This article was originally published on Assay Depot blog.

In the world of drug discovery, pharmaceutical companies face a very sobering statistic – more than 90% of the drugs that reach clinical testing will fail. This high failure rate is not only a major financial concern for the pharma industry, but it also negatively affects the millions of patients that are sick and desperately waiting for new medicines. Reducing the clinical failure rate is a critical step in creating a more successful and sustainable pharmaceutical industry.

Researchers in pharma/biotech and academia faced a similar challenge during the late 1980s and early 1990s with AIDS/HIV. At that time, the scientific community was able to rapidly and successfully develop several anti-HIV drugs thanks, in no small part, to the use of pre-competitive research collaborations. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA), writes, “precompetitive research is a subset of translational research that focuses on improving the tools and techniques needed for successful translation, and not on development of a specific product.” In a precompetitive collaboration, a variety of different organizations (that typically would compete with each other) work together or share information. For AIDS/HIV research, partners that worked together precompetitively included pharmaceutical and biotech companies, academic research centers and government research institutes.

Pharmaceutical companies have historically done all of their drug discovery research in house. But in the last 10 years, it has become increasingly clear that the pharmaceutical industry must change its research model if it is to remain viable. Challenges facing the industry include:

  1. Increasing cost of research coupled with abysmal rates of clinical success
  2. Expiration of patent protection leading to loss of exclusivity (the so-called patent cliff)
  3. Competition from biosimilars and generics

Precompetitive Collaboration – A Strategy for Success

To address these challenges, some pharmaceutical companies are, for the first time, engaging in precompetitive partnerships with other pharma competitors, with government organizations and with academic research centers. For example, the large pharma company GlaxoSmithKline recently formed a precompetitive collaboration with the Wellcome Trust Sanger Institute and the European Bioinformatics Institute to establish the Center for Therapeutic Target Validation (CTTV). The three organizations will pool resources to discover new potential drug targets that all of the partners will be able to access.

Precompetitive Collaboration
Precompetitive Collaboration is rapidly becoming a necessity in drug development (Image Credit: NIH.gov)

Similarly, the US National Institutes of Health (NIH) launched a precollaborative effort called the Accelerating Medicines Partnership (AMP) to identify efficacy and safety issues for compound collections that serve as the starting points for many new drug discovery projects. By working precompetitively to identify compound liabilities early in the research process, it is hoped that everyone will benefit from reduced clinical failure rate.

Additional precompetitive partnership examples include the Innovative Medicines Initiative (IMI) in Europe, the Critical Path Institute (CPI) in the US, the Structural Genomics Consortium (SGC) and Oxford University’s Target Discovery Institute (TDI). These partnerships are specifically geared toward translational research that will lead ultimately to the commercialization of new medicines.

Pharmaceutical companies and other large research organizations are beginning to work together precompetitively in other ways as well. Pfizer, AstraZeneca, the US National Cancer Institute and a host of other biotech, pharma and academic organizations have worked together with Assay Depot to create preclinical research marketplaces that share precompetitive information. Each Assay Depot client has its own private research marketplace but the underlying supplier and service databases are shared precompetitively. In 2015, some of the pharma companies will begin sharing supplier ratings as well.

Precompetitive research partnerships can, at times, be difficult to manage owing to the size and bureaucratic nature of large research partners. At times there are also legal challenges involving intellectual property rights that are often difficult to overcome. Nevertheless, the pooling of resources early in the drug discovery process, before a drug candidate has been selected for the clinic, should have an outsized effect on pharma productivity, leading to both increased innovation and reduced costs.

That said, it is important to understand that the time to act and establish precompetitive collaboration is now; as Janet Woodcock says in her article, “(T)he success of the drug development enterprise over the next decade may be at stake.”

This week witnessed a horrifying plane crash in Ukraine. Another Malaysian Airlines flight went down – this time shot down by a missile. Almost 300 lives were lost in this crash. Among the people killed on this flight was a group of AIDS researchers, traveling to the International AIDS Conference to be held in Australia. The entire AIDS research is in a state of shock. “These were men and women who had dedicated their own lives to saving the lives of others, and they were taken from us in a senseless act of violence,” said President Barack Obama at a White House news conference.

Here’s a roundup of other articles and news on genomics, medicine, business and policy from this week.

sciberomics roundup genomics
Sciberomics Weekly Roundup (Image Credit: www.dhs.gov)

Science and Medicine

Malaria and resistance to drugs

Resistance is an emerging problem for drugs used to treat malaria. Newer, more effective approaches are necessary to counter this scourge. Now, researchers from Australia report in a recent study published in Nature about a protein designated PTEX that can form a novel drug target against malaria.

