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Musings of a Cancer Doctor
Wide-ranging views and perspective from George W. Sledge, Jr., MD
Thursday, September 27, 2012
On Cross-Training

Several years ago I worked with a young woman who was a triathlete. She had that superb physique that comes from cross training, where every muscle looks well toned and health seems to ooze from every pore. As is usual in the presence of such physical perfection, I felt like a lower life form, something not quite so far along the evolutionary path, or maybe one of nature’s many mistakes. Particularly when, to the astonishment of all, she performed a triathlon and then immediately (and I mean immediately) had an appendectomy. A paper cut would have incapacitated me for longer than it took her to recover.

 

I thought of her the other day when I read about a new study on progeria, that terrible inherited disease characterized by premature aging, where 10-year-old kids have the bodies of 80 year olds and are usually dead by age 13.  Progeria (or Hutchinson-Gilford Progeria Syndrome, its proper name) is caused by an accumulation of progerin, a mutant form of the Lamin A protein. The article described the application of a new drug (or, at least, new to progeria) called lonafarnib. Lonafarnib significantly improved weight and growth patterns in progeria kids.

 

Lonafarnib is a farnesyl transferase inhibitor, and one that I am quite familiar with.  Farnesyl transferase inhibitors, you may recall, were going to be the solution to the Ras oncogene problem. FTI’s inhibit Ras pathway activation by blocking the main post-translational modification of the Ras protein, preventing its localization to the inner surface of the plasma membrane and subsequent activation of downstream molecules.

 

That didn’t work (Ras has been an exceptionally tough target), because Ras could be activated via an alternate mechanism (geranylgeranyltransferase) and sidestep farnesyl transferase inhibition.  Hence the zero for denominator response rate in metastatic breast cancer that our group saw in a Phase II trial, and the failure of similar agents in a wide variety of human tumor types.

 

So lonafarnib (and more generally, FTI’s) failed the first law of triathletes: you ought to be halfway decent at something before you try something else. 

 

But it turns out that FTIs inhibit the farnesyl groups that are thought to cause progerin’s toxic effects, and this appears to improve the condition of kids with progeria. The senior investigator for this work, a pediatric oncologist who had led an FTI trial for pediatric brain cancer, got the idea from his trial experience. Oncologists can cross-train, too.

 

I might add that this is an exceptionally rare disease, and that the 28-patient trial was thought to have recruited roughly three quarters of the world’s active progeria patients. Carrying off such a trial required support from Merck (which obviously will never get rich off of progeria sales) and the Progeria Research Foundation, which raised $2 million to support the trial. Kudos to them, but talk about an orphan drug indication.

 

Might progerin inhibition do something for the aging process the rest of us encounter? Who knows? In my clinic the drug caused a fair amount of diarrhea, so I’m not sure I would want to live a decade longer if I had to take it every day.

 

But lonafarnib does represent the first drug ever to do anything useful for progeria, even if, as the authors are at pains to stress, it does not represent a cure for the disease. Going forward it will serve a backbone for new combinations in progeria.

 

Lonafarnib joins a list of drugs originally developed for one disease that ends up treating another.  Others on the list include Viagra (erectile dysfunction/pulmonary hypertension), paclitaxel (cancer/cardiac stents), dutasteride (BPH/male pattern baldness), and bimatoprost (glaucoma/eyelash thickener).

 

Such multiple-use drugs (and the list is much longer) cross-train for a variety of reasons.  One, of course, is that many of our drugs are delightfully impure, targeting more than one biologic process.  Sometimes the same biologic process (e.g., microtubule polymerization for paclitaxel) is important in more than one physiologic process; nature likes repeating useful motifs. And sometimes a drug will mimic or replace a natural hormone or cytokine that evolution decided long ago was too good to use for just one thing.

 

A megestrol acetate will be used to treat women with breast cancer, and in doing so will give them the munchies.  Their complaints will lead to the use of the drug in AIDS patients with severe weight loss.  Some of the women treated for breast cancer will also notice that their hot flashes improve on the megestrol acetate, and the drug will be used for that indication as well. Megestrol is basically progesterone, and progesterone has protean effects.

 

In the past we’ve largely discovered these multiple uses through the happenstance of clinical anecdotes. Might we effectively cross-train with the many drugs that populate the US Pharmacopeia?

 

Investigators at the Broad Institute in Boston asked this question in developing cmap, or the Connectivity Map. They reasoned that if you knew the gene expression pattern associated with a particular disease, you might be able to find drugs that inhibited that expression pattern. To date they’ve generated more than 7,000 expression profiles representing over 1300 compounds.  (For more information on the Connectivity Map, you can visit its website: http://www.broadinstitute.org/cmap/ or read a paper at: Nature Reviews Cancer 7, 54-60 (January 2007) | doi:10.1038/nrc2044).

 

Such intentional cross-training for drugs has several charms: the drugs are often off-patent, cheap, easily available, and have already passed through the preclinical testing and jumped through the early drug development hoops that render modern medicines so expensive.  But this also means (particularly for the off-patent drugs) that there may be nobody pushing the drug development for a novel indication: no intellectual property protection equals no profits equals no one willing to put up the cash required for a Phase III trial.

 

Perhaps we should put aside a certain portion of the NIH budget for repurposing old drugs.  You can teach old dogs new tricks, and doing it systematically rather than haphazardly might do our patients a great deal of good.

 

But I doubt it will happen.  I say this because of triathletes. These folks are arguably our greatest athletes: you try an Ironman Triathlon and see how you feel after a 2.4 mile swim, a 112-mile bike ride, and a 26.2-mile marathon.

 

But who, outside of the triathlon ghetto, ever hears of triathletes? We give millions to sports specialists (a quarterback or an outfielder or a point guard), televise them, even worship them. Cross-training triathletes are largely anonymous: who ever heard of Craig Alexander or Chrissie Wellington, the record holders for the Ironman World Championships?

 

It’s not just that we tend to think of drugs as specialists; the specialists who use the drugs rarely think of them as potential triathletes.  And this might be the real barrier to drug cross training: our lack of imagination, our narrow scope of vision, the blinkers we wear when join our subspecialty guilds. Maybe we need to return, at least every now and then, to the proposition that generalists (what we used to call Renaissance men) might be useful in the world of medicine.

 

Not that I have any intention of flying to Hawaii for the Ironman competition. But I’ll happily cheer you on.

 

 

 

 

 

 

 

About the Author

George W. Sledge, Jr., MD
GEORGE W. SLEDGE, JR., MD, is Chief of Oncology at Stanford University. His OT writing was recognized with an APEX Award for Publication Excellence in the category of “Regular Departments & Columns.”

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