The Making of a Revolution (of Genomic Medicine)

Dov Michaeli

Posted 12/7/11 on The Doctor Weighs In

Incredulous Dov

In response to a previous column (TDWI, Dec.2, 2011) The Era of Individualized Cancer Therapy has ArrivedI received an email from my friend Michael Millenson saying, in part:

Like a true advocate, you write here in what I call “present tense hopeful.” In actual English, “has arrived” means something is here. And so it is for a very few cancers in a very few ways, none of which are generally curative. (See current Medscape article that came out this week.)

As you yourself note, it’s 3-5 years away. Reminiscent of the wag who said of personalized medicine that it’s like soccer in the U.S.: the sport of the future and always will be.

Am also disappointed you didn’t refer to the downsides, etc. of personalized medicine in the white paper I sent you.

My response: I plead nolo contendre, or in English: I plead no contest. I don’t dispute the facts of Michael’s complaint, nor do I think that they negate the fact that the genomic revolution has begun. My response is in fact, Clintonian: it depends what you mean by ‘has arrived’.

First, the points with which I agree with Michael. The advent of relatively cheap and fast methods of sequencing DNA has spawned a cottage industry that offers the unsuspecting the tantalizing prospect of knowing what ails them on the genetic level, with the implied promise of a specific treatment. Nonsense; most common diseases (cardiovascular, diabetes, cancer) are multigenic, and each mutation makes only a minor contribution to the disease. Also, the genetic testing industry is plagued with lack of standardization, and sometimes shoddy practices. But this is not a flaw that cannot be remedied with proper standards-setting and enforcement. Likewise, I might add, is the threat of insurance discrimination- just enforce the law. By the way, isn’t the mere fact that we are grappling with these issues evidence that genomic medicine is already here.

To see how a scientific revolution develops, let me take you on a fascinating tour of scientific discoveries that morphed into life-saving drugs.

The Gleevec story

Curiously, one could argue that genomic medicine got its start even before the publication of the human genome. Here is the remarkable story of Gleevec, a drug thatessentially cures CML, or chronic myelogenous leukemia. In this disease, white blood cells proliferate at a rapid, and uncontrolled, rate. A milliliter of blood from a healthy person contains 4,000 to 10,000 white blood cells; the same volume of a CML patient’s blood contains 10 to 25 fold this number. The disease was quite lethal (30% 5-year survival) despite debilitating chemotherapy, or bone marrow transplantation as a desperate measure.  In 1960, scientists at the University of Pennsylvania noticed that one chromosome in the blood cells of many CML patients was shorter than normal – it was missing a big chunk of its DNA. The stubby chromosome was nicknamed “the Philadelphia chromosome” and marked the first time that a chromosomal defect was linked to cancer. Thirteen years later, in 1973, a researcher at the University of Chicago discovered that the missing end of the short chromosome had moved and fused with another chromosome. And this was the state of our knowledge when I trained in medicine. Result of a blood test with Ph+ (Philadelphia chromosome positive) cells was very bad news.

By the 1980s, scientists were able to use genetic mapping to show that the two ends of the broken chromosomes produced an oncoprotein (a cancer-causing protein), known as Bcr-Abl. In 1986 and 1987, researchers writing in Science identified the oncoprotein as a tyrosine kinase (TK), an enzyme that, among other things, helps regulate cell growth and division. What happened on the way to malignancy was that the fusion of bcr, which codes for TK, with abl caused the enzyme to be permanently ‘on’, driving the cell to divide uncontrollably. The drug company Ciba-Geigy (today’s Novartis) already had a TK inhibitors program. The compound that would become Gleevec was synthesized in 1992, and in 2001, the
FDA approved the drug with unprecedented speed after an expanded phase 1 study gave astounding results of almost complete response in the few patients that participated in the study. The drug had almost no significant side effects.

Now, when you go back and look at the dates of the Gleevec discovery story you’d realize that it took about 40 years (1960-2001). But it also ushered in the era of molecular medicine, and the, yes, genomic revolution.

The profound implication of Gleevec’s discovery was acknowledged in 2009 when Druker, Lydon and Sawyers, the three academic investigators who were the development of the drug, received the Lasker-DeBakey Clinical Medical Research Award in 2009 for “converting a fatal cancer into a manageable chronic condition”. As an aside, the Lasker award is an excellent predictor of Nobel Prize winners several years thereafter. Stay tuned.

Remarkably, in the same year that Gleevec was approved, 2001, the human genome sequencing project was finished.

GWAS and the new phase of the genomic revolution.

A scant 5 years after the approval of Gleevec and the completion of sequencing the human genome, a new method of genetic analysis, GWAS ( Genome-Wide-Association Study) became possible because of giant strides in the speed of DNA sequencing and capabilities of DNA sequencing machines, as well as a dramatic reduction in the costs of the analysis. In this method, researchers look for association between many (tens to hundreds of thousands) specific genetic variations and particular diseases.

There are two goals for the genomic studies: understand the biologic mechanisms of the disease, and apply that knowledge to personalized medicine. Molecular biologists, structural biologists, specialists in bioinformatics, pharmaceutical chemists and biochemists, toxicologists, and clinicians –all take part in these gargantuan and impossibly complex studies. And the first fruits are already being
announced. One example:

The December 5 online issue of the journal Oncogene reports a study (A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer) carried out at Yale Cancer Center. I know it’s a mouthful, but here is the essence of the study. The K-RAS gene is the first human oncogene to be identified. Ras is mutated in about 25% of all human tumors. For cancer patients, the presence of an activated Ras oncogene is a poor prognosis marker.

Ras has a molecular on-off switch, activated by the energy transfer molecule GTP. In the “on” position, the oncogene activates critical cell signaling pathways involving cell proliferation, cell migration and cell differentiation, all of which are in hyper-drive in tumors.

The Yale scientists identified a SNP, a mutation involving one nucleotide base in the chain of thousands of nucleotides that make up the gene. Women with this mutation are three times more resistant to standard platinum chemotherapy than women without the variant. Also, post-menopausal women with the variant are significantly more likely to die from ovarian cancer. About 12-15 percent of Caucasians and 6 percent of African-Americans are born with the variant of the gene, which helps regulate destruction of c ells. This variant is found in up to 25% of newly diagnosed ovarian cancer patients.

But the story doesn’t end there. Why not make a drug that would inhibit the protein that is the product of the mutated gene, you might ask? Now that we know about Gleevec and its specific inhibition of the TK enzyme in CML, why not do the same with Ras? The answer is that unlike TK, drug developers couldn’t find a point of attack, where a drug could bind the protein and inhibit its activity…that is, until December 5, the same day that the Yale group published its results on the Ras mutation in ovarian cancer. On that day, A drug discovery team at Genentech, Inc., reported at the American Society for Cell Biology’s 51st Annual Meeting in Denver that it uncovered a chink in the molecular armor of Ras, The chink, binding pocket of “functional significance” on the Ras oncoprotein could provide the long-sought attack point for a therapeutic agent, making the “undruggable” Ras oncogene “druggable.

Two things should be noted here. First, Ras is present in several cancers in a large proportion of patients (25%), and is associated with aggressiveness of the tumor. Second, note the incredible acceleration of scientific progress. Compare the Ras timeline to gleevec’s. Given the tremendous strides made in computer-based drug design and synthesis since the Gleevec time, I don’t think it would be unrealistic to expect a Ras-specific drug in a few short years.

So we come back to the original question: has the genomic revolution arrived? I think it is unfolding in front of our eyes.

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