Gene Therapy and the heart

A study published this week demonstrates that ordinary cardiac muscle cells can be converted into specialized cells that beat steadily. These cells were converted by using a gene therapy procedure. If successful, this procedure may replace implanted electronic pacemakers for cardiac patients with rhythm abnormalities.

We choose our friends wisely!

It has always been a mystery as to how we “choose” friends. Now genetics or genomics may have the answer. Or at least, an answer. A recent study using genome-wide association studies (GWAS) shows that we pick friends who have more DNA in common with us than those we do not. Friends are as similar genetically as fourth cousins (~1% genes similar).

Gut microbiome and disease

Our gut is home to hundreds of thousands of microbes that are increasingly being recognized as being important in maintaining our health. However, the question still remains whether sequencing the gut microbiome is of any value in predicting the health. This article discusses how we can detect changes in our health by looking at our microbiome.

Clinical Studies

New Alzheimer’s Trial

In partnership with Banner Alzheimer’s Institute from Phoenix, AZ, Novartis will conduct a clinical study to test experimental drugs for patients with Alzheimer’s who are genetically predisposed to the disease but without symptoms. The two test drugs will target the amyloid protein that accumulates in the brains of Alzheimer’s disease patients. This study will be funded in part by the National Institutes of Health, through a $33.2 million grant.

Regulatory

Approval for CombiMatrix test

The molecular diagnostics company, CombiMatrix Corporation recently developed a chromosomal microarray analysis (CMA) test that can identify development disorders in children with developmental delays, birth defects, physical deformities or autism or autism spectrum disorder. This test was conditionally approved by the New York Department of Health for patient samples.

Business

Translation of Genomics - Illumina buys Myraqa

The sequencing giant Illumina recently acquired Myraqa, a consulting firm that specializes in companion diagnostics. Experts believe that this deal will strengthen Illumina’s capabilities to take genomics into the clinic. Myraqa is expected to provide Illumina with expertise in regulatory, quality, clinical, biostatistics and development, focusing on regulatory strategy and application support.

What a week! I spent most of it at the 2014 BIO International Convention and truly enjoyed the feeding frenzy. Sessions covering biopharmaceutical companies, business partnering, new therapies, science, the business of science, talks, panel discussions, high-profile keynotes by Richard Branson and Hillary Clinton, exhibitor sessions, receptions, and watching World Cup football (soccer) matches – there was so much to listen to, so much to learn, so much to think about.

Sciberomics Science Biotech BIO2014
Former Secretary of State Hillary Rodham Clinton at the Keynote Luncheon, BIO2014 with Jim Greenwood, President and CEO of BIO (Image by author)

Towards the end of BIO2014, the Scientific American WorldView session featured a thought-provoking discussion on the biotech and life sciences development on the global stage. David Brancaccio, host of Marketplace Morning Report moderated this session. It was here that the latest issue of Scientific American worldVIEW was released.

Biotech San Diego BIO2014
David Brancaccio, host of Marketplace Morning Report at the BIO2014 Scientific American worldVIEW super-session (Image by author)

In addition, at Sciberomics, I have posted articles that I wrote while covering sessions at #BIO2014.

Sciberomics

Bioethics of Compassionate Use of Drugs

Drug Development – A Bioethical Minefield

Future of Cancer Therapeutics

Are Public-Private Partnerships The Way Forward?

Here’s a roundup of other articles and news on science, medicine, and policy from this week.

Science and Medicine

California governor Jerry Brown signed into law a state budget allocating $2 million for California Blueprint for Research to Advance Innovations in Neuroscience (Cal-BRAIN) project. This project will be run in coordination with the national Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative.

We are so “connected” to our cellphones today that phones now carry the microbiomes of their owners. Read more in the original study on microbiome and cellphone.

In a recent study published in the journal Nature, researchers have developed a vaccine against brain cancer and tested it in mice. This vaccine targets a specific mutation of isocitrate dehydrogenase 1 – IDH1, found in a subgroup of patient with the brain tumor, glioma. Studies in mice show that this vaccine can prevent tumor progression.

A new study shows that an implant into the brain of a paralyzed person helped him move his hand with the power of thought.

UK has revived an old competition and the people voted on what area of science this competition should cover. Antibiotic resistance was the people’s choice. Known as Longitude Prize, this initiative involves a prize of £10 million ($17 million).

