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at #JPM16 – Moderna Therapeutics turns away an extra $200 million: with AstraZeneca (collaboration) & with Merck ($100 million investment)

Reporter: Aviva Lev-Ari, PhD, RN

 

per SOURCES quoted:

 

AstraZeneca, for one, has sent an important validating signal to outsiders by continuing to invest in 29 Moderna drug candidates at last count. The financial community can’t get enough. As ambitious as Moderna has been with a dream to disrupt conventional small molecule drugs and protein therapies, it recognizes it can only do so much. Moderna turned away an extra $200 million of investment that would have made its $500 million round a $700 million round. The company didn’t need that much. “It’s bizarre,” Bancel said. “I used to spend my time begging for money. Now I had to go to my board and say ‘We’re going to turn down $200 million.”

READ MORE @SOURCE

http://www.forbes.com/sites/luketimmerman/2015/01/13/merck-joins-messenger-rna-frenzy-betting-100m-on-moderna-therapeutics/#2715e4857a0b3c845e263de9

 

AstraZeneca and Moderna Therapeutics announce new collaboration to co-develop and co-commercialise immuno-oncology mRNA therapeutics™

PUBLISHED 11 January 2016

Moderna to lead preclinical development; AstraZeneca to lead clinical development; Moderna to co-commercialise and share profits on resulting products in the US

11 January 2016

AstraZeneca, along with its global biologics research and development arm, MedImmune, and Moderna Therapeutics today announced a new collaboration to discover, co-develop and co-commercialise messenger RNA (mRNA) therapeutic candidates for the treatment of a range of cancers. The collaboration is in addition to the agreement announced by the companies in 2013 to develop mRNA Therapeutics™ for the treatment of cardiovascular, metabolic and renal diseases as well as selected targets in oncology.

The collaboration will combine MedImmune’s protein engineering and cancer biology expertise with Moderna’s mRNA platform. mRNA-based therapies are an innovative treatment approach that enables the body to produce therapeutic protein in vivo, opening up new treatment options for a wide range of diseases that cannot be addressed today using existing technologies.

READ MORE @SOURCE

https://www.astrazeneca.com/our-company/media-centre/press-releases/2016/AstraZeneca-and-Moderna-Therapeutics-announce-new-collaboration-to-co-develop-and-co-commercialise-immuno-oncology-mRNA-therapeutics-11012016.html

 

Merck Joins Messenger RNA Frenzy, Betting $100M On Moderna Therapeutics

I’m the founder and editor of Timmerman Report.

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JP Morgan Healthcare Day Two: Thermo Fisher; Qiagen; Danaher; Counsyl; Human Longevity; Adaptive Bio, 10X Genomics and Pacific Biosciences, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

JP Morgan Healthcare Day Two: Thermo Fisher; Qiagen; Danaher; Counsyl; Human Longevity; Adaptive Bio, 10X Genomics and Pacific Biosciences

Reporter: Aviva Lev-Ari, PhD, RN

 

JPM16 & BTS16: A dour start to biopharma’s big week as stocks feel the pain

 

BioPharma Dive is here in San Francisco attending the Biotech Showcase 2016 and the 34th Annual JPMorgan Healthcare Conference. The city is swamped with biopharma companies, healthcare firms, investors & VCs, and analysts of all stripes for what has grown to be the biggest week for the life sciences.

But unlike last year, when the industry’s bullishness about 2015 was palpable, the conferences this year got off to a decidedly more downbeat start on Monday. Here are the topline takeaways you need to know from yesterday’s events and presentations.

Biopharma stocks continue to feel the New Year pain

READ MORE @ SOURCE

http://www.biopharmadive.com/news/jpm16-bts16-a-dour-start-to-biopharmas-big-week-as-stocks-feel-the-pain/411935/

GENOMICS in Focus

JP Morgan Healthcare Day Two: Thermo Fisher; Qiagen; Danaher; Counsyl; Human Longevity; Adaptive Bio, 10X Genomics, Pacific Biosciences

Reporters: Staff Reporter @ genomeweb.com

 

 

JP Morgan Healthcare Day Two: Thermo Fisher; Qiagen; Danaher; Counsyl; Human Longevity; Adaptive Bio, 10X Genomics, Pacific Biosciences

SAN FRANCISCO (GenomeWeb) – The 34th Annual JP Morgan Healthcare Conference entered its second day here Tuesday with several life science research tools and diagnostic firms making presentations to investors and other attendees.

The following are capsules from the presentations and breakout sessions of

  • Thermo Fisher Scientific,
  • Qiagen,
  • Danaher,
  • Counsyl,
  • Human Longevity, and
  • Adaptive Biotechnologies.

SEE DETAILS in

SOURCE

https://www.genomeweb.com/business-news/jp-morgan-healthcare-day-two-thermo-fisher-qiagen-danaher-counsyl-human-longevity

10X Genomics, Pacific Biosciences Provide Business Updates at JP Morgan Healthcare Conference

Among the presenting companies were sequencing technology firms 10X Genomics and Pacific Biosciences. Executives from these firms provided attendees with an update on recently launched products and platforms, and future technology developments.

  • 10X Genomics and
  • Pacific Biosciences

SEE DETAILS in

SOURCE

https://www.genomeweb.com/sequencing-technology/10x-genomics-pacific-biosciences-provide-business-updates-jp-morgan-healthcare

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Driver of DNA repair pathway

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Molecule Driving DNA Repair Disorder Revealed    

GEN News    http://www.genengnews.com/gen-news-highlights/molecule-driving-dna-repair-disorder-revealed/81252230/

 

http://www.genengnews.com/Media/images/GENHighlight/thumb_106235_web1881582438.jpg

This image shows a teratoma formed by induced pluripotent stem cells with defective Fanconi anemia DNA repair. Even with defective FA DNA repair, the induced stem cells were able to start the process of forming specific tissues until the DNA repair defect killed them off. Teratomas are benign tumors containing a haphazard array of cells and tissues of different organ systems. [Cincinnati Children’s Hospital Medical Center]

 

The importance of maintaining genomic integrity becomes readily apparent when determining the underlying causes of various genetic diseases with mutations residing within DNA repair pathways. Researchers at the Cincinnati Children’s Hospital Medical Center believe they have identified a molecular target and experimental treatment strategy for DNA repair defects behind Fanconi anemia—a multifaceted genetic disorder responsible for birth anomalies, organ damage, anemia, and cancer.

“This study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia (FA) conditions, which have no cure and limited treatment options,” explained senior study author Susanne Wells, Ph.D., director of the epithelial carcinogenesis and stem cell program at the Cincinnati Children’s Hospital Medical Center. “Our findings also raise a number of important questions, so there is a lot more to be done.”

