5:51 PM
May 30, 2019
 |  BC Innovations  |  Targets & Mechanisms

Targeting cancer evolution offers a way to foil drug resistance

Solutions to cancer drug resistance could come from new understanding about tumor evolution and advances in liquid biopsies.

A growing crop of researchers and companies are tackling cancer drug resistance by preempting tumors’ tendencies to adapt, rather than responding to resistance after it develops. Though still in their infancy, these therapies could get a lift from up-and-coming liquid biopsy technologies that can catch tumors early and monitor their evolution.

Oncologists typically fight drug resistance through sequential treatment with different lines of therapy. Molecularly targeted drugs and diagnostics for resistance mutations have made the process more rational, but treatment strategies remain overwhelmingly reactive.

“It’s the equivalent of playing whack-a-mole, which can work for a while, but is kind of a losing game,” said James DeGregori, a professor of biochemistry and molecular genetics, molecular biology and immunology at University of Colorado Anschutz Medical Campus.

The limits of the reactive approach were made clearer by sequencing data accumulated through the TRAcking Cancer Evolution through therapy (Rx) (TRACERx) trials led by Charles Swanton, chief clinician at Cancer Research UK and a group leader at the Francis Crick Institute.

“The amount of diversity in the tumor is simply immense,” said Swanton. “There’ll always be one or more cells in the tumor that are resistant to the therapy you’re using, just by chance alone.”

He and other researchers are aiming to get ahead of resistance at the DNA level.

Swanton’s team has two therapeutic approaches. ApoGen Biotechnologies Inc. has picked up the first, which involves blocking the mutagenic enzyme APOBEC3B. Achilles Therapeutics Ltd., which Swanton co-founded in 2016, is developing the second, targeting neoantigens that are shared across a tumor’s evolutionary trajectory.

“There’ll always be one or more cells in the tumor that is resistant to the therapy you’re

Some groups are going after epigenetic enzymes, others are focusing on components of the tumor microenvironment that control tumor evolution, and a third approach is to use mathematical modeling to design treatment regimens that anticipate tumor evolution.

The strategies could lead to multi-purpose therapies capable of avoiding many forms of resistance, instead of addressing each resistance mechanism separately.

Liquid biopsies could be a difference-maker.

Curtailing cancer evolution is likely to be most effective early in disease, when tumors are still relatively homogeneous.

Liquid biospy companies like Grail Inc., Guardant Health Inc. and newly launched Thrive Earlier Detection Corp. are advancing detection methods to catch cancers early (see “Thrive’s Quest to Bring Multicancer Liquid Biopsy Test into Routine Clinical Use”).

According to Kornelia Polyak, a professor of medicine at Dana-Farber Cancer Institute and...

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