Medicine

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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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Stop the presses! We have a new addition to the list of diseases that benefit from next-generation sequencing – infections.

In a case study published last week in The New England Journal of Medicine, routine medical and laboratory testing failed to identify the cause of encephalitis in a 14-year old patient [1], leaving him in a medically induced coma, with few treatment options and little hope. Encephalitis is brain inflammation, and can lead to severe neurologic abnormalities and death. Identifying the exact cause is critical for therapy but may be challenging. In this case, routine testing failed to provide a definitive diagnosis. Even a brain biopsy was inconclusive. As a last resort, doctors used a novel approach to figure out what was wrong with the patient. They analyzed his cerebrospinal fluid (CSF) using next-generation sequencing.

Next-generation sequencing infections
Sequencing for infectious diseases (Image Credit: Thomas Anthony Zampetti, Flickr)

Basically, researchers studied the CSF for evidence of microorganisms, in the form of DNA sequences. They used an unbiased approach to next-generation sequencing. I asked Charles Chiu, MD, PhD, Assistant Professor and Director of UCSF-Abbott Viral Diagnostics and Discovery Center, who is senior author on the study, about this approach.

“The term alludes to the fact that we are not targeting any specific pathogen or type of pathogen,” explained Chiu. It means that the researchers used sequencing and analysis to search for all known pathogens, including rare organisms.

Within 48 hours of receiving the CSF sample, next-generation sequencing and bioinformatics analysis revealed an obscure cause of encephalitis in this teenager – leptospirosis, an infection caused by the bacterium leptospira. Inability to accurately diagnose and treat this condition can be fatal. The good news: once diagnosed, leptospirosis is easily treatable with regular, old-fashioned penicillin. This antibiotic was administered in high doses, and the patient recovered completely.

Leptospirosis, Next-Generation Sequencing
Brain MRI of patient with encephalitis: Panels A, B, and C - images before treatment show signs of inflammation (arrows); Panel D - 7 days after penicillin treatment, shows inflammation resolved. From The New England Journal of Medicine, Wilson MR et al., Actionable Diagnosis of Neuroleptospirosis by Next-Generation Sequencing. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Next-generation sequencing identified the cause of infection in 2 days – something that months of traditional testing had not achieved. It saved the life of this teenager.

Clinical Translation of Next-Generation Sequencing

Next-generation sequencing is increasingly used in oncology for tumor profiling; in addition, it is a valuable tool for the diagnoses of various rare diseases and genetic disorders. The big question is: can successful diagnosis of an infection lead to the routine use of sequencing for other difficult-to-diagnose infections?

Charles Chiu believes so.

“I view this technology as being used as a broad-spectrum, second-line diagnostic assay after initial screening tests are negative and physicians have to resort to costly additional tests for rare and uncommon infections”, said Chiu.

However, this technology is far from clinic-ready. We need to come up with means to reliably identify disease-producing organisms, with high sensitivity and specificity, and differentiate them from the normal microbiome in relevant areas of the body. For example, the human gut contains 300-500 different species of bacteria [2]. So, one can appreciate the challenge of identifying an infection-causing microorganism from among the gut microbiome, by sequencing. Moreover, using next-generation sequencing routinely in the clinic for infectious diseases would require comprehensive testing and technology validation in order to obtain regulatory approval.

Clinically diagnosing infections (especially in cases of emergency) requires rapid sequencing and reliable analysis to deliver actionable results to the clinician. And all this needs to happen at affordable costs. Elaine Mardis, PhD, Professor of Medicine and Co-Director of The Genome Institute at Washington University, St. Louis, who was not part of The New England Journal of Medicine study agrees, “Probably the biggest hurdle is making it faster, cheaper and better than current assays.”

The Future

Once in routine clinical use, next-generation sequencing can prove critical for diagnosing cases of encephalitis and meningitis, like the one reported here. In addition, it will be beneficial for many zoonotic and infectious diseases that are difficult to diagnose using routine testing. Sequencing-driven diagnoses may be valuable, especially in critically ill patients with severe infections, including sepsis. In such cases, sequencing may not only identify the responsible microorganisms, but may also provide clues on drug resistance.