A recent NPR news article talks about CRISPR, a new technology that allows editing the genome.

Business

The pharmaceutical giant Roche and startup Stratos Genomics will now collaborate to develop a method for single molecule sequencing of DNA fragments using protein nanopores.

That is all for this week. Now, it is time to ruminate on everything that went on this week. And I'm looking forward to a quiet weekend, watching football matches from the round of 16.

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Even with major advances in biomedical sciences over the past decade, we have not succeeded in “curing” a number of diseases. These diseases remain an unmet clinical need and require development of new therapeutics. Today, pharmaceutical and biotech companies and, to some extent, academia are relentlessly pursuing drug discovery and development programs. However, a majority of the drug candidates fail in late stages, mainly due to lack of efficacy. One way to prevent failures of experimental drugs in late stages is to choose “appropriate” targets for drug development.

Appropriate targets for a particular disease are those that drive the disease and can slow or reverse the disease if they are manipulated. Once these targets are identified, they need to be validated rigorously and then used for drug development. And this is a daunting task. The scientific community, specifically the NIH and pharmaceutical companies recognize that this challenge is too great for any of these organizations to achieve by themselves.

Novel Application of Public-Private Partnerships

Out of this realization was born a unique public-private partnership. This partnership was established in February 2014 to facilitate identifying and validating potential druggable targets for subsequent drug development. It is a partnership between government organizations (the National Institutes of Health, NIH and the Food and Drug Administration, FDA), 10 biopharmaceutical companies, and numerous non-profit organizations. This is the Accelerating Medicines Partnership (AMP).

AMP and other public-private partnerships
Accelerating Medicines Partnership (Image Credit: NIH)

A super-session at BIO2014 on Wednesday, June 25, 2014 titled “AMP-lifying Innovation: NIH, Patient Organizations & Leading Biopharma Firms Mobilize to Tackle Tough Diseases” discussed this partnership. This session featured NIH director Francis Collins, the force behind the AMP program; Jan Lundberg, president of Lilly research laboratories; and Meryl Comer, president of the Geoffrey Beene Foundation.

Public-Private Partnership
Panel at the 2014 BIO International Convention featuring (from L to R): Kay Holcombe, Jan Lundberg, Meryl Comer, and Francis Collins. (Image: by author)

Kay Holcombe, senior vice-president of BIO introduced the session. She acknowledged the huge challenge we face in developing effective cures for diseases. Comparing this to President John F. Kennedy’s goal of sending a man on the moon, Holcombe said, “Biopharmaceutical R&D and the challenge of our goal, which is to prevent, treat or cure 7000 diseases…is the moonshot of our life”.

However, Lundberg, who is a member of the executive committee of AMP believes that these public-private partnerships “will bring great minds together to help solve tough biomedical challenges and thus accelerate breakthroughs for patients.”

In the initial phase, AMP has listed three specific disease areas to work on:

  1. Alzheimer’s disease
  2. Type II diabetes
  3. Autoimmune diseases (specifically rheumatoid arthritis/systemic lupus erythematous)

For this stage of the partnership, AMP plans to invest $230 million. There are plans to expand the budget and the disease areas tackled after a review of the early phase. Collins is optimistic about the success of AMP. In addition to identifying and validating biomarkers for drug development, he hopes that researchers will work with the FDA “from the beginning to ensure a viable clinical path forward for biomarkers”.

But there have been other public-private partnerships that have not been successful. How is AMP different then?

Lundberg believes that AMP will succeed where others have failed because of the clear goals and deliverables that have been defined here. Moreover, he praised the leadership of Francis Collins and the commitment of the team, which according to Lundberg will make a difference.

“We are committing publicly to make this a success,” announced Lundberg. “I promise!”

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The tide is turning. Finally!

It has been four decades since the initiation of President Nixon’s “War on Cancer”, but never have the signs for victory looked so encouraging. This is an exciting phase in cancer research, so much so that some in the field are even using the “c” word. Cure!

So what is happening in the world of cancer therapeutics? And where are we headed? This was the topic of the Super Session: “A New Paradigm in Oncology Treatment” on Tuesday, June 24, 2014 at the 2014 BIO International Convention.

