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GOVINDAN: OUTSIDE THE BOX: Decoding the Mysteries of Life: From an Ancient Man to a Modern Disease

Govindan, Ramaswamy MD

doi: 10.1097/

Two obscure news items caught my attention the other day. Both involved deciphering complex genomic maps of individuals by accomplished investigators using modern technology. A stellar team from Johns Hopkins reported that changes in the large chunks of DNA in response to therapy could potentially guide cancer treatment in the future.

The other story involves reconstructing the whole genome of an ancient man who lived more than 4,000 years ago. This ancient man came from the first known culture known to inhabit Greenland. Apart from accomplishing the admirable task of piecing together pieces of genomic data from the wisps of tissues from a time long past, it was possible to discern a few things about this individual. We also learned that he was at risk for going bald or was probably “balding” (a touch of irony since the only tissue we have from him is a tuft of hair) and must have had dry ear wax.

Both these efforts are spinoffs from the landmark effort to sequence the human genome several years ago. It took one billion dollars, four large dedicated genome sequence centers, and eight years to sequence one pooled human genome.

That was then. With rapid advances in technology, the cost of sequencing an entire human genome has now come down. Reading the genome in its entirety and discerning major changes will have an immediate impact on those diseases where genomic alterations dictate the course of the disease like cancer.

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Waves of Progress

Progress in medical research comes in waves interspersed with sometimes imperceptible incremental advances. The six decades of modern cancer research is no exception. The first few decades were driven by the brute force of cytotoxic chemotherapy spurred initially by some dramatic improvements in the treatment of hematological malignancies.

Surfing the second wave were the seminal studies that defined cancer biology. Key pathways were identified and basic facts about the development of cancer were firmly established—the oncogenes, tumor suppressor genes, pathways of signal transduction, and apoptosis etc.

Impressive advances in understanding of cancer biology, unfortunately, were not immediately translated into major advances in therapy until the arrival of the third wave that brought with it the concept of molecularly targeted therapies. Signal transduction inhibitors finally became a reality. Small molecules transformed a few lethal diseases in a big way.

Many challenges still remain. Common cancers still remain incurable in their advanced stages. Only a fraction of our patients with these cancer types benefit dramatically from the recent advances. How do you increase the proportion that would benefit significantly from these innovative and often gentle therapies? How to ensure that the dramatic responses are more durable and curative, even?

For these things to happen, we need to wrap our arm around the complex, altered, and ever-changing genetic codes of the multitude of cancer cells. Mutations and alterations in large chunks of DNA transform a well-behaved, disciplined normal cell into an anarchic cancer cell.

Far from looking at these changes through a keyhole, gene by gene, protein by protein, we can now have the panoramic view of the rugged genomic landscape of the cancer cell through modern genomic technology. This most recent wave washing over the shores of cancer research will be a transformative one in cancer research and cancer treatment.

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Massive Effort

Resequencing (to use the correct technical term) the genomes of several (thousands?) of a wide variety of cancer types is a place to start. A feat that seemed almost impossible a decade ago is now happening all around us.

Several institutions have begun their own efforts to sequence some selected cancer types. The Cancer Genome Atlas (TCGA) project led by the National Cancer Institute and the National Human Genome Research Institute (NHGRI) is currently resequencing several hundreds of specimens, and plans are under way to develop a complete genomic map of some common cancers.

This is a massive effort involving millions of dollars, hundreds of individuals, and scores of institutions. Serious real computer power will be deployed to analyze the complex data emerging from genomic analysis. Even within the past few months, complete genomes of two patients with acute myeloid leukemia and a patient with high-grade glioma have been reported.

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New Pathway Involved in Carbohydrate Metabolism, a Potential Target for Therapy

Out of this research has emerged a new pathway of great interest that is involved in carbohydrate metabolism, a potential target for therapy. When several thousands of specimens are sequenced and analyzed, we will redefine common cancers very differently. We will come to appreciate how identically appearing cancers are so different molecularly.

RAMASWAMY GOVINDAN, MD, OT's Clinical Advisory Editor for Oncology, is Director of the Thoracic Medical Oncology Program at the Alvin J

RAMASWAMY GOVINDAN, MD, OT's Clinical Advisory Editor for Oncology, is Director of the Thoracic Medical Oncology Program at the Alvin J

It is these molecular changes that should guide our therapy. These changes are not static. They will evolve over time naturally as the cells proliferate and in response to the selection pressure exerted by our current therapy.

Serial evaluation like the one pioneered by the Hopkins team will, in a more polished, simpler, and cheaper form, guide therapy.

We need to do a better job of collecting and storing fresh tumor specimens and link them with clinical outcomes more diligently than we have done in the past.

If we can obtain tissue specimens left in a permafrost in a remote part of the world thousands of years ago, we should be able to collect and intelligently analyze malignant tissues from current living patients with some effort, persistence, and ingenuity of technology.

We are indeed turning a corner in the treatment of cancer, as never before.

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Hear More!

Hear Dr. Govindan talk more about this article in an OT Broadcast News podcast available at (under the Podcasts link) and on iTunes.

© 2010 Lippincott Williams & Wilkins, Inc.
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