The findings from this study were published recently in Stem Cell Reports through an article entitled “Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage.”

In the current study, the investigators utilized induced pluripotent stem cells (iPSCs), which have the ability to be reprogrammed into any cell type in the body. The induced stem cells were donated by FA patients and contained the defective DAN repair pathway. The research team carefully studied the stem cells in laboratory cultures and cells injected into humanized mouse models, monitoring their genetic, molecular, and developmental progression.

Interestingly, even with defective FA DNA repair, the stem cells were still able to transform into different tissues. However, the researchers said the DNA repair defect eventually started to kill off the pluripotent stem cells by blocking cell division and causing programmed cell death.

“To determine the effect of failed repair of endogenous DNA lesions on PSC biology, we generated iPSCs harboring a conditional FA pathway,” the authors wrote. “Upon FA pathway loss, iPSCs maintained pluripotency but underwent profound G2 arrest and apoptosis, whereas parental fibroblasts grew normally.”

Upon subsequent examination, the researchers noticed an enzyme that serves as a DNA regulatory checkpoint during cell division (CHK1) showed a dramatic increase in activity within the stem cells—speeding up their deaths. Using existing pharmacologic inhibitors of CHK1 to block the hyperactive enzyme at a critical stage of the stem cell cycle, the investigators were able to override what usually are unfixable errors in the FA repair pathway.

“Our findings establish that the FA pathway is essential for proliferation and survival of iPSCs and implicates CHK1 as a crucial factor in their extreme sensitivity to accrued DNA damage,” the authors stated.

Surprisingly, after targeted treatment, FA-pathway-deficient pluripotent stem cells resumed dividing and expanding normally. Moreover, the scientists were amazed that the resumption of cell growth occurred without what they had expected to be massive chromosome abnormalities, leading the ranchers to postulate that a compensating DNA repair process is engaged in the reinvigorated cells.

“A key question for us is what type of DNA repair kicks in under these conditions—and is it error free or error prone?” noted Dr. Wells. “A novel mode of emergency DNA repair might indeed be discovered in the iPSC cells. We believe some type of compensatory DNA repair must be driven by CHK1 inhibition when cells have FA pathway loss. Otherwise, the cells would have died off very quickly.”

The scientists plan to follow up this study with additional testing in humanized and genetic mouse models, attempting to improve embryonic development and post-birth fitness in FA-pathway deficient mice with a uniform application of the CHK1 inhibitor. The researchers hope that their findings and approach may lead to treatments for all of the clinical manifestations of the disease.

 

Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage

Timothy M. Chlon, Sonya Ruiz-Torres, Logan Maag, …., James M. Wells, Susanne I. Wellscorrespondence
Stem Cell Reports Jan 2016;  6(1), 44–54, 12  http://dx.doi.org/10.1016/j.stemcr.2015.12.001
Figure thumbnail fx1
Highlights
  • Self-renewal but not pluripotency of iPSCs depends on FA pathway function
  • Hyperactive CHK1 limits self-renewal in a conditional FA-deficient iPSC model
  • CHK1 inhibition rescues long-term growth of FA-deficient iPSCs

 

Summary

Pluripotent stem cells (PSCs) maintain a low mutation frequency compared with somatic cell types at least in part by preferentially utilizing error-free homologous recombination (HR) for DNA repair. Many endogenous metabolites cause DNA interstrand crosslinks, which are repaired by the Fanconi anemia (FA) pathway using HR. To determine the effect of failed repair of endogenous DNA lesions on PSC biology, we generated iPSCs harboring a conditional FA pathway. Upon FA pathway loss, iPSCs maintained pluripotency but underwent profound G2 arrest and apoptosis, whereas parental fibroblasts grew normally. Mechanistic studies revealed that G2-phase FA-deficient iPSCs possess large γH2AX-RAD51 foci indicative of accrued DNA damage, which correlated with activated DNA-damage signaling through CHK1. CHK1 inhibition specifically rescued the growth of FA-deficient iPSCs for prolonged culture periods, surprisingly without stimulating excessive karyotypic abnormalities. These studies reveal that PSCs possess hyperactive CHK1 signaling that restricts their self-renewal in the absence of error-free DNA repair.

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Healthcare conglomeration to access Big Data and lower costs, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Healthcare conglomeration to access Big Data and lower costs

Curator: Larry H. Bernstein, MD, FCAP 

 

 

UPDATED on 3/17/2019

https://www.medpagetoday.com/cardiology/prevention/78202?xid=nl_mpt_SRCardiology_2019-02-25&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioUpdate_022519&utm_term=NL_Spec_Cardiology_Update_Active

Medicare Advantage plans may be driving up quality of care in terms of preventive treatment for coronary artery disease patients, but that has had little impact on outcomes compared with fee-for-service Medicare, researchers reported in JAMA Cardiology.

 

The expected benefits are not as easily realized as anticipated.   The problem of access to data sources is not as difficult as the content needed for evaluation.

 

Healthcare Big Data Drives a New Round of Collaborations between Hospitals, Health Systems, and Care Management Companies

DARK DAILY   DARK DAILY info@darkreport.com

 

January 13, 2016

Recently-announced partnerships want to use big data to improve patient outcomes and lower costs; clinical laboratory test data will have a major role in these efforts

In the race to use healthcare big data to improve patient outcomes, several companies are using acquisitions and joint ventures to beef up and gain access to bigger pools of data. Pathologists and clinical laboratory managers have an interest in this trend, because medical laboratory test data will be a large proportion of the information that resides in these huge healthcare databases.

For health systems that want to be players in the healthcare big data market, one strategy is to do arisk-sharing venture with third-party care-management companies. This allows the health systems to leverage their extensive amounts of patient data while benefiting from the expertise of their venture partners.

Cardinal Health Acquires 71% Interest in naviHealth

One company that wants to work with hospitals and health systems in these types of arrangements is Cardinal Health. It recently acquired a 71% interest in Nashville-based naviHealth. This company partners with health plans, health systems, physicians, and post-acute providers to manage the entire continuum of post-acute care (PAC), according to a news release on the naviHealth website. NaviHealth’s business model involves sharing the financial risk with its clients and leveraging big data to predict best outcomes and lower costs.

“We created an economic model to take on the entire post-acute-care episode,” declared naviHealth CEO and President Clay Richards in a company news release. “It’s leveraging the technology and analytics to create individual care protocols.”

Click here to see image

“The most basic, and the most important, thing is … they [Cardinal Health] share the same core values as we do, which is to be on the right side of healthcare,” naviHealth CEO Clay Richards told The Tennessean. “It’s about how you deliver better outcomes for patients with lower costs: How do you solve the problems [with growing costs]? That’s what we and Cardinal define as being on the right side of healthcare.” (Caption and image copyright: The Tennessean.)

Provider Investments Signal Continuation of Trend

Cardinal Health intends to combine its ability to reduce costs while providing effective care with naviHealth’s evidence-based, personalized post-acute-care plans. This is one approach to harness the power of big data to improve patient care. One goal is focus this expertise on post-acute care, which is one of Medicare’s quality measures.

Patients and their families often are unsure of what to expect after being discharged. And, according to an article published in Kaiser Health News, a 2013 Institutes of Medicine (IOM) report noted a link between the quality of post-acute care and healthcare spending following the discharge of Medicare patients.

However, maximizing the use of healthcare big data requires the participation of multiple stakeholders. Information scientists, hospital administrators, software developers, insurers, clinicians, and patients themselves must all perform a role in order for big data to reach its full potential. No single sector will be able to bring the benefits of big data to fruition; rather collaboration and partnerships will be necessary.

Other Collaborations and Alliances Target Healthcare Big Data

Two other organizations engaged in a similar collaboration are the Mayo Clinic andOptum360, a revenue management services company that focuses on simplifying and streamlining the revenue cycle process. In a press release, the companies announced that they were partnering to “develop new revenue management services capabilities aimed at improving patient experiences and satisfaction while reducing administrative costs for healthcare providers.” (See Dark Daily, “When It Comes to Mining Healthcare Big Data, Including Medical Laboratory Test Results, Optum Labs Is the Company to Watch,” December 14, 2015.)

In order to accomplish this, Mayo will have to share its revenue cycle management (RCM) data with Optum360, which will use the data to devise improved revenue cycle processes and systems.

“What we’re trying to find out, if we can, is what does healthcare cost, and what of that spend really adds value to a patient’s outcome over time, especially with these high-impact diseases,” stated Mayo Clinic President and CEO John Noseworthy, MD, in a story published by the Star Tribune. He was referencing another big data project Mayo is engaged in with UnitedHealth Group. “Ultimately, we as a country have to figure this out, so people can have access to high-quality care and it doesn’t bankrupt them or the country.”

Click here to see image

Mayo Clinic President and CEO John Noseworthy, MD, believes big data may be the key to transforming healthcare costs by informing clinical decision-making and altering patient outcomes. (Photo copyright: Mayo Clinic.)

Another interesting healthcare big data partnership is the Pittsburgh Health Data Alliance (The Alliance). It involves a collaboration between Carnegie Mellon University (CMU), the University of Pittsburgh (PITT), and the University of Pittsburgh Medical Center (UPMC). The aim of The Alliance is to take raw data from wearable devices, insurance records, medical appointments, as well as other common sources, and develop ways to improve the health of individuals and the wider community.

The common thread among all these collaborative efforts is a desire to improve outcomes while reducing costs. This is the promise of healthcare big data. And no matter which direction the effort takes, clinical laboratories, which generate a vast amount of critical health data, are in a good position to play important roles involving the contribution of lab test data and identifying ways to use healthcare big data projects to improve patient care.
—Dava Stewart

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Anti-diabetic Drugs Affect Gut bacteria

Reported by: Irina Robu

Gut bacteria produces several types of substances that affect human physiology and health. However, any change in composition of this gut microbiome can have negative health effects. In a recent study, scientists have tried to understand the signatures of gut microbiota in diabetic patients. 

Using over 700 available human gut metagenomes, the scientists analyzed in detail the effects of the most widely used antidiabetic drug – metformin. Their findings indicated that metformin causes favorable changes in the gut microbiota of type 2 diabetes patients. The drug boosts the capability of the gut bacteria to produce butyric acid and propionic acid. These molecules act to reduce blood glucose levels in diabetics.

Metformin is known for its negative effects on the gastrointestinal tract, such as bloating and flatulence. The patients treated with metformin were found to have more coliform bacteria in their gut and it may be one of the reasons for these adverse effects. When looking at type 2 diabetes patients that were not treated with metformin, the researchers concluded that they had fewer bacteria that produced butyric acid and propionic acid. The study underscores the need to disentangle the gut microbiota signatures of human diseases from medication-induced effects.

Source

http://www.ncbi.nlm.nih.gov/pubmed/26633628

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Fluidigm Microfluidic Technology: Contributions to Life Science Industry – the Biomark™ HD and C1™systems.

Reporter: Aviva Lev-Ari, PhD, RN

 

Technology

https://www.fluidigm.com/about/technology

Products

https://www.fluidigm.com/products

Applications

  • Ag-Genomics

A look at the latest agricultural biology DNA sampling applications and approaches

  • Single-Cell Analysis

Fluidigm supports six significant single-cell biology methods to help accomplish more

  • Sample Identification

Discover solutions to persistent issues with sample collection and biorepository work

https://www.fluidigm.com/applications

Company Profile

Fluidigm creates and manufactures innovative technologies and life-science tools designed to revolutionize biology through a relentless pursuit of scientific truth. Its core technologies are based on microfluidics and mass cytometry, and enable the exploration and analysis of individual cells, as well as the industrial application of genomics.

Most microfluidics experts in the 1990s worked with rigid substances like silicon, glass or plastic, but a young Stephen Quake, PhD, endeavored to create complex microplumbing from a novel rubber substrate. He and co-inventor Marc Unger built a microscopic valve to control the flow of fluids within microchannels—and a new approach to integrating biological liquid handling was born.

Meanwhile, Gajus Worthington, a college classmate of Quake’s, was acquiring the skills and experience necessary to build a successful company. Mentored in his early 20s by thought leaders such as Jim Collins, he set upon his personal mission to create an organization that would make lasting contributions to science and technology. In 1999 Worthington and Quake united the possibilities of Quake’s breakthrough with the desire to enable ever greater biological discoveries and co-founded Fluidigm. Today the company’s integrated fluidic circuits (IFCs) offer rapid, efficient, highly parallel and reproducible analysis of up to hundreds of genetic markers across thousands of DNA samples in just hours, rather than days or weeks, all the way down to the level of the individual cell.

The Fluidigm microfluidic technology supports genomics-based applications such as single-cell gene expression, high-throughput SNP genotyping, protein expression analysis, digital PCR, mutant detection and more. Additionally, two of the company’s instruments have proven to be workhorses within the life science industry: the Biomark™ HD and C1™systems.

Originally introduced in 2006 and updated in 2011, Biomark HD stands alone in the world of analytical instrumentation as a multiapplication platform without compromise, providing high quality results for every experimental approach. Since its debut in 2012, the C1 system has been revolutionizing single-cell research by enabling researchers to rapidly and reliably isolate, process and profile individual cells for genomic analysis.

C1 researchers study cell differentiation, measure individual cell responses to specific stimuli, verify critical disease biomarkers, validate RNAi knockdown and conduct candidate drug screens. Select BioSciences, an independent research company, said in its January 2011 report on Single Cell Analysis (SCA) that “Fluidigm is the leading microfluidics company for SCA…[and] Fluidigm is well-positioned to become a leader in SCA.”

By 2013 the company’s position in the single-cell movement was clear: Independent research firm DeciBio in its August report entitled Single Cell Genomics (SCG): Market Size, Segmentation, Growth, Competition and Trends identified Fluidigm as the “undisputed leader in single-cell genomics.”

In 2014 Fluidigm expanded into single-cell proteomics with its acquisition of technology leader DVS Sciences, the inventor of CyTOF®, a multi-parameter single-cell protein analysis system. The CyTOF 2 mass cytometer analyzes antibody and metal complexes using an innovative method of atomic mass spectrometry, and solidifies Fluidigm’s position at the leading edge of single-cell biology.

Today more than 400 people work for Fluidigm worldwide. The company works with more than 1,000 valued customers pioneering the field of single-cell biology or using applied genomics in industrial applications to improve and protect our food supplies, track samples in the world’s largest biobanks and in general provide faster, more accurate, lower cost workflows to help improve people’s lives.

Fluidigm is headquartered in South San Francisco, California, with sales and sales support operations from Beijing to Tokyo to Paris to San Francisco. Fluidigm conducts its Research and Development activities and manufactures its instruments, integrated fluidic circuits and reagents in its factories in South San Francisco, Singapore and Markham, Ontario.

1999

Founding of Fluidigm Corporation (originally Mycometrix) to commercialize IFC technology developed in the Caltech laboratory of biophysicist Stephen Quake, PhD.

2003

Launch of the TOPAZ® System for Protein Crystallization, including integrated fluidic circuits (IFCs) that assemble 768 crystallization conditions in parallel and instrumentation and software that automate the digital imaging and analysis of experiments.

2004

Development of intellectual property around a new class of IFCs referred to as Dynamic Array™ IFCs and of prototypes yielding as many as 9,216 parallel data points.

DVS Sciences, founded by Dmitry Bandura, Vladimir Baranov, Scott Tanner, and Olga Ornatsky, was spun out of MDS Sciex.

2005

Opening of a 15,000 square-foot IFC fabrication facility in Singapore

2006

Launch of the Biomark™ system for Genetic Analysis, a multi-application hardware/software platform based on Fluidigm Dynamic Array IFCs. Introduction of the Biomark™ system heralded a practical solution for ultra-sensitive detection by PCR.

Launch of the 12.765 Digital Array™ IFC to provide absolute counting of target molecules, often within samples as small as a single cell. The Digital Array™ IFC is the method of choice to achieve such quantification known as digital PCR, which had been too impractical for routine use until this product was available.

2007

Launch of high-throughput SNP genotyping on the Biomark system, enabling breakthroughs for the study of genetic variation within large populations.

Launch of the Fluidigm 48.48 Dynamic Array IFC that, for the first time in microfluidics, provided a matrixed chip architecture which enabled both a high density of experiments (2,304 per chip) and effective mixing of nano-volume scale fluids.

2008

Launch of the Fluidigm 96.96 Dynamic Array IFC which is capable of performing 9,216 simultaneous real-time PCR experiments in nanoliter quantities. This new generation IFC enabled life science researchers to achieve new levels of cost and logistical efficiency and flexibility, as well as comprehensive profiling from miniscule amounts of sample down to the scale of individual cells.

Launch of the Fluidigm EP1™ System for genetic analysis. This is Fluidigm’s most efficient system for high sample throughput SNP genotyping and end point digital PCR. It allows extremely low running costs and provides the easiest workflow for low to mid multiplex SNP genotyping.

Launch of the DVS Sciences CyTOF Single-cell Protein Analysis System technology which identifies proteins in individual cells by seeding them with antibodies that have metal labels. It uses an atomic mass spectrometer to measure the metal labels informing the researcher about the protein composition of the cell.

2009

Launch of the Fluidigm 48.770 Digital Array IFC, the highest density commercially available integrated fluidic circuit (IFC) to date. This IFC can test up to 48 individual samples at a time and automatically partition each of the samples into separate sets of 770 reaction chambers—delivering a total of 36,960 simultaneous digital PCR reactions.

Launch of the Fluidigm Access Array™ System specifically designed to support high-throughput re-sequencing, targeted enrichment, sample barcoding, and library preparation for sequencing using amplicon tagging.

2010

MIT’s Technology Review magazine selects Fluidigm Corporation as one of the top 50 most innovative companies in the world.

Launch of the reusable FR48.48 Dynamic Array IFC—the world’s first reusable bio-chip for the SNP genotyping market.

DVS Sciences Toronto manufacturing facility established.

2011

Launch of the Biomark™ HD Real-time PCR System, the company’s most advanced instrument for genomic analysis. The Biomark HD System provides the sensitivity and throughput needed to study gene expression down to the single-cell level—especially those who have limited amounts of sample or study rare populations of cells.

Fluidigm complete its initial public offering. Shares trade on The NASDAQ Global Market under the symbol “FLDM.”

Fluidigm Singapore factory achieves a manufacturing milestone, building and shipping more than 1 billion microscopic NanoFlex™ valves since its inception. Each NanoFlex valve is so small that it takes 10 of them to span the width of a human hair.

Launch of Fluidigm assays and primers optimized for the company’s integrated fluidic circuit technology. The products are marketed as Delta Gene™ Assays (gene expression), SNP Type™ Assays (SNP genotyping), and Access Array™ Target-specific Primers (target enrichment for next-generation sequencing).

Launch of the 192.24 Dynamic Array™ IFC, designed to genotype 192 samples against 24 SNP assays in a single run, providing 4,608 data points in just one hour.

2012

Launch of the C1™ Single-Cell Auto Prep System which revolutionizes single-cell research. The C1 enables researchers to rapidly and reliably isolate, process, and profile individual cells for genomic analysis. For the first time, single-cell researchers could extract, reverse transcribe, amplify, and ultimately detect and analyze cell activity using just one technology, reducing the variability caused by multi-platform technical errors.

Fluidigm China office opens.

The Broad Institute and Fluidigm launch the world’s first research center dedicated to accelerating the development of research methods and discoveries in mammalian single-cell genomics. The Single-Cell Genomics Initiative is a hub for collaboration among single-cell genomics researchers in many pioneering fields, including stem cells and cancer biology.

2013

Fluidigm and the Genome Institute of Singapore open the Singapore Single-Cell Research Centre opening the door for Asian biological discoveries. It is the first single-cell centre of excellence in Asia.

Launch of the DVS Sciences CyTOF 2 Single-Cell Protein Analysis System a multi-parameter single-cell protein analysis system which analyzes antibody/metal complexes using atomic mass spectrometry. The technology enables high-parameter single-cell protein analysis for applications in biological research.

2014

Fluidigm Completes Acquisition of DVS Sciences—Creating a Single-Cell Technology Powerhouse.

SOURCE

https://www.fluidigm.com/about/aboutfluidigm

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Big Deals in the Biotech-Supplier Venue: Is there More to Come in 2016? Illumina and Affymetrix

 

UPDATED on 3/28/2016

to Stick With Thermo Fisher’s Takeover Proposal

http://www.nytimes.com/2016/03/29/business/dealbook/affymetrix-to-stick-with-thermo-fishers-takeover-proposal.html?&moduleDetail=section-news-3&action=click&contentCollection=DealBook&region=Footer&module=MoreInSection&version=WhatsNext&contentID=WhatsNext&pgtype=article

UPDATED on 3/23/2016

Affymetrix Postpones Stockholder Meeting as Origin Ups Acquisition Offer; Board Backs Thermo Bid

 

UPDATED on 3/21/2016

Former Affymetrix Execs Offer to Buy Company in Alternative to Thermo Fisher Deal

NEW YORK (GenomeWeb) – Origin Technologies Corporation, founded by former Affymetrix executives for the purpose of purchasing the company, proposed today to acquire Affy for $16.10 per share in an all-cash transaction valued at approximately $1.5 billion.

The proposal comes about a week before Affy shareholders are scheduled to vote on a different deal, Thermo Fisher Scientific’s proposed acquisition of Affy for approximately $1.3 billion, which the boards of directors of both firmsunanimously approved in January.

According to a letter sent by Origin to Affymetrix today, its proposal represents a 75 percent premium to Affymetrix’s unaffected closing share price of $9.21 on the last trading day prior to the announcement of Thermo Fisher’s proposed acquisition.

Fully financed by SummitView Capital, Origin said its all-cash offer represents a 15 percent premium for Affy stockholders relative to the proposed transaction with Thermo, under which stockholders would receive $14.00 per share in cash.

As part of the offer, Origin also pledged to fund payment of the $55 million termination fee that would be due to Thermo under the terms of Thermo and Affy’s January agreement.

Wei Zhou, president of the newly formed Origin, wrote in the letter to Affy today that Origin strongly believes that its offer is superior to Thermo’s based on several criteria.

First, it offers substantially higher value to Affy’s stockholders, he said. Additionally, Origin believes it is in a better position to help Affy achieve its potential as a standalone, global company focused on genomics and proteomics. The deal would also offer an opportunity to acquire new technologies in the complete human genome sequencing space, Zhou wrote.

If the Origin-Affy merger goes through, Origin would have a separate option of combining with another company founded by Zhou in 2009, Centrillion Technology Holdings Corporation.

SOURCE

https://www.genomeweb.com/business-news/former-affymetrix-execs-offer-buy-company-alternative-thermo-fisher-deal

 

Reporter: Stephen J. Williams, Ph.D.

Both Fisher Scientific and Illumina have made huge deals in early January 2016.  These deals seem to be centered on a reinvigorated interest in high-throughput sequencing and microarray for biomarker determination and clinical diagnostics.

Thermo Fisher Scientific (TMO) Swallows Up Affymetrix (Santa Clara, California) (AFFX) in $1.3 Billion Deal

Thermo Fisher Scientific to Acquire Affymetrix

  • Strengthens Leadership in Biosciences and Genetic Analysis
  • Significantly Expands Portfolio of Antibodies and Assays for High-Growth Flow Cytometry and Single-Cell Biology Applications
  • Adds Complementary Genetic Analysis Products Serving Research, Clinical and Applied Markets
  • Offers Opportunity to Leverage Thermo Fisher’s Commercial and Geographic Scale
  • Creates Attractive Financial Benefits; Expected to be Immediately Accretive to Adjusted Earnings per Share (EPS)

WALTHAM, Mass. and SANTA CLARA, Calif.–(BUSINESS WIRE)–Thermo Fisher Scientific Inc. (NYSE: TMO), the world leader in serving science, and Affymetrix Inc. (NASDAQ: AFFX), a leading provider of cellular and genetic analysis products, today announced that their boards of directors have unanimously approved Thermo Fisher’s acquisition of Affymetrix for $14.00 per share in cash. The transaction represents a purchase price of approximately $1.3 billion.

“The acquisition of Affymetrix will strengthen our leadership in biosciences and create new market opportunities for us in genetic analysis”

Affymetrix’s technologies enable parallel and multiplex analysis of biological systems at the cellular, protein and genetic level, facilitating the transition of research tools into clinical and applied markets. The company’s products are used by customers working in life sciences and translational research, molecular diagnostics, reproductive health and agricultural biotechnology. Based in Santa Clara, California, Affymetrix has approximately 1,100 employees worldwide and maintains sales and distribution operations primarily in the U.S., Europe and Asia. The business, which has annual revenues of approximately $350 million, will be integrated into Thermo Fisher’s Life Sciences Solutions Segment.

“The acquisition of Affymetrix will strengthen our leadership in biosciences and create new market opportunities for us in genetic analysis,” said Marc N. Casper, president and chief executive officer of Thermo Fisher Scientific. “In biosciences, the company’s antibody portfolio will significantly expand our offering in the fast-growing flow cytometry market, and customers will have greater access to these products through our global scale and commercial reach. In genetic analysis, Affymetrix’s technologies are highly complementary and present new opportunities for us in targeted clinical and applied markets. For shareholders, we expect the transaction to create value by generating attractive financial returns, including immediate accretion to our adjusted EPS.”

Frank Witney, president and chief executive officer of Affymetrix, said, “Joining Thermo Fisher creates significant value for our customers, employees and shareholders. We will be able to build on our strong history of close collaboration with customers in our target markets by leveraging Thermo Fisher’s deep relationships, particularly in biopharma, as well as their global scale and leading presence in Asia-Pacific. We are excited about the opportunity to combine our portfolios and strengthen our position in high-growth markets such as single-cell biology, reproductive health and AgBio. Our employees will benefit by being part of an industry-leading company, which brings many opportunities for career growth and development. We look forward to working closely with the Thermo Fisher team to ensure a smooth transition and integration.”

Casper concluded, “We’re pleased to welcome our new colleagues from Affymetrix to Thermo Fisher. Frank Witney and the entire Affymetrix team have done a great job of strengthening the business, and we’re excited about the opportunity to leverage Thermo Fisher’s scale and depth of capabilities to build on that momentum and accelerate growth.”

Benefits of the Transaction

  • Significantly Expands Antibody Portfolio to Strengthen Leadership in Biosciences. Affymetrix’s eBioscience offering for cellular analysis will enhance Thermo Fisher’s leading biosciences capabilities. Specifically, the company specializes in a range of antibodies, multiplex RNA, and protein and single-cell assays. These technologies serve the fast-growing flow cytometry market segment as well as new high-growth applications including single-cell biology, immunotherapy and infectious disease research.
  • Adds Genetic Analysis Capabilities Serving Clinical and Applied Markets. Affymetrix adds complementary products in genetic analysis that are used in cytogenetics, genotyping and gene expression. The company’s innovative microarray platform will strengthen Thermo Fisher’s presence in certain clinical and applied markets, including reproductive health and agricultural biotechnology.
  • Offers Opportunity to Leverage Commercial and Geographic Scale. Affymetrix will benefit from Thermo Fisher’s access to the biopharma industry through its unique customer value proposition, as well as its world-class e-commerce capabilities and extensive customer channels. Thermo Fisher will also significantly extend the geographic reach of Affymetrix’s products by leveraging its market presence and infrastructure in Asia-Pacific, particularly China.
  • Creates Attractive Financial Benefits. The transaction is expected to be immediately accretive to Thermo Fisher’s adjusted EPS1, adding $0.10 of accretion in the first full year of ownership. Thermo Fisher expects to realize total synergies of approximately $70 million by year three following the close, consisting of approximately $55 million of cost synergies and approximately $15 million of adjusted operating income1 benefit from revenue-related synergies.

Approvals and Close

The transaction, which is expected to be completed by the end of the second quarter of 2016, is subject to the approval of Affymetrix shareholders and the satisfaction of customary closing conditions, including applicable regulatory approvals. Thermo Fisher intends to use cash on hand and short-term debt to finance the transaction.

Advisors

JP Morgan is acting as financial advisor to Thermo Fisher, and Wachtell, Lipton, Rosen & Katz is serving as legal counsel. Morgan Stanley is acting as financial advisor to Affymetrix, and Davis, Polk & Wardwell LLP is serving as legal counsel.

Use of Non-GAAP Financial Measures

In addition to financial measures prepared in accordance with generally accepted accounting principles (GAAP), we use the non-GAAP financial measures adjusted operating income and adjusted earnings per share. Adjusted operating income excludes restructuring and other costs/income and amortization of acquisition-related intangible assets. Adjusted earnings per share also excludes certain other gains and losses, tax provisions/benefits related to the previous items, benefits from tax credit carryforwards, the impact of significant tax audits or events and discontinued operations. We exclude the above items because they are outside of our normal operations and/or, in certain cases, are difficult to forecast accurately for future periods. We believe that the use of non-GAAP measures helps investors to gain a better understanding of our core operating results and future prospects, consistent with how management measures and forecasts the company’s performance, especially when comparing such results to previous periods or forecasts.

About Thermo Fisher

Thermo Fisher Scientific Inc. (NYSE: TMO) is the world leader in serving science, with revenues of $17 billion and approximately 50,000 employees in 50 countries. Our mission is to enable our customers to make the world healthier, cleaner and safer. We help our customers accelerate life sciences research, solve complex analytical challenges, improve patient diagnostics and increase laboratory productivity. Through our premier brands – Thermo Scientific, Applied Biosystems, Invitrogen, Fisher Scientific and Unity Lab Services – we offer an unmatched combination of innovative technologies, purchasing convenience and comprehensive support. For more information, please visit www.thermofisher.com.

About Affymetrix

Affymetrix technologies enable multiplex and simultaneous analysis of biological systems at the cell, protein, and gene level, facilitating the rapid translation of benchtop research into clinical and routine use for human health and wellness. Affymetrix provides leadership and support, partnering with customers in pharmaceutical, diagnostic, and biotechnology companies as well as leading academic, government, and non-profit research institutes in their quest to use biology for a better world. More than 2,300 microarray systems have been shipped around the world and more than 94,000 peer-reviewed papers have been published citing Affymetrix technologies. Affymetrix is headquartered in Santa Clara, California, and has manufacturing facilities in Cleveland, San Diego, Vienna and Singapore. Affymetrix has about 1,100 employees and maintains sales and distribution operations worldwide. For more information about Affymetrix, please visit www.Affymetrix.com.

Illumina (ILMN) Raises $100 Million with Amazon (AMZN)’s Bezos, Bill Gates and Others to Launch Pan-Cancer Test Company Grail

San Diego-based Illumina (ILMN), world leader in DNA sequencing technology, announced yesterday that it raised more than $100 million in Series A financing to start a new company, Grail, to develop a blood test to identify all types of cancers. Illumina was joined by ARCH Venture Partners, Sutter Hill Ventures, and Bezos Expeditions, run by Amazon founder and chief executive officer Jeff Bezos. Also joining was Microsoft co-founder Bill Gates.

Grail’s goal is ambitious, perhaps overly so. Illumina’s chief executive officer, Jay Flatley, told BloombergBusiness that Grail intends to create a “pan-cancer” screening test able to diagnose cancer at an early stage prior to symptoms. “This is a massive market,” Flatley said. “Depending on your assumptions, it’s somewhere between a $20 billion and $200 billion market opportunity.”

One simple reason for skepticism is that cancer is not a single disease, but numerous diseases that have a commonality of uncontrolled cell growth. Finding something in the blood that is common to all of them is unlikely, and developing a screening test to identify all possible cancerous mutations is ambitious, to say the least. On the other hand, if there’s any company in the world with the technology power to come up with a pan-screening test, it’s probably Illumina.

Other companies have developed “liquid biopsy” tests that use blood to detect cancers instead of, or as a supplement to, conventional biopsies. Guardant Health, for example, raised $100 million recently to fund its work, and Exosome Diagnostics recently raised $60 million.

Pathway Genomics in 2015 began offering a liquid biopsy test for early-stage cancer. The , however, dropped the hammer, questioning its reliability and indicating the test required regulatory approval. The FDA stated that there was not “any published evidence that this test or any similar test has been clinically validated as a screening tool for the early detection of cancer.”

Illumina’s Flatley argues that Grail plans to conduct DNA sequencing on 30,000 to 50,000 people over time as a way of building approval for its test. He also indicates that the test could possibly cost less than $1,000. That’s the current cost of being able to fully sequence the entire human genome using one of Illumina’s sequencers, although it is a complicated, expensive machine. However, prices are dropping dramatically.

Grail hopes to start a large-scale clinical trial in 2017. It also plans to have a single-cancer test available in 2017 as well. Optimistically, Flatley believes the pan-cancer test could be on the market in 2019.

To date, liquid biopsies are primarily used on patients who have already been diagnosed with cancer. They are generally used to narrow in on particular mutations in order to better select appropriate drugs, or to monitor treatment. Early-stage cancer detection has a number of complicating factors, including that all cells, not only cancer cells, shed DNA into the blood stream. Also, there are billions of possible mutations in each individual’s genome, not all of which are cancerous.

“As you age, you have mutations,” Luis Diaz, associate professor of oncology at Johns Hopkins, told The New York Times. Various structures in the body, including polyps, moles, and benign growths, also have similar mutations to tumors.

In order for Grail’s test to be really usable, it has to factor in the risks of false positives, which would cause patients significant stress with false cancer diagnoses, as well as the potential risk of unnecessary and potentially harmful biopsies, tests and treatments.

“Patients ought to be hesitant until there is really good data that this actually helps people,” Gilbert Welch, professor of medicine at Dartmouth and author of the book “Less Medicine, More Health” told The New York Times, “and they should remember that it could harm people.”

On the other hand, with the increasing power of gene sequencing technology and complex bioinformatics platforms, this could represent a paradigm shift in cancer diagnosis. “If this pans out,” Jose Baselga, physician in chief at Memorial Sloan Kettering Cancer Center, and head of Grail’s science advisory board, said to The New York Time, “this could be a real game changer.”

 

 

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Day One at #JPM16: Breakout sessions of 23andMe, Myriad Genetics, Genomic Health, and Alere, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Day One at #JPM16: Breakout sessions of 23andMe, Myriad Genetics, Genomic Health, and Alere

Reporter: Aviva Lev-Ari, PhD, RN

JP Morgan Healthcare Conference, Day One: 23andMe; Myriad Genetics; Genomic Health; Alere

Jan 11, 2016

a GenomeWeb staff reporter

 

the_westin_st._francis_hotel_san_francisco

the_westin_st._francis_hotel_san_francisco.jpg

Image SOURCE

Wikimedia Commons

 

SAN FRANCISCO (GenomeWeb) – The 34th Annual JP Morgan Healthcare Conference began here Monday with several life science research tools and diagnostic firms making presentations to investors and other attendees.

The following are capsules from the presentations and breakout sessions of 23andMe, Myriad Genetics, Genomic Health, and Alere. Coverage of Illumina’s presentation is available here.

SEE Detailed reports on

  • 23andMe;
  • Myriad Genetics;
  • Genomic Health;
  • Alere

https://www.genomeweb.com/business-news/jp-morgan-healthcare-conference-day-one-23andme-myriad-genetics-genomic-health-alere?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Daily%20News:%20Day%20One%20of%20the%20JP%20Morgan%20Healthcare%20Conference%20%E2%80%93%20Updates%20from%2023andMe,%20Myriad%20Genetics,%20Genomic%20Health,%20and%20Alere%20-%2001/12/2016%2011:20:00%20AM

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#JPM16: Illumina’s CEO on new genotyping array called Infinium XT and Bio-Rad Partnership for single-cell sequencing workflow, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

#JPM16: Illumina’s CEO on new genotyping array called Infinium XT and Bio-Rad Partnership for single-cell sequencing workflow

Reporter: Aviva Lev-Ari, PhD, RN

 

Illumina Unveils Mini Targeted Sequencer, Semiconductor Sequencing Project at JP Morgan Conference

SAN FRANCISCO (GenomeWeb) – Illumina today announced two new next-generation sequencing platforms, a targeted sequencing system called MiniSeq and a semiconductor sequencer that is still under development.

Illumina disclosed the initiatives during a presentation at the JP Morgan Healthcare conference held here today. During the presentation, Illumina CEO Jay Flatley also announced a new genotyping array called Infinium XT; a partnership with Bio-Rad to develop a single-cell sequencing workflow; preliminary estimates of its fourth-quarter 2015 revenues; and an update on existing products. The presentation followed the company’s announcement on Sunday that it has launched a new company called Grail to develop a next-generation sequencing test for early cancer detection from patient blood samples.

The MiniSeq system, which is based on Illumina’s current sequencing technology, will begin shipping early this quarter and has a list price of $49,500. It can perform a variety of targeted DNA and RNA applications, from single-gene to pathway sequencing, and promises “all-in” prices, including library prep and sequencing, of $200 to $300 per sample, Flatley said during the JP Morgan presentation.

SOURCE

https://www.genomeweb.com/sequencing-technology/illumina-unveils-mini-targeted-sequencer-semiconductor-sequencing-project-jp

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Novel Mechanisms of Resistance to Novel Agents

 

Curators: Larry H. Berstein, M.D. FACP & Stephen J. Williams, Ph.D.

For most of the history of chemotherapy drug development, predicting the possible mechanisms of drug resistance that ensued could be surmised from the drug’s pharmacologic mechanism of action. In other words, a tumor would develop resistance merely by altering the pathways/systems which the drug relied on for mechanism of action. For example, as elucidated in later chapters in this book, most cytotoxic chemotherapies like cisplatin and cyclophosphamide were developed to bind DNA and disrupt the cycling cell, thereby resulting in cell cycle arrest and eventually cell death or resulting in such a degree of genotoxicity which would result in great amount of DNA fragmentation. These DNA-damaging agents efficacy was shown to be reliant on their ability to form DNA adducts and lesions. Therefore increasing DNA repair could result in a tumor cell becoming resistant to these drugs. In addition, if drug concentration was merely decreased in these cells, by an enhanced drug efflux as seen with the ABC transporters, then there would be less drug available for these DNA adducts to be generated. A plethora of literature has been generated on this particular topic.

However in the era of chemotherapies developed against targets only expressed in tumor cells (such as Gleevec against the Bcr-Abl fusion protein in chronic myeloid leukemia), this paradigm had changed as clinical cases of resistance had rapidly developed soon after the advent of these compounds and new paradigms of resistance mechanisms were discovered.

speed of imitinib resistance

Imatinib resistance can be seen quickly after initiation of therapy

mellobcrablresistamplification

Speed of imatinib resistance a result of rapid gene amplification of BCR/ABL target, thereby decreasing imatinib efficacy

 

 

 

 

 

 

 

 

 

 

Although there are many other new mechanisms of resistance to personalized medicine agents (which are discussed later in the chapter) this post is a curation of cellular changes which are not commonly discussed in reviews of chemoresistance and separated in three main categories:

Cellular Diversity and Adaptation

Identifying Cancers and Resistance

Cancer Drug-Resistance Mechanism

p53 tumor drug resistance gene target

Variability of Gene Expression and Drug Resistance

 

Expression of microRNAs and alterations in RNA resulting in chemo-resistance

Drug-resistance Mechanism in Tumor Cells

Overexpression of miR-200c induces chemoresistance in esophageal cancers mediated through activation of the Akt signaling pathway

 

The miRNA–drug resistance connection: a new era of personalized medicine using noncoding RNA begins

 

Gene Duplication of Therapeutic Target

 

The advent of Gleevec (imatinib) had issued in a new era of chemotherapy, a personalized medicine approach by determining the and a lifesaver to chronic myeloid leukemia (CML) patients whose tumors displayed expression of the Bcr-Abl fusion gene. However it was not long before clinical resistance was seen to this therapy and, it was shown amplification of the drug target can lead to tumor outgrowth despite adequate drug exposure. le Coutre, Weisberg and Mahon23, 24, 25 all independently generated imatinib-resistant clones through serial passage of the cells in imatinib-containing media and demonstrated elevated Abl kinase activity due to a genetic amplification of the Bcr–Abl sequence. However, all of these samples were derived in vitro and may not represent a true mode of clinical resistance. Nevertheless, Gorre et al.26 obtained specimens, directly patients demonstrating imatinib resistance, and using fluorescence in situ hybridization analysis, genetic duplication of the Bcr–Abl gene was identified as one possible source of the resistance. Additional sporadic examples of amplification of the Bcr–Abl sequence have been clinically described, but the majority of patients presenting with either primary or secondary imatinib resistance fail to clinically demonstrate Abl amplification as a primary mode of treatment failure.

This is seen in the following papers:

Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Science. 2001 Aug 3;293(5531):876-80. Epub 2001 Jun 21.

and in another original paper by le Coutre et. al.

Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. le Coutre P1, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, Gambacorti-Passerini C. Blood. 2000 Mar 1;95(5):1758-66

The 2-phenylaminopyrimidine derivative STI571 has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr/abl fusion protein. The activity of this inhibitor has been demonstrated so far both in vitro with bcr/abl expressing cells derived from leukemic patients, and in vivo on nude mice inoculated with bcr/abl positive cells. Yet, no information is available on whether leukemic cells can develop resistance to bcr/abl inhibition. The human bcr/abl expressing cell line LAMA84 was cultured with increasing concentrations of STI571. After approximately 6 months of culture, a new cell line was obtained and named LAMA84R. This newly selected cell line showed an IC50 for the STI571 (1.0 microM) 10-fold higher than the IC50 (0.1 microM) of the parental sensitive cell line. Treatment with STI571 was shown to increase both the early and late apoptotic fraction in LAMA84 but not in LAMA84R. The induction of apoptosis in LAMA84 was associated with the activation of caspase 3-like activity, which did not develop in the resistant LAMA84R cell line. LAMA84R cells showed increased levels of bcr/abl protein and mRNA when compared to LAMA84 cells. FISH analysis with BCR- and ABL-specific probes in LAMA84R cells revealed the presence of a marker chromosome containing approximately 13 to 14 copies of the BCR/ABL gene. Thus, overexpression of the Bcr/Abl protein mediated through gene amplification is associated with and probably determines resistance of human leukemic cells to STI571 in vitro. (Blood. 2000;95:1758-1766)

This is actually the opposite case with other personalized therapies like the EGFR inhibitor gefinitib where actually the AMPLIFICATION of the therapeutic target EGFR is correlated with better response to drug in

Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs.Ono M, Kuwano M. Clin Cancer Res. 2006 Dec 15;12(24):7242-51. Review.

Abstract

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, including EGFR, HER2/erbB2, and HER3/erbB3, is an attractive target for antitumor strategies. Aberrant EGFR signaling is correlated with progression of various malignancies, and somatic tyrosine kinase domain mutations in the EGFR gene have been discovered in patients with non-small cell lung cancer responding to EGFR-targeting small molecular agents, such as gefitinib and erlotinib. EGFR overexpression is thought to be the principal mechanism of activation in various malignant tumors. Moreover, an increased EGFR copy number is associated with improved survival in non-small cell lung cancer patients, suggesting that increased expression of mutant and/or wild-type EGFR molecules could be molecular determinants of responses to gefitinib. However, as EGFR mutations and/or gene gains are not observed in all patients who respond partially to treatment, alternative mechanisms might confer sensitivity to EGFR-targeting agents. Preclinical studies showed that sensitivity to EGFR tyrosine kinase inhibitors depends on how closely cell survival and growth signalings are coupled with EGFR, and also with HER2 and HER3, in each cancer. This review also describes a possible association between EGFR phosphorylation and drug sensitivity in cancer cells, as well as discussing the antiangiogenic effect of gefitinib in association with EGFR activation and phosphatidylinositol 3-kinase/Akt activation in vascular endothelial cells.

 

Mutant Variants of Therapeutic Target

 

resistant subclones in tissue samples and Tyrosine Kinase tumor activity

 

Mitochondrial Isocitrate Dehydrogenase and Variants

Mutational Landscape of Rare Childhood Brain Cancer: Analysis of 60 Intercranial Germ Cell Tumor Cases using NGS, SNP and Expression Array Analysis – Signaling Pathways KIT/RAS are affected by mutations in IGCTs

 

AND seen with the ALK inhibitors as well (as seen in the following papers

Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib.

Hashida S, Yamamoto H, Shien K, Miyoshi Y, Ohtsuka T, Suzawa K, Watanabe M, Maki Y, Soh J, Asano H, Tsukuda K, Miyoshi S, Toyooka S. Cancer Sci. 2015 Oct;106(10):1377-84. doi: 10.1111/cas.12749. Epub 2015 Sep 30.

In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.

Nanjo S, Nakagawa T, Takeuchi S, Kita K, Fukuda K, Nakada M, Uehara H, Nishihara H, Hara E, Uramoto H, Tanaka F, Yano S. Cancer Sci. 2015 Mar;106(3):244-52. doi: 10.1111/cas.12600. Epub 2015 Feb 17.

Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib. Ou SH, Klempner SJ, Greenbowe JR, Azada M, Schrock AB, Ali SM, Ross JS, Stephens PJ, Miller VA.J Thorac Oncol. 2014 Dec;9(12):1821-5

Reports of chemoresistance due to variants have also been seen with the BRAF inhibitors like vemurafenib and dabrafenib:

The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF.

Watson IR, Li L, Cabeceiras PK, Mahdavi M, Gutschner T, Genovese G, Wang G, Fang Z, Tepper JM, Stemke-Hale K, Tsai KY, Davies MA, Mills GB, Chin L.Cancer Res. 2014 Sep 1;74(17):4845-52. doi: 10.1158/0008-5472.CAN-14-1232-T. Epub 2014 Jul 23

 

 

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