The thought-provoking discussion in this session reviewed current approaches and obstacles in oncology treatment, and discussed the way forward. Moderated by Susan Schaeffer of BioCentury, the panelists included:

  1. Ronald DePinho, MD Anderson Cancer Center
  2. Peter Lebowitz, Janssen Pharmaceutical Companies of J & J
  3. Bahija Jallal, AstraZeneca and MedImmune
  4. Robert Hugin, Celgene Corporation
  5. Jeff Allen, Friends of Cancer Research
Big Data, Cancer Therapeutics
Panelists at the Super Session "A New Paradigm for Oncology Treatment" (from L to R): Susan Schaeffer, Ronald A. DePinho, Peter Lebowitz, Bahija Jallal, Robert Hugin, Jeff Allen (Image Credit: BIO via Flickr)

Advances in Cancer Biology and Medicine

Developments in the omics fields have enabled scientists to molecularly characterize different cancers. Since each person’s cancer is different, the ability to profile a cancer is proving to be a valuable tool in the clinician’s armamentarium. In addition, we are witnessing the rapid development of newer targeted drugs. In the year 2012, the US Food and Drug Administration approved 39 targeted drugs for cancer (18 in the year 2013). Owing to these factors, oncologists can now develop personalized medicine approaches to treat cancer patients.

During the panel discussion, Peter Lebowitz agreed that better understanding of the disease biology has driven this progress; however, he hopes that technological advances would help us, especially to understand the tumor microenvironment, since that is crucial for cancer growth and maintenance.

Cancer Immunotherapy

With the advent of successful immunotherapy, the possibilities for cancer therapeutics have expanded even further. The success of immunotherapy over the past few years is just becoming obvious; it has succeeded in prolonging disease-free survival in patients with aggressive malignancies, such as non-small cell lung cancer and melanoma. Previously, clinicians rarely saw such durable responses with targeted therapies.

“Immunotherapy is definitely transforming the way we look at cancers,” said Bahija Jallal.

Ronald DePinho is excited by the success of immunotherapy and believes that it is the best approach for solid tumors, which are highly heterogeneous. However, he feels that we cannot entirely overlook targeted therapy. According to both DePinho and Robert Hugin, the ideal approach would be to use combinations in ways that produce synergies.

Regarding the use of immunotherapy, Lebowitz had a word of caution. “Often our dogma gets us in trouble” he quipped.

Lebowitz insisted that we should study and understand how each therapy acts, before using combinations in the clinic. This would prevent counter-productive effects of either therapy on cancer, when administered together.

Novel Approaches to Clinical Oncology

With better disease understanding, clinicians are matching targeted therapies to cancers. It is clear now that the one mutation-one drug paradigm for treating cancers is a gross over-simplification and does not work in the clinic. Successful cancer treatment requires the use of a panel of biomarkers to identify effective therapy. Generating these biomarker panels is possible due to newer technologies in the fields of genomics and proteomics. Further, in order to identify effective therapeutic options, innovative algorithms are required that account for the complexity of cancer and make predictions.

Apart from therapies, the field of clinical cancer medicine is shifting towards innovative clinical trials, such as the recent Lung-MAP trial – the first precision medicine trial from the National Clinical Trials Network. This is a multi-drug, biomarker-driven clinical trial for patients with advanced squamous cell lung cancer that will be conducted under a public-private collaboration. Such emerging public-private collaborations may hold the key to future success in developing disease-targeted therapies.

The world of cancer research, academia and industry, represents an ecosystem. The key to success in this ecosystem is collaboration – integrating research data and clinical data, and sharing it freely between academia and industry. This synergistic collaboration will benefit both clinicians and researchers – to draw conclusions, to facilitate clinical decision-making, and to drive research.

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Consider a case where a patient has a disease with high mortality and no effective treatment available. A new experimental drug is now being tested in a clinical trial. However, this is a randomized clinical trial, which means that it will have a treatment group and a placebo group (that does not get the actual drug). Is it really ethical to include a placebo group in case of a disease with no other treatment options? Are we effectively condemning this and many other patients to death by assigning them to the placebo group – albeit randomly?

In such cases, clinical trial design presents a major ethical dilemma in the area of drug development. This and other ethical dilemmas were discussed at length at a special session “The Bioethics of Drug Development – You Make the Call!” on Monday, June 23, 2014 at #BIO2014 the 2014 BIO International Convention.

Una Ryan from Bay Area BioEconomy Initiative feels that the “old way is broken”. A previous advocate of the randomized control trial, she thinks that in the era of big data, it is possible to design open-label trials with no placebo controls and yet draw meaningful conclusions by comparing data with historical controls (control groups from previous studies and from clinical data on the disease).

