various cancers (Nagrath S, et al. Isolation of rare circulating tumous cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235-1239; http://www.ncbi.nlm.nih.gov/pubmed/18097410). In addition, an investigative CellSearch Profile approach (for research use only) detected an approximately 30-fold higher number of the median CTC in the same paired blood samples (Flores LM, et al. Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer. 2010;102(10):1495-502; http://www.ncbi.nlm.nih.gov/pubmed/20461092). Such measurement discrepancies indicate that the actual CTC numbers in the blood of patients could be at least 30-100 fold higher than that currently reported by the only FDA-cleared CellSearch system.

Thus, although promising, the CTC technology faces several challenges both in detection and interpretation, which has resulted in its limited clinical acceptance and use. In order to prepare the CTC technology for future widespread clinical acceptance, a comprehensive guideline for all phases of CTC technology development was published by the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium. The guidelines describe methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the FDA and the National Cancer Institute (NCI) (Parkinson DR, et al. Considerations in the development of circulating tumor cell technology for clinical use. J Transl Med. 2012;10(1):138; http://www.ncbi.nlm.nih.gov/pubmed/22747748).

Reference:

  1. Langley RR and Fidler IJ. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev. 2007 May;28(3):297-321; http://www.ncbi.nlm.nih.gov/pubmed/17409287
  2. Husemann Y et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008 Jan;13(1):58-68; http://www.ncbi.nlm.nih.gov/pubmed/18167340
  3. Chiang AC and Massagué J. Molecular basis of metastasis. N Engl J Med. 2008 Dec 25;359(26):2814-23; http://www.ncbi.nlm.nih.gov/pubmed/19109576
  4. Vona G, et al, Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol, 2000 Jan;156(1):57-63; http://www.ncbi.nlm.nih.gov/pubmed/10623654
  5. Baccelli I, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology 2013 31, 539–544; http://www.ncbi.nlm.nih.gov/pubmed/23609047
  6. Cristofanilli M, et al, Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004 Aug 19;351(8):781-91; http://www.ncbi.nlm.nih.gov/pubmed/15317891
  7. Miller MC, et al. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J Oncol. 2010; http://www.ncbi.nlm.nih.gov/pubmed/20016752
  8. Stoecklein NH, et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell. 2008 May;13(5):441-53; http://www.ncbi.nlm.nih.gov/pubmed/18455127
  9. Hong B and Zu Y. Detecting circulating tumor cells: current challenges and new trends. Source. Theranostics. 2013 Apr 23;3(6):377-94; http://www.ncbi.nlm.nih.gov/pubmed/23781285
  10. 10. Sturgeon C. Limitations of assay techniques for tumor markers. In: (ed.) Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz MK. Tumor markers: physiology, pathobiology, technology, and clinical applications. Washington, DC: AACC Press. 2002:65-82
  11. Gion M and Daidone MG. Circulating biomarkers from tumour bulk to tumour machinery: promises and pitfalls. Eur J Cancer. 2004;40(17):2613-2622; http://www.ncbi.nlm.nih.gov/pubmed/15541962
  12. Nagrath S, et al. Isolation of rare circulating tumous cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235-1239; http://www.ncbi.nlm.nih.gov/pubmed/18097410
  13. Flores LM, et al. Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer. 2010;102(10):1495-502; http://www.ncbi.nlm.nih.gov/pubmed/20461092
  14. Chaffer CL and Weinberg RA. Science 2011,331, pp. 1559-1564; http://www.ncbi.nlm.nih.gov/pubmed/21436443

Other related articles on circulation cells as biomarkers published on this Open Access Scientific Journal, include the following:

Blood-vessels-generating stem cells discovered

Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2012/10/22/blood-vessel-generating-stem-cells-discovered/

Cardiovascular and circulating endothelial cells as BIOMARKERS for prediction of Disease progression risks

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation Curator, Author,Writer, Reporter: Larry Bernstein, MD, FCAP

Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs Author and Curator: Aviva Lev-Ari, PhD, RN

Vascular Medicine and Biology: Macrovascular Disease – Therapeutic Potential of cEPCs Curator and Author: Aviva Lev-Ari, PhD, RN

Repair damaged blood vessels in heart disease, stroke, diabetes and trauma: Cellular Reprogramming amniotic fluid-derived cells into Endothelial Cells

Reporter: Aviva Lev-Ari, PhD, RN

Stem cells in therapy

A possible light by Stem cell therapy in painful dark of Osteoarthritis” – Kartogenin, a small molecule, differentiates stem cells to chondrocyte, healthy cartilage cells Author and Reporter: Anamika Sarkar, Ph.D and Ritu Saxena, Ph.D.

Human embryonic pluripotent stem cells and healing post-myocardial infarctionAuthor: Larry H. Bernstein, MD

Stem cells create new heart cells in baby mice, but not in adults, study showsReporter: Aviva Lev-Ari, PhD, RN

Stem cells for the rescue of mitochondrial dysfunction in Parkinson’s diseaseReporter: Ritu Saxena, Ph.D.

Stem Cell Research — The Frontier is at the Technion in Israel Reporter: Aviva Lev-Ari, PhD, RN

Research articles by MA Gaballa, PhD

Harris DT, Badowski M, Nafees A, Gaballa MAThe potential of Cord Blood Stem Cells for Use in Regenerative Medicine. Expert Opinion in Biological Therapy 2007. Sept 7(9): 1131-22.

Furfaro E, Gaballa MADo adult stem cells ameliorate the damaged myocardium?. Human cord blood as a potential source of stem cells. Current Vascular Pharmacology 2007, 5; 27-44.

 

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Texas Heart Institute: 50 Years of Accomplishments

Reporter: Aviva Lev-Ari, PhD, RN

 

Texas Heart Institute’s Overachieving President and Medical Director Dr. James T Willerson Profiles THI’s 50 Years Of Accomplishments


Posted Thursday , April 25,2013

The Texas Heart Institute is a not-for-profit cardiology and heart surgery center located at the Texas Medical Center in Houston. Founded in 1962 by Dr. Denton A. Cooley, the mission of the Texas Heart Institute has been to reduce the devastating toll of cardiovascular disease through innovative programs in research, education and improved patient care. Over the past 51 years the Institute has been involved in training cardiologists, heart surgeons, imaging specialists in cardiovascular medicine and cardiac electrophysiology, and pathologists, and educated hundreds of cardiovascular specialists.

texasheart

A nonprofit organization in the truest sense, and unlike most institutions that have a source of operating revenue, the Texas Heart Institute relies solely on government grants, research contracts and, above all, philanthropy, with donations from grateful patients, foundations, corporations, physicians, and the general public account for more than half of the Institute’s annual operating budget. The Institute’s location in and affiliations with St. Luke’s Episcopal Hospital and Texas Children’s Hospital have assured that all age groups will be treated, and has freed the Institute of the burden of financing a health care facility.

The Texas Heart Institute (THI) and its clinical partner, St. Luke’s Episcopal Hospital, have become one of America’s largest cardiovascular centers, whose 160-member professional staff have reportedly performed more than 100,000 open heart operations, 200,000 cardiac catheterizations, and 1,000 heart transplants.

In its 2010 annual survey of “America’s Best Hospitals,” U.S. News & World Report ranked the Texas Heart Institute at St. Luke’s Episcopal Hospital number four in the United States for heart care, marking this its 20th consecutive year of inclusion as one of the top 10 heart centers in the country.

willersonIn an interview with the European science news journal Research Media, THI President and Medical Director, Dr. James T Willerson, says that when he originally came to the Institute in 2004, then still President Dr Cooley wanted him to be Medical Director of Cardiovascular Research, and upon Dr. Cooley’s resignation in 2008, he asked Dr. Willerston to succeed him in that position.

In the interview, Dr. Willerston, a native Texan, profiles the THI’s achievements and shares his thoughts on reducing the heavy burdens of Cardiovascular disease, which is estimated to cost the economy $449 billion annually.

Accounting for over a quarter of all deaths in the U.S. each year, cardiovascular disease is obviously a major health concern, but mortality from coronary heart disease (CHD) has substantially decreased in recent decades. Dr. Willerston attributes the decrease to research discoveries that have provided insights into mechanisms responsible for thrombosis in injured coronary and cerebral arteries, and led to improved treatment.

He cites as an example that increased understanding of ‘bad’ low-density lipoprotein (LDL) cholesterol in patients to values well below 100 mg/dl has been a very important contribution, as has the development of statins to lower LDL has also been crucial, the use of low-dose aspirin and other medications to control blood pressure, avoidance of smoking and use of recreational drugs, control of blood sugar in patients who are diabetic, emphasis on diet and exercise, and improved imaging techniques for blood vessels and the cardiovascular system, as factors that have played a role in protecting CHD patients and decreasing mortality risk.

However, he notes that the greatest GHD risk factor is a genetic one, and a remaining priority must be to identify genes that contribute to this risk; ultimately silencing the most dangerous ones using microRNA methodology. Dr. Willerston says numerous clinical studies in patients with cardiovascular disease using a variety of stem cell types, including mesenchymal stem cells taken from the bone marrow or adipose tissue have been conducted, and that through the pioneering work of Dr Doris Taylor, scientists are now able to deplete human hearts of their cellular structure and then restore that same heart to normal function by the infusion of stem cells. With continued success, these efforts could fill a great unmet need and pave the way to a new area of transplant medicine.

Dr. Willerston maintains that prevention would be the single most effective means of reducing healthcare costs, and should be the main concern initiated at very young ages and continue throughout adulthood.

Dr. James T. Willerson, born in Lampasas, Texas, is President of The University of Texas Health Science Center at Houston where he is the Alkek-Williams Distinguished Professor and holds the Edward Randall III Chair in Internal Medicine. In October 2004, Dr. Willerson was named President-Elect of the Texas Heart Institute in Houston, Texas. He holds the Dunn Chair in Cardiology Research and the John O’Quinn Chair named the “James T. Willerson Distinguished Chair in Cardiovascular Research,” both at the Texas Heart Institute, Houston, Texas. From 1989 through 2000, he was the Chairman of the Department of Internal Medicine at The University of Texas Medical School at Houston where an Annual Lectureship has been established in his name. During this same period, he served as the Chief of Medical Services at Memorial Hermann Hospital. He is also the Medical Director, Director of Cardiovascular Research, and Co-Director of the Cullen Cardiovascular Research Laboratories at the Texas Heart Institute. He is an Adjunct Professor of Medicine at Baylor College of Medicine and at The University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Willerson also founded TexGen Research, a collaboration which brings together all of the institutions in the Texas Medical Center to collect blood samples necessary for the discovery of those genes and proteins that play a key role in causing major diseases. With TexGen, each Texas Medical Center institution obtains blood samples from patients who have a personal or family history of cardiovascular disease, stroke, dementia, or selected cancers and who are admitted to their hospitals. Great progress is being made by this collaborative biomedical research effort.

A graduate of the Texas Military Institute in San Antonio, Texas, where he was the Battalion Commander, President of the Senior Class, Editor of the school newspaper, and a state swimming champion, Dr. Willerston attended The University of Texas at Austin, graduating as a Phi Beta Kappa, member of the Texas Cowboys, and where he lettered for three years in varsity swimming. Upon graduating as a member of Alpha Omega Alpha from Baylor College of Medicine in Houston, Texas, he completed his medical and cardiology training as an intern, resident, and research and clinical fellow at the Massachusetts General Hospital in Boston, Massachusetts, and as a Clinical Associate at the National Institutes of Health in Bethesda, Maryland.

He is the former Chairman of the National American Heart Association Research Committee and of the Cardiovascular and Renal Study Section of the National Institutes of Health. He has received the Award of Merit from the American Heart Association and has served as a member of the Board of Directors and Steering Committee of the National American Heart Association. Before coming to The University of Texas Medical School at Houston, Dr. Willerson was Professor of Medicine and Director of the Cardiology Division at The University of Texas Southwestern Medical School in Dallas, Texas, and Director and Principal Investigator of the National Heart, Lung, and Blood Institute’s Specialized Center of Research under a major grant from the NIH. Upon his departure, the “James T. Willerson, M.D. Distinguished Chair in Cardiovascular Diseases” was established at The University of Texas Southwestern Medical School.

Dr. Willerson has served as visiting professor and invited lecturer at more than 220 institutions worldwide, and has received numerous national and international awards, as well as having served on editorial boards for many professional publications including: The New England Journal of Medicine, Journal of Clinical Investigation, Circulation, Circulation Research, Arteriosclerosis and Thrombosis, American Journal of Medicine, Journal of the American College of Cardiology, American Journal of Cardiology, American Heart Journal, and Cardiovascular Medicine. From 1993 to 2004, he was the longest-serving Editor of Circulation, the major publication of the American Heart Association. In 1998, the monthly journal was converted to a weekly publication and attained the highest Impact Factor of any cardiology journal in the world. He has edited or co-edited twenty-four textbooks, including the Third Edition of Cardiovascular Medicine which was released in February of 2007. Additionally, he has published more than 850 scientific articles.

Dr. Willerson has been elected to membership in numerous professional societies, including the American Society of Clinical Investigation, the Association of American Physicians, the Association of Professors of Medicine, and the Institute of Medicine of the National Academy of Sciences. He was named a Distinguished Alumnus by the Baylor College of Medicine in 1998 and a Distinguished Alumnus of The University of Texas at Austin in 1999.

SOURCE:

http://bionews-tx.com/news/2013/04/25/texas-heart-institutes-overachieving-president-and-medical-director-dr-james-t-willerson-profiles-this-50-years-of-accomplishments/

Comment of Note

Dr. Lev-Ari, was a visitor at Texas Heart Institute, Perfusion Program, and shadowed Open Heart Surgery in 8/2005.

The museum on the First floor of the building represents a Historical exhibit of Images of Cardiac Procedures. On display is a complete array of surgical tools used in Cardiac Repair during the last 50 years of unprecedented development in Cardiac Medical Devices and Procedures. A duplicate of the exhibit is available at the Smithsonian Museum at WashDC.

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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

https://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

https://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

https://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.

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

Ritu Saxena’s interview

https://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.

Fig1a

SOURCES:

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

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

https://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.”

https://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).

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

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

Fourth:

Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper

Fig2a

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:

Fifth:

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

Fig2b

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

(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”

https://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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Image

Reporter: Ritu Saxena, Ph.D.

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

Researchers at the MD Anderson Cancer center initiated a personalized medicine program by moving to phase I early clinical trials. The tumors were analyzed for molecular aberrations and matched with suitable targeted agents. Treatment assignment was not randomized. With a study involving 144 patients with advanced cancer stages, the authors found that the patients that underwent matched therapy based on their single aberration type, showed better results in terms of survival as compared to similar single aberration carrying patients who underwent systemic therapy (median, 13.4 vs. 9.0 months; p = 0.017).

The findings have been published a few days ago in the November 15th issue of Clinical Cancer Research Journal.

Abstract: Tsimberidou AM et al, Personalized medicine in a phase I clinical trials program: the MD anderson cancer center initiative. Clin Cancer Res. 2012 Nov 15;18(22):6373-83.

Authors’ Affiliations: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program; and Departments of Hematopathology and Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

PURPOSE:

We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations. Patient and Methods: Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy.

RESULTS:

Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P < 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P = 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001).

CONCLUSION:

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

Sources:

Research article by Tsimberidou AM et al. Clin Cancer Res. 2012 Nov 15;18(22):6373-83.

News brief by Virginia Postrel, a Bloomberg View Columnist, Cancer Breakthroughs Meet Market Realities, November, 2012.

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