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Stumbling block

In any competitive sport, you know that what worked one time down the field/floor/ice is VERY unlikely to work again the second time. We would use that principle to adjust the truism that “past success is no guarantee of future performance” to “past success is LIKELY to hurt future performance.” Biology is a bit like that. You gotta separate the wheat from the chaff. What about the drug discovery success is general and portable–and what is not?

The recent failure of the combination treatment of MEK inibitor with PD-1 biologic offers some lessons. FDA approved biologic drugs that are monoclonal antibodies (mAbs) blocking PD-1 revolutionized metastatic melanoma cancer treatment. The PD-1 signal emanating from cancer cells turned off attacking immune cells, allowing the incurable metastatic cancer to thrive. Anti-PD-1 mAbs turned the signal back on and, lo and behold: whole body immune attack on the metastatic cancer and major gains in survival for patients.

You can imagine the excitement when basically the first proven treatment for an incurable metastatic cancer hit the streets since . . . well, forever. (You might wonder what all those Ras and oncogene scientists have been doing with your billions of cancer research taxpayer dollars for 40 years, but we digress . . .) Then people noticed that only 1 in 5 patients responded. The others largely did not have cancer markers for the immune system to attack in the first place. So now the race was on to find ways to “light up” the cancer for the immune system: i.e. upregulate the immune cell major histocompatibility complex (MHC) receptors. Well, someone tried a MEK inhibitor in some cells and surprise! (not) MHC went up. So, snowball city. All the way to a clinical trial. Which failed. Spectacularly. Not only was the treatment significantly WORSE than the comparator groups, but a high level of adverse events, prominently peripheral edema was noted. DENIED!

Now, MEK inhibitors target a growth factor pathway. Remember those oncogene scientists who took all the research money for 40 years and couldn’t cure cancer? Well, they LOVE growth factor pathways, and they didn’t just resign. They’re still hanging out, hoping for something that could make their work relevant. But, er, someone forgot to look at the simple question of whether MEK is overexpressed in colorectal cancer or in cells, such as immune cells that could underlie peripheral edema. Well, maybe they didn’t forget. Maybe the tools to do so are just not well-known enough . . .

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