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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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April 22, 2013

Cancer: Back to N-of-One

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Posted by Derek

From Nature comes this news of an effort to go back to oncology clinical trials and look at the outliers: the people who actually showed great responses to otherwise failed drugs.

By all rights, Gerald Batist’s patient should have died nine years ago. Her pancreatic cancer failed to flinch in the face of the standard arsenal — surgery, radiation, chemotherapy — and Batist, an oncologist at McGill University in Montreal, Canada, estimated that she had one year to live. With treatment options dwindling, he enrolled her in a clinical trial of a hot new class of drugs called farnesyltransferase inhibitors. Animal tests had suggested that the drugs had the potential to defeat some of the deadliest cancers, and pharmaceutical firms were racing to be the first to bring such compounds to market.

But the drugs flopped in clinical trials. Companies abandoned the inhibitors — one of the biggest heartbreaks in cancer research over the past decade. For Batist’s patient, however, the drugs were anything but disappointing. Her tumours were resolved; now, a decade later, she remains cancer free. And Batist hopes that he may soon find out why.

That's a perfect example, because pancreatic cancer has a well-deserved reputation as one of the most intractable tumor types, and the farnesylation inhibitors were indeed a titanic bust after much anticipation.. So that combination - a terrible prognosis and an ineffective class of compounds - shouldn't have led to anything, but it certainly seems to have in that case. If there was something odd about the combination of mutations in this patient that made her respond, could there be others that would as well? It looks as if that sort of thing could work:

Early n-of-1 successes have bolstered expectations. When David Solit, a cancer researcher also at Memorial Sloan-Kettering, encountered an exceptional responder in a failed clinical trial of the drug everolimus against bladder cancer, he decided to sequence her tumour. Among the 17,136 mutations his team found, two stood out — mutations in each of these genes had been shown to make cancer growth more dependent on the cellular pathway that everolimus shut down1. A further search revealed one of these genes — called TSC1 — was mutated in about 8% of 109 patients in their sample, a finding that could resurrect the notion of using everolimus to treat bladder cancer, this time in a trial of patients with TSC1 mutations.

So we are indeed heading to that dissection of cancer into its component diseases, which are uncounted thousands of cellular phenotypes, all leading to unconstrained growth. It's going to be quite a slog through the sequencing jungle along the way, though, which is why I don't share the optimism of people like Andy von Eschenbach and others who talk about vast changes in cancer therapy being just about to happen. These n-of-1 studies, for example, will be of direct benefit to very few people, the ones who happen to have rare and odd tumor types (that looked like more common ones at first). But tracking these things down is still worthwhile, because eventually we'll want to have all these things tracked down. Every one of them. And that's going to take quite a while, which means we'd better get starting on the ones that we know how to do.

And even then, there's going to be an even tougher challenge: the apparently common situation of multiple tumor cells types in what looks (without sequencing) like a single cancer. How to deal with these, in what order, and in what combinations - now that'll be hard. But not impossible and "not impossible" is enough to go on. Like Francis Bacon's "New Atlantis", what we have before us is the task of understanding ". . .the knowledge of causes, and secret motions of things; and the enlarging of the bounds of human empire, to the effecting of all things possible". Just don't put a deadline on it!

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials


COMMENTS

1. KK on April 22, 2013 12:10 PM writes...

Excellent points, Derek. I'll just add my two cents:
1. This information should also be useful in designing clinical trials in the future and allowing targeted therapy to live up to its potential.
2. Knowing the near-complete mutation profile of the tumors should also allow for smart decisions to be made with respect to targeted combination-therapies.

Permalink to Comment

2. emjeff on April 22, 2013 12:29 PM writes...

I share your lack of enthusiasm. These n of 1 trials are not going to gain traction because payers are not going to pay the price companies would have to charge to make these niche therapies a reality.If your potential market is only 4-5% of a given cancer type, and you have fixed costs for development, the only way to make that drug a reality is to charge a boat-load of money for it. Payers will balk at that, and the public will blame the "greedy" pharma companies for not giving their product away.

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3. Doug Steinman on April 22, 2013 12:51 PM writes...

It is certainly a great accomplishment to treat a cancer patient and achieve a state of no evidence of disease. However, while it is possible that the drug is what drove the patient's cancer into remission, it is also possible that the cancer went into remission spontaneously. The only way to discover if the remission was due to the drug treatment is to find other patients with the same mutations and see if the same result is obtained. Despite the relatively high cost to benefit ratio, it is certainly worth the effort to pursue this as the knowledge gained could prove to be extremely valuable. More often than not, cancer wins in the end so we should grab onto anything that can tip the odds in our favor.

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4. DCRogers on April 22, 2013 1:13 PM writes...

This will present plenty of new, painful, "opportunities" for every failed Phase II or III trial -- you can take the subset that worked, find the thousands of mutations in-common, postulate which are the (possible) culprits, and run a new trial.

Between confirmation bias, sunk-cost bias, and management-would-rather-keep-their-jobs-for-a-few-more-years-bias, there will be lots of hand-wringing, lots of additional money wasted, but perhaps the few wins will find a few drugs (and pathways) that would have remained undiscovered.

Hopefully, the scrapings at the bottom of the barrel will contain at least a few gold nuggets, but it's a reflection on the poor overall drug discovery rate that these Hail-Mary-pass searches are being taken seriously.

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5. David Formerly Known as a Chemist on April 22, 2013 1:29 PM writes...

"Just don't put a deadline on it!"

Or a small budget. Imagine needing to create and clinically evaluate expensive antibodies for ever more segmented patient populations. The target patient populations are already getting smaller and smaller (especially in oncology), but this is rapidly moving toward VERY small patient subsets for each active agent. Is society ready to eat the costs of where this direction is leading? Therapies costing hundreds of thousands of dollars? Especially if the benefits provided don't improve substantially over those we see with today's generation of new agents. I know you can't put a price tag on a life, or even a two-month extension of life, but when society is asked to pay for it (in the form of increased Medicare taxes and increased insurance premiums), these abstract existential questions become real issues.

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6. Imaging guy on April 22, 2013 2:15 PM writes...

Yesterday there was an article in New York Times about using whole genome sequencing to predict patients who would respond to a particular therapy (“Cancer Centers Racing to Map Patients’ Genes”). The new buzz word is Precision Medicine. Millions of dollars are being spent on buildings, labs and salaries. In new future we will be seeing Journal of Precision Medicine, International Journal of Precision Medicine or World Journal of Precision Medicine. Let’s see how long this trend will last?

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7. newnickname on April 22, 2013 3:45 PM writes...

It has come up here in the past ("Personalized Medicine" 20-Mar-2012; "Brute Force", 12-Mar-2012) that searching for cancer cures in cell culture is a losing proposition. Whole animals are a lot more complicated than cells in culture. And humans are more complicated than mice ("Mouse Models", 13-Feb-2013).

I only just recently learned that one person, Jane C. Wright, is credited with the move from cancer screening in whole animals to cell culture. Wright's wikipedia entry says, "Wright is credited with developing the technique of using human tissue culture rather than laboratory mice to test the effects of potential drugs on cancer cells."

Another note is that one or two mutations can alter the expression of many other normal proteins. Sometimes it might be better to target the normal proteins rather than the mutation.

But, ultimately, I think it would be great to run a $1000 personalized genetic screen, see what's wrong and take the best guess using the most up to date data regarding treatment choices.

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8. MDA Student on April 22, 2013 3:45 PM writes...

So why not take the opposite approach? Start the trial by enrolling patients with completely different cancers? Then narrow down the cancer type, then the specific mutations? Especially as there are drugs that have been found to treat other cancers after they were approved.
As a grad student I would call this "fishing," but science guys don't makes these decisions and it follows the encompassing>narrowing down method physicians use to diagnose and treat in the clinic.

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9. Johannes on April 22, 2013 3:56 PM writes...

I not sure this is such a bad idea, if it helps elucidate cancer's strategies. But I don't expect that the future involves completely sequencing the completely heterotypic tumor mass.

I hope we can possible target every single strategy combinatorial to avoid relapse.

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10. ESIMS on April 22, 2013 6:47 PM writes...

@Johannes
Well I think that will happen (sequence all exons at least). You just need enough sequence coverage and you can determine heterogeneity. Also the algorithms for analysis get better and better.

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11. Morten G on April 23, 2013 5:35 AM writes...

There's a lot of people working on PCR and deep sequencing methods to quantify the death / turnover of cancer cells in a patient. Remember how the very efficient cancer therapies almost shut down kidneys because there's too much cell debris in the blood stream? Cancer cells are dying all the time because of genomic instability but the idea is that if the cancer debris in the blood increases then the therapy is killing the cells. If the debris decreases then the therapy is inhibiting growth of the cancer (which can also lead to death in the long run).

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12. packet2pruner.jigsy.com on April 24, 2013 6:30 AM writes...

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Google, and found that it is truly informative. I'm going to watch out for brussels. I will be grateful if you continue this in future. A lot of people will be benefited from your writing. Cheers!

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