Memorial Sloan-Kettering and Eureka Go After ‘Undruggable’ Targets

Xconomy New York — 

Drug developers have thrown an arsenal of technologies at tumor cells: nanomachines, vaccines, antibodies, radiation, you name it. David Scheinberg has tried them all in his search for new cancer therapies at Memorial Sloan-Kettering Cancer Center in New York. But in spite of successes amid all these efforts in recent decades, Scheinberg says most of the really interesting therapeutic targets in tumor cells still fall into a class called “undruggable.”

As many as 80 percent of the important cell molecules suspected of promoting cancer remain too difficult to tackle through current drug design strategies because they are inside the cell and not on the cell surface, Scheinberg says. Targeted antibody drugs like Genentech’s trastuzumab (Herceptin) have had great success by specifically hitting molecular targets on the surface of cancer cells. But antibodies generally are too bulky to get inside cells, where many of the cancer targets are. Traditional small-molecule drugs can get inside, but they sometimes fall short as drugs because they bind with too many other structurally similar targets.

Many biotech companies have been formed over the years to go after some of the remaining “undruggable” targets in cells, and the desire to hit these targets is part of what has driven the growth of a new class of drugs that work by binding with RNA targets. But instead of inventing a whole new type of drug, Scheinberg’s team at Sloan-Kettering and collaborators he recruited at Emeryville, CA-based Eureka Therapeutics believe they can engineer antibodies to hit some of the targets that no one in the pharma industry has been able to effectively hit before.

“It’s a huge untapped area,” says Scheinberg, chair of the Sloan-Kettering Institute’s Molecular Pharmacology and Chemistry Program.

David Scheinberg, chair of the Sloan-Kettering Institute’s Molecular Pharmacology and Chemistry Program.

Taking on that challenge, Scheinberg teamed up with Cheng Liu, the founder and CEO of Eureka Therapeutics, to develop a drug aimed at one of the most talked-about “undruggable” tumor proteins: WT1, short for “Wilm’s tumor 1” protein.

The first results from animal studies of their experimental drug ESK1, published in the journal Science Translational Medicine this month, were promising enough that Scheinberg says he is planning for clinical trials in leukemia within about a year.

The WT1 molecule is found in few normal cells, but is overproduced in many cancer cell types, including solid tumors of the brain, breast, and gastrointestinal tract, as well as in several forms of leukemia.

That’s exactly the profile drug developers look for—a unique tumor cell element they can attack while leaving healthy cells unharmed. But WT1, like other difficult drug targets, lives inside the cell, rather than on the surface of the cancer cell where big antibody drug molecules can get at them.

Small molecule drugs can pass through the cell membrane, but … Next Page »

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