Richard Moscicki, Deputy Center Director, Science Operations at the US Food and Drug ADministration (FDA) agrees that randomized control trials may not always be the best way to conduct trials but in some cases, are “the most acute tool” for us to show efficacy and obtain regulatory approval for drugs. A factor that may make open-label trials difficult is the lack of good historical control data in some cases. However, the panelists agreed there is no need for randomized control trials for drugs that have clear disease reversing effects.

Russell Medford from Salutramed Group had similar views and said that randomized control trials, though currently the gold standard, are not always required. He advocates a frank, open discussion with the FDA while designing trials.

All panelists agreed that in today’s age, there is room for innovative trial designs, such as adaptive clinical trials or open-label clinical studies. It cannot be overstated that, especially for patients with lack of treatment options, we need to identify the optimal approach for designing clinical trials and find a middle ground.

Drug Pricing and Ethics

Finally, drug pricing and access is another thorny issue in the bioethics arena. Most drugs that get approved are introduced into the market with an intimidating price tag. But the fact remains that the drug-pricing curve has a sharp rise and a sharp fall. This fall in prices comes as drugs from competitors with similar efficacy enter the market. Prices drop further as generics enter the market once companies lose their sole monopoly over drugs.

Drug Development Bioethics
Drug Pricing and Bioethics (Image Credit: www.atg.wa.gov)

The calculation of drug pricing is aimed at increasing return on investment for a company; drug companies have to consider the cost of successfully bringing a drug to the market – including the failures that never made it past the discovery or early development stages. With these calculations, the price tag on every approved drug ranges from anywhere between $1 billion to $12 billion. From a business point of view, companies need to take into account all these factors for long-term sustainability. Of course, business ethics tend to clash with healthcare ethics, necessitating the search for a middle ground. Most panelists were of the opinion that high drug prices are justified as long as they are “fair”.

There were other ethical issues to be considered too. Would it be prudent to incorporate differential pricing globally or have static pricing? What about pricing for drugs used in rare diseases that have a small market? And what about patients/patient groups unable to pay for the high costs of these drugs? These are some troubling questions that need a lot of thought and discussion among key players globally.

It was clear at this session that there is no one correct answer or solution to either of the ethical issues discussed at this BIO2014 session. These issues lie at the crossroads of business, healthcare, and public health. Stimulating a public debate and encouraging dialogue between the pharmaceutical companies, healthcare professionals, patient interest groups, and regulatory agencies would go a long way in navigating these ethical minefields.

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#BIO2014 begins! The much-awaited 2014 BIO International Convention kicked off with a day of special sessions on Monday, June 23rd, 2014.

A special session on Monday afternoon titled “The Bioethics of Drug Development – You Make the Call!” featured an interactive discussion on the bioethics of a new drug on the market. This session involved a mock board meeting of a fictional company iCures. The panel moderator, Steve Usdin of BioCentury served as chairman of the board. The other panelists served as board members and included:

  • Timothy Mackey from UC San Diego
  • Rich Moscicki from the Food and Drug Administration
  • Una Ryan from Bay Area BioEconomy Initiative
  • Josh Sommer from Chordoma Foundation
  • Russell Medford from Salutramed Group, who acted as CEO of iCures
Compassionate Use in Drug Development
Bioethics Special Session in progress at BIO2014. On stage (from L to R): Tim Mackey, Rich Moscicki, Russell Medford, Una Ryan, Leighton Read, Josh Sommer, and Steve Usdin. Image Credit: BIO

Usdin started off the session by discussing the case of Joshua Hardy, an 8-year old boy from Fredericksburg, VA who had a rare cancer and was treated with bone marrow transplantation. Following his transplantation, Joshua developed a life-threatening adenovirus infection and the primary drug to fight this infection damaged his kidneys. At that stage, it was believed that an experimental drug brincidofovir (CMX001) was the only life-saving option for Josh. This drug was in clinical testing and not FDA-approved – hence unavailable in the market. Joshua’s parents hoped to get this drug under the compassionate use clause, from Chimerix, the biotech company that owns and manufactures brincidofovir.

However, the company refused, stating that it would ethically be wrong to do so for one patient and not for others who had approached them in a similar manner. What followed was a social media storm and pressure from people all over the country. Chimerix finally relented and made the drug available to Joshua, whose condition improved dramatically.

So, was it ethically right for Chimerix to initially withhold the drug for compassionate use before giving in to the pressure? Were patients justified in expecting to receive the drug for compassionate use? Where does the company draw the line?

At the BIO2014 session, the panel (board of the fictional iCures) talked about a similar but hypothetical case of a woman requesting an experimental drug based on compassionate grounds. As CEO of iCures, Russell Medford listed the main issues associated with approving an experimental drug in response to such requests:

  1. Limited supply of the drug that is primarily manufactured for the clinical trial at hand
  2. The price tag for off-the-trial drug treatment for the company
  3. More than one patient requesting drug for indications not being tested in the trial – if drug given to one, what about the other requests
  4. Can providing open access to drug for other indications affect chances of its regulatory approval for the intended clinical indication?

Medford conceded that a biotech company with a drug likely to benefit patients would like to help, but are faced with real challenges that need to be addressed as well.

Una Ray believes that regulatory issue may not be a concern, considering that the US Food and Drug Administration (FDA) already supports expanded access. However she insists that selection should be fair and medically indicated rather than “someone who has the best social media campaign”. Another factor to consider: if a patient benefits from the drug, a company may ethically “be required” to supply the drug for a long duration (or perhaps lifelong). A related practical consideration is the added costs it will entail. How does a company cover this expense? Do they go back to investors? Do they raise funds from other sources? Ray feels the best approach is to avoid another capital raise and prevent diluting these funds. She favors finding a non-diluted way to fund this added cost. Timothy Mackey suggested that patients or advocacy groups could using crowdfunding to support the costs involved for drug treatment under compassionate use.

In addition, compassionate use of a drug already in clinical testing bears the risk of affecting the ongoing clinical trial; it may not be able to recruit patients to the randomized control trial (with placebo group) that the FDA and the company have agreed to.

Russell Medford agrees and opines, “We have to somehow find a balance between compassionate use from a patient advocacy standpoint for individuals in crisis and the broader groups of patients that are patiently and sometime desperately waiting for us to finalize our clinical trial programs so that we can get the drug out.”

Leighton Read wondered if, by allowing compassionate use, we are going down a slippery slope – making sure that the drug is not toxic, but not really caring much about efficacy? This aspect needs to be focused on to prevent a drug being used indiscriminately.

Though compassionate use of a drug in clinical trials raises legitimate ethical concerns for the biotech company, for regulatory agencies and for society as a whole, the panelists at this BIO2014 session agreed unanimously on this use, after acknowledging these concerns. It remains to be seen how biotech and pharmaceutical companies, regulatory agencies, healthcare providers, patient advocacy groups, and patients can address these concerns.

Happy Solstice Day!

As we wind up this week, I am already looking forward to the exciting event next week, right here in San Diego – 2014 BIO International Convention, the “world’s largest biotechnology gathering”. I will be blogging from BIO2014, though it has been hard to decide which sessions to write about because there are so many good ones to choose from. Stay tuned!

Here’s a roundup of articles and news on science, medicine, and policy from this week.

Sciberomics

This week I blogged about high diversity of cells in glioblastoma – a brain cancer with extremely poor prognosis. RNA sequencing (RNA-seq) or transcriptomics of single cells from patient tumors was able to identify a highly heterogeneous population of cells in a tumor. This has implications for glioblastoma diagnosis and therapy. You can read more on my blog RNA-seq reveals glioblastoma heterogeneity.

Science Research Clinical Medicine
Weekly science roundup (Image credit: ASBMB.org)

Science and Medicine

The human immunodeficiency virus, aka HIV is notoriously difficult to eliminate from the body with drug therapy. This is at least in part because this virus can hide in the body. One way around it is to try and make the virus “announce” where it is. For this, in a recent study published in Science, scientists tried increasing the variation in the gene expression of the virus. In other words, they increased its “noise”, which in turn reactivated the latent, hidden HIV. This form of the virus is more sensitive to drugs.

The first precision medicine trial from the National Clinical Trials Network, Lung-MAP was launched. This trial will be conducted under a public-private collaboration. This trial is a multi-drug, biomarker-driven clinical trial for patients with advanced squamous cell lung cancer.

Takeda Pharmaceutical has voluntarily decided to end the development program for its investigational compound, orteronel (TAK-700). This is a nonsteroidal, selective inhibitor of 17,20-lyase that was being tested for prostate cancer. Orteronel was unable to extend overall survival in patients in phase III clinical trials.

Increasing advances in the microbiome research have revealed that the composition of microbiota in the gut can play an important role in the development of metabolic disorders. A recent study now shows that the diabetic drug, metformin can modulate the gut microbiome and in turn lead to better control of blood sugar.

