The ability of a cancer cell to ‘escape malignancy’ and return to a normