Simple Cancer Biomarkers are Inadequate to Enable Personalized Medicine

It seems that researchers are finding that using single cancer biomarkers to develop companion diagnostics (CDx’s) to be used with future targeted therapeutics is very challenging. An article in the November 15 issue of Genetic Engineering and Biotechnology News, called Traversing the Cancer Biomarker Labyrinth, by Kathy Liszewski, is a very interesting read.

Apparently progress in this field has slowed in finding clinically useful biomarkers for diagnostics and making other tests that guide doctors for disease prognosis and prediction. Researchers are using a variety of reductionist technical approaches that range from analysis of certain glycans, key microRNAs, and epigenetic changes, to big data analysis of massive data stores of genomic data to tease out more clues to what is going on in cancers.

Scientists seek to develop early detection blood tests that can detect cancers of interest.  Such a blood test could be considered a ‘liquid biopsy’ and might include a panel of a dozen or more miRNAs that represent a biomarker signature.  An oncologist might one day be enabled to quickly screen certain patients with a blood test that would help them diagnose, stage or predict the potential outcome of a cancer.

Achillion vs. Actelion More Biotech M&A’s to Come

Last week’s announcement by Swiss drug maker, Roche Holding AG, that it was buying biotech firm InterMune, Inc. for $8.3 billlion sparked speculation by industry watchers about who would be the biotechs that might be involved in the next round of M&As. InterMune makes a drug, Esbriet (pirefnidone) that treats a lung condition, idiopathic pulmonary fibrosis. Esbriet is approved in Canada and Europe. The drug has the potential to become a blockbuster seller. InterMune’s product would join Roche’s Pulmozyme and Xolair to build up its lung drug portfolio.

A number of names popped up such as Achillion Pharamaceuticals, Actelion, Puma Biotechnology, Intercept Pharmaceuticals, and others. Maybe people heard Achillian but were attracted to similar sounding Actelion.

  • Achillion Pharamaceuticals makes Phase II hepatitis C virus (:HCV) candidate, ACH-3102.
  • Puma Biotechnology is developing its Phase III breast cancer candidate neratinib, PB272.
  • Intercept Pharmaceuticals makes its phase II nonalcoholic steatohepatitis drug, obeticholic acid, OCA.
  • Actelion Pharmaceuticals makes a cancer drug to treat a rare form of non-Hodgekin’s lymphoma.

Some in the big pharma side are still holding out hopes of buying a biotech that can make their next blockbuster. So which will it be? Achillion? Actelion? Others? To be sure, we will need wait and see.

Pros and Cons of Sharing Personal Genomes on Social Media

I recently particpated in an online conference session held by NGS Leaders when CHI held its Beyond Sequencing conference in San Francisco recently on June 21, 2011. The session was moderated by NGSLeaders’ Eric Glazer and a panel of NGS experts.  The panelists included Kevin Davies, PhD.(Bio-IT World) Pillar Ossorio , PhD. (Univ. of Wisconsin), Johnathan Eisen, PhD, (UC Davis), and Kamamiesh (Kam) Patel, PhD. (Sandia National Labs).  This panel session was about “When People Share Their Genomes on Facebook.”  Both Kevin and Kam participated by telephone and the others were with a live audience in the meeting room.  The session used WebEx to link remote participants.

Kevin summarized the recent history of personal genomics services since the field was started by 23andme.com and deCode Genomics.  He pointed out that these services were marketed as services that enabled consumers to learn much about their genetic make up.  The services just provide information that might help people learn more about their risk for common disease or for geneology.  The customers’ genetic information is not to be used as a diagnostic. While the technology is initially based on microarrays and SNPs, some companies hoped to use NGS when the cost gets low enough.  However, Kevin said that the future of personal genomics is still in the hands of the FDA to decide on guidance to the industry.  Johnathan predicted that we will see a lot of push inside of genomes and personal microbiomes.  Microbiomes are the total kinds of microscopic things that live in or on our bodies.

As the discussion turned to social media, Kam said that the social media giants have big potential uses for health information.  A person could meet with their doctor, then the doctor could later access the person’s Facebook page and follow the progress of a treatment regimen.  But there are pros and cons to watch out for such as exploiters and cost issues.

Johnathan spoke about ‘crowd sourcing’ would be useful for health information.  He said that Facebook is only partly open.  He noticed a new push for open science such as to post lab notebooks on a social media site.  As for citizen science, he predicted that personal genomics, open science projects and citizen science will merge together.  When that happensm then anybody can make or use the information for their own open science projects.

A big question is who owns the personal genetic information held on social media sites.  Pillar, a lawyer, said that  we can think about this in terms of copyrights and patents.  She said that for example, when I get genetic information, I might just get a license for personal use, — it might be limited or unlimited.  The media site rules migth determine who can use the information, etc. At least we have the GINA law to protect our rights regarding employment and insurance discrimation.  However, she thinks that much of this is unknowns.  Pilliar said that the courts would likely say that if you put your genetic information on a public social media site, you are effectively giving away information to the public domain.  She said that people need to be educated about the subject so people would know who should participate.  She said that George Church has a screening process to weed out ignorant people.  He makes applicants take a genomics class and his program has a high cost.

Eric asked the panel when might clinical use will happen or become routine.  Johnathan said that technology will happen soon, but he did not know when clinical practice will happen.  Kevin said that the clinical use of personal genomics is happening now and cited the case of the boy from Wisconsin who was helped by NGS based diagnostics.  He said that there is a huge amount of genetic medical education that is needed.  Pillar said that she believes that the clinical context will take some time to work out.  My take on personal genomics and social media is that we are still in the early early days.

Biotechs Seek Opportunities with Social Media, FDA Still Murky…

On 6/16/11, I attended the BioConference Live interactive online-only life science conference and attended the Panel Discussion titled, “Social Media in Regulated Industries: What are the Opportunities and where is the line?”  I thought I would share some the interesting points brought up during the discussion.  Panelists included Moderator Tina Baumgartner from Accella Group, Pamela Lund from PL Interactive, and Lianne McLean and Mya Thomae from Myraqa.

Baumgartner said that some of the opportunities in social media are the ability to “listen to customers, recruiting employees, attracting funding, and increasing visibility.”  She discussed three of the common misconceptions of social media, which include that it is primarily a tool for marketing and PR, it is too complicated and time consuming, and it has the same regulatory compliance risk as traditional PR and advertising.  None of which are true, according to Baumgartner.

McLean discussed a number of challenges to marketing in a regulated environment such as companies are only allowed to promote their product for the legally approved label and they must report adverse reactions.  She also pointed out that “the FDA’s regulatory stance has been unclear.”  Apparently, the FDA has been promising a guidance document since 1996.  In the meanwhile, the FDA has been issuing warning letters to companies that they think have crossed the line.   In July 2010, the FDA sent Novartis a letter issuing four violations for its “Facebook Share” widget saying among other things that it did not present a balanced viewpoint of its leukemia drug, Tasigna.

One of the attendees asked the panel, “will there be regulatory documents coming soon from the FDA?”  The answer was “not really.”  Another attendee asked, “what is the time horizon of widespread adoption of social media?”  Panelist McLean said “in the next couple of years or so.”  She also said that “pharma companies would adopt more quickly than diagnostic companies.”

Next Gen. Sequencing for Dx – Exome v. Whole Genome?

While I was at CHI’s Molecular Medicine Tri-Con in San Francisco last week (Feb 23rd), I had a chance to sit in at a discussion table at the end of the day.  The topic at Table 6 was about diagnostic applications that used next generation sequencing (NGS).  About 16 people discussed the pros and cons of targeted resequencing versus whole genome sequencing. Karl Voelkerding M.D.,(Assoc. Professor, Pathology, Univ. of Utah; Medical Director, Advanced Technology and Bioinformatics, ARUP Laboratories), moderated the discussion. Karl said that NGS is being applied to multi-gene panels, exomes and whole genomes in clinical research and diagnostics. Each approach has different costs and complexity of data analysis and interpretation.

NGS for Multi-gene Panels v. Whole Genome
Karl started off by talking about multi-gene panels and NGS. Karl briefly talked about using multi-gene panels and Marfan Syndrome.  He said that the challenge involves sample preparation and noted that Fluidigm has a workable solution for this.

He asked the group “What’s being seen in Europe?” A person from Europe said that he has seen targeted NGS vs. whole genome NGS used by a fee-for-service company in Europe.  A person from Genomic Health said that, “if cost is not an issue, it’s OK to use whole genome.  But otherwise it’s better to use targeted resequencing.”  Karl said that at his lab, it takes over a year to do a CE- based multi-gene sequence [ vs. NGS].

Others at the table asked about costs.  The person from RainDance said that they have an in-solution capture method that could reduce costs.  Karl said that even there, there are non-trivial labor costs.  He said that “Some commercial companies do use robatic liquid handlers to reduce cost.”

Scenarios, Approaches, Costs
He said that this area is a moving target.  Amplified appproaches in multi-gene panels increase specificity for up to ten genes.  Otherwise if over ten genes, it takes many months of CE sequencing work. Researchers need to develop a special workflow for this type of CE- sequencing.  Karl said “An elusive goal is to make sequencing work like PCR.”  They are not there yet.

One person asked about simplifying the data content in a database by choosing some data as benign.  Karl said that academics are randomly updating their data by using a grad student or even an undergrad student.  But this approach gives inconsistant data quality.  He said that some commercial-based databases use more regularly scheduled updating.

He said that you need to ask the question “Are the genes associated with pathology?  Some genes are benign, some others are linked to disease.  We need to know, over time, what data items get classified as a changed data set.”
Some companies do targeted resequencing as a business and make IP from the database content. The database tells what is benign or what is something else.

A consultant asked “It would be interesting to see what in the database is predictive.”  Karl said “Extract the DNA, do PCR, do CE-seq, and analyze.”
The consultant also asked “What if you do NGS, then find genes, then pass data on to CE-seq to verify for Dx accuracy?” Karl said “Some research corelabs do exome sequencing for genome sequencing.  NHGRI is good with that approach.  He does 30x coverage at his lab.

Another person asked “What is the control level for false positives?
Karl said that, downstream, it depends on technologies used such as mass spec, v. NGS v. CE sequencing v. PCR.  Karl mentioned that the American College of Cardiology considered testing for hypertrophic cardiomyopathy (HCM)  and asked “Should we do multi-gene testing”  They test by using using echocardiograms.  Karl give the statitics for WW incidence.

So with the exome v. whole genome question. Karl asked, “When can you use gDNA for Illumina. The workflow is to do DNA sonograph, do Agilent Bioanalyzer 2100 to get total DNA, do qPCR to get fragment library which can go to the SOLiD or to the Illumina cluster [for HiSeq2000].

The sequencing workflow is:

  • Day 1 do gDNA
  • Day 2 do qPCR,  then transfer to Cbot
  • Day 3 run the HiSeq2000 at 2×100 for 8 days
  • Then run SeqTest, run QSeqTest, then output in Qfile format

Karl said it takes 105 days from start to end.

He said that, if you do exome sequencing, you need to do a purification step at the beginning, which adds 3-4 days to the workflow, but the exome sequencing is at a lower cost. Karl said the his lab is hooked up to the Univ. of Utah’s cluster computer and can do a data alignment in 1-day.  The cluster computer at the Univ. of Utah is also HIPPA compliant for privacy.

So cost drives exome sequencing. Karl said that “When doing exome sequencing you are doing a lot less sequencing, but you do more sample preparation.  You sequence on 2 lanes v. on 8 lanes [on Illumina].

Some List Prices
Karl gave some cost numbers.

  • For whole genome sequencing it costs $10K  with all reagents, including for library preparation.
  • For exome sequencing, it costs $1,200-$1,300 at 200X to 900X coverage.

So an answer for supporting multi-gene sequencing is to use exome sequencing of all genes in a panel.  e.g. Broad can sequence 2000 exomes per week. They streamlined a special workflow for this. Anyway, at the end of the day, you need to do down stream validation.

Consent Approaches that Should be Considered
A woman asked, “But in the clinical environment, what if you find other genetic information?, Some other genetic information?, Do you not tell the clinician?”
Karl said that “the key is informed consent.”  He said “ARUP is developing a tiered consent process — its mostly used for pediatrics now. So if they set out looking for one genetic area, but what if they find something else?  They age-level at age-14 for consent.”

Karl gave an example about the rare disease area at the NIH..  The NIH does exome sequencing.  Their success rate is 20% to identify a suspicious gene.  “So why just 20% with de novo mutations?”  He said that they are using exome sequencing and they just use a small population.  He mentioned a paper in Nature Genetics involving a group in the Netherlands  that saw a lot of power in NGS of a child that is an alternative to use laborious CE sequencing.

Karl said that the items not covered in the consented area are marked off.  He said that this is usually done in laboratory medicine.  When it comes to a recessive gene, the answer is often guided by family history.  Therefore “consent with tiering” is the way to be able to manage what diagnostic information is delivered to clinicians.  Karl wrapped up the discussion by saying that “NGS is pushing the envelope!”

Recent AMP Meeting Brings Signs of Life to McEnery Convention Center

The Association for Molecular Pathology’s annual meeting was held at the McEnery Convention Center in San Jose on November 18 and 19, 2010. This impressive meeting included about 319 vendor exhibits, many poster exhibits, and numerous plenary talks about molecular pathology and diagnostics.

The first session that I attended was the “Single Cell Analysis Of Circulating Tumor Cells In Cancer.”  Stefanie Jeffrey, MD, at Stanford University School of Medicine discussed single cell analysis of circulating tumor cells in cancer.  She talked about the 20 most commonly expressed genes, CTC’s grown in vivo, and FAST (fiber array scanning technology).

I listened to Madhuri Ramanathan from the University of Medicine and Dentistry in New Jersey who gave a talk about autism.  She discussed the percentage of pro-inflammatory genotypes. In another session Betty Wong, MS, at Sunnybrook Health Sciences Centre in Canada discussed the search for functional polymorphisms in the vitamin D binding protein gene, Gc.  She said that Gc was discovered in 1959 and named Group-specific component or Gc.  She said the objective was to search for functional DBP gene polymorphisms.  The study population was 66 percent Hispanics, 23 percent African-Americans, and 11 percent Europeans or other descent.  The methodology was denaturing HPLC and sequencing, etc.  The results were 24 different DBP gene variations in their 2-tail sample.  DBP is a highly polymorphic multifunctional protein.  Very little is known about the molecular variations responsible.

The size of the vendor exhibition suggested to me that business might be picking up in the molecular diagnostic product space.  Companies such as Roche Diagnostics, Illumina, Abbott Molecular, Illumina, Agilent, Qiagen, Siemens and others were there. Maybe 2011 will become a growth year for these vendors.

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