Regulatory

The FDA is taking social media seriously as well. And it is about time. As a testament to this fact, the FDA has now proposed specific rules for listing risks on social media platforms.

Qiagen received FDA approval for CMV RGQ MDx Kit for human cytomegalovirus (CMV) – an assay that can allow rapid quantification of CMV DNA in patient samples, an important test for transplant patients.

Policy

The European Medicines Agency (EMA) has announced that it is relaxing data-sharing rules to enable clinical trials data to undergo public scrutiny.

Business

The life sciences company Sequenom Laboratories is now collaborating with Quest Diagnostics. As part of this collaboration, Quest is set to offer national access to Sequenom’s MaterniT21 PLUS test. This test analyzes chromosomal material in cell-free fetal DNA of pregnant women and can help diagnose fetal chromosomal abnormalities.

It is the age of mergers and acquisitions. Now an academic institute is getting in on the game. University of Southern California is in discussions to possible acquire or merge with the Scripps Research Institute.

So let's call it a week. See you back next week with lots of exciting news from BIO2014.

Diversity defines cancer.

Thanks to technological advances, we know that each person’s cancer is different. Just like a snowflake, no two are alike. This diversity between different individuals is termed intertumoral heterogeneity. Its corollary is that we need personalized therapy or individualized medicine, in order for cancer treatment to be effective.

Another layer of complexity is intratumoral heterogeneity, which means all cells in a single tumor are not necessarily the same (molecularly). Different groups of cells in a tumor (also called clones) likely have diverse molecular features. This is true in case of most cancers. Of these, glioblastoma is considered to be one of the most heterogeneous cancers.

An aggressive brain cancer, glioblastoma is very difficult to treat and recurs in most cases even after treatment. Out of every 100 patients with glioblastoma, 50 die in less than 15 months of diagnosis and very few live more than 5 years. An important reason for this dismal prognosis is the high degree of intratumoral heterogeneity. Individual cells within this tumor are different from each other, both genetically and functionally. Hence these cells respond to treatment differentially, making this tumor difficult to eradicate completely and more prone for recurrence.

Numerous previous studies have looked at genomic profiles of glioblastoma by analyzing chunks of tumors, each containing hundreds of thousands of tumor cells. One such landmark study, conducted by Verhaak and colleagues as part of The Cancer Genome Atlas (TCGA), used genomic analysis and found different tumors to have distinct genomic characteristics [1]. Based on these genomic profiles, they classified glioblastoma into 4 subtypes:

  1. Classical
  2. Mesenchymal
  3. Proneural
  4. Neural

These different subtypes of glioblastoma can each have variable degree of intratumoral heterogeneity. However, the diverse cellularity has never been systematically quantified. A recent study published in Science on June 12, 2014 does just that. Researchers from Broad Institute and Harvard use next-generation sequencing of individual cells in the tumor [2] and show that glioblastoma cells are far more heterogeneous than “previously thought”.

RNA-seq analysis of Glioblastoma

These researchers took 430 individual glioblastoma tumor cells isolated freshly from five different patients, and analyzed each cell by RNA sequencing (RNA-seq), an approach that involves profiling the transcriptome of the cell. The transcriptome includes all RNA in the cell – total RNA, messenger or mRNA, and other RNAs such as microRNA. Transcriptome sequencing or RNA-seq is a highly sensitive technique to detect genomic abnormalities commonly associated with cancer, such as gene fusion events or mutations. Change in expression of genes (either over-expression or decreased expressed) is an anomaly frequently seen in cancer; RNA-seq identifies gene expression levels in cancer cells as well.

RNA-seq glioblastoma
Single-cell RNA-seq reveals glioblastoma heterogeneity and may help design new, more effective therapies (Image Credit: cancer.gov)

In the Science study, RNA-seq analysis of glioblastoma cells revealed a high degree of cell-to-cell variability. Cells had different expression profiles of tyrosine kinase receptors, which are important targets for therapy. A direct clinical implication of this is that any single targeted therapeutic agent, no matter how effective will not kill all tumor cells. This provides a strong rationale for the use of combinations therapy for this and possibly other cancers.

This study also used RNA-seq to determine what state individual cells are in. Each tumor comprised cells in different states:

  • Some were differentiated, mature and hence sensitive to therapeutic agents,
  • Some were stem cell-like (glioma stem cells), had the potential for self-renewal and were resistant to most treatments, and
  • Some were in different intermediate states and showed variable responses to treatments

Considering this level of diversity, no single drug can completely kill all cells. Also, there are subtypes of cells that can reform the tumor after therapy. Hence, almost all glioblastoma tumors eventually recur even following the most aggressive therapies.

Researchers also determined which TCGA subtype (listed above) the individual tumor cells belong to. Surprisingly, every glioblastoma tumor was a heterogeneous mixture of cells from these different subtypes, pointing to the true diversity in tumor cells that we would miss when analyzing data from whole tumor chunks.

Clinical Implications

Important from a clinical standpoint, this study showed that increased heterogeneity in tumors is associated with poor prognosis (decreased patient survival). Heterogeneity thus has direct translational relevance and need to be considered for therapy. Bradley Bernstein from the Broad Institute, one of the senior authors on this study said in the press release, “Understanding the cellular landscape can provide a blueprint for identifying new therapies that target each of the various sub­populations of cancer cells, and ultimately for tailoring such therapies to individual patient tumors.”

This study is probably the first to quantify the extreme heterogeneity of glioblastoma. It reveals glioblastoma to be a formidable disease to manage clinically. While it underscores the challenge in successfully treating a cancer like glioblastoma, knowing this diversity helps us understand its basic biology. An ideal approach would be to leverage data on intratumoral heterogeneity to design new and effective therapeutic strategies against this deadly disease.

References

  1. Verhaak, R.G., et al., Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 2010. 17(1): p. 98-110. doi: 10.1016/j.ccr.2009.12.020
  2. Patel, A.P., et al., Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science, 2014. DOI: 10.1126/science.1254257

 

Here’s a roundup of articles and news on science, medicine, and policy from this week.

Sciberomics

This week, I blogged about the use of next-generation sequencing for diagnosing infections – based on a case study published in last week’s issue of The New England Journal of Medicine.

Around the Globe

Neuroscience World Cup
Neuroscience research allowed paraplegic to kick the football at the opening ceremony.

On 12th June 2014, the world witnessed the kickoff of the FIFA World Cup, 2014 in São Paulo, Brazil. And the biggest celebrity at this grand opening ceremony was neuroscience research! A 29-year old paraplegic (= paralyzed below the waist) wearing a min-controlled robotic suit kicked off the ball that marked the beginning of the World Cup. This suit was designed by a neuroscientist Miguel Nicolelis. Read more on this on the NIH Director’s blog.

Science and Medicine

Why did I have that extra cookie? Or why did I not get up earlier this morning? Regrets…we all know what they are. Now, in an elegant study, neuroscientists show that rats show regret after making “wrong” choices. Read this news article in National Geographic news and the original paper in Nature Neuroscience.

Scientists have developed a new molecule that can glow either red or blue, depending on the drug levels in a patient’s blood. This molecule finds application for patients taking different drugs for diseases and it can be used to prevent overdosing. The glow from this molecule can be seen using a digital camera and can give “instant results”.

Are we an inherently violent species? Is our violence so deeply ingrained that evolution actually “takes this into account” while shaping us? Now a study published in Biological Reviews suggests that the human face (particularly the male) evolved to reduce the effect of injuries from direct punches to the face.

Science Research Clinical Medicine Roundup
Weekly science roundup (Image Credit: ASBMB.org)

Scientists from Imperial College London have produced genetic modified mosquitoes such that it will eventually lead to a “crash” in the mosquito population and help eradicate malaria. The Guardian has a detailed report: "GM mosquitoes a ‘quantum leap’ towards tackling malaria." The original study can be found here.

In a potentially game-changing study for the field of HIV medicine, by modifying the genome of inducible pluripotent stem cells (iPSCs), scientists have succeeded in producing white blood cells that are resistant to the human immunodeficiency virus.

A study conducted at the Broad Institute and Massachusetts General Hospital, and published in this week’s issue of Science used single-cell RNA sequencing of glioblastoma tumor cells. This study demonstrates the high degree of intratumoral heterogeneity and complexity in glioblastoma that can have implications for treatment.

Regulatory

The U.S. Food and Drug Administration approved Biogen Idec Inc.'s long-lasting hemophilia A drug, Eloctate. This drug is likely to be available in the US starting July.

FDA Approved Panitumumab Plus FOLFOX for Wild-Type KRAS Metastatic Colorectal Cancer.

Policy

Researchers should take heart – NIH funding for research is set to improve. A Senate Subcommittee approved a 2% increase in the NIH budget for research.

Business

WaferGen Biosystems, Inc. a biotech company working in the genomic analysis space recently filed for $40 million public offering.