The successful use of next-generation sequencing by Chiu and colleagues provides us a rare window into a world where this technology can drive treatment decisions by diagnosing infections. As Elaine Mardis reflects, “(This study) beautifully illustrates how an unbiased look and smart bioinformatic analysis can provide answers that are life-saving.”

References Cited

  1. Wilson, M.R., et al., Actionable Diagnosis of Neuroleptospirosis by Next-Generation Sequencing. N Engl J Med, 2014. DOI: 10.1056/NEJMoa1401268
  2. Guarner, F. and J.R. Malagelada, Gut flora in health and disease. Lancet, 2003. 361(9356): p. 512-9. DOI: 10.1016/S0140-6736(03)12489-0

 

Revolution! It drives radical transformation.

The omics revolution over the past decade has been a tour de force leading to unprecedented advances in biomedical sciences. Omics is a generic term for all fields of biomedicine with the suffix –omics. For instance, genomics indicates study of genome, epigenomics indicates study of epigenetic modifications, and so on for other fields such as proteomics, transcriptomics, microbiomics, metabolomics, etc. (each of these words deserves a separate blog post and will get one in due course). Advances in these areas have arguably been the most disruptive innovations of our time.

Breakthroughs in Biomedical Sciences

Technological innovations in the nineties spurred rapid development of the omics field, leading to a never-before-seen “intersection of biology and technology” (“Steve Jobs” by Walter Isaacson, 2011). The international Human Genome Project was a key landmark or rather, a precursor of this revolution. What started out as an extremely expensive venture has now made genome sequencing affordable enough for routine clinical application (almost!). The cost of sequencing has dropped precipitously, from $3 billion in the late nineties to approximately $1000 for a single genome today. This rate of advancement in sequencing technologies has truly defied Moore’s law.

Newer technologies and their application to biomedical research meant more and more data generated everyday. Making sense out of these data required additional technologies, which in turn, drove systematic evolution of a specialized field – computational or quantitative biology. This discipline uses techniques in physics, mathematics, computer sciences and related branches to decipher riddles in biology. Today, closely related interdisciplinary branches such as bioinformatics, systems biology, and network pharmacology have emerged. These varied branches are driving progress by analyzing and interpreting the tremendous amounts of data generated in the omics world.

Projects in academia and in industry are becoming increasingly collaborative in nature. Successfully translating these research findings into the clinic is critical to providing more effective treatment options for many diseases. These developments are poised to make personalized medicine or individualized medicine a reality.

Science, Medicine, Sequencing, Biology, Cancer
Sciberomics - Snapshots of Science and Life (Image by author)

Sciberomics and Science Outreach

In light of the interdisciplinary research and its application to humans, science communication assumes a vital role. Not only does it inform curious minds, but it also serves as an antidote to ignorance and misinformation. It spreads public awareness about science and facilitates dialog between peers. Science outreach is critical to driving public opinion, which can, directly and indirectly influence policy and funding. Add to that the availability of innumerable platforms for communication, and one would have to agree that there has been no better time for science writing.

All this has prompted me to join the world of active blogging. I am really excited to launch my new blog, and to use this platform to communicate science. How did I decide on a name for the blog? Well, I have to confess I am guilty of neologizing. I wanted the name to reflect the fact that this blog will communicate science, in cyberspace. Though I intend to cover all areas of science, I realize that I may end up being partial to the omics field. Taking all these factors into consideration, the newly minted word Sciberomics seems like a good fit as a name.

At Sciberomics, I will discuss recent developments in biology and medicine, focusing on how they affect human life. Blog posts will include studies that are hot off the press, areas that are mired in controversies and topics that are hotly debated. Active discussion and feedback from readers, in the form of comments are welcome and will provide flavor to the blog. The aim of Sciberomics is outreach to peers and non-scientific audience alike.

So, here goes Sciberomics – Snapshots of Science and Life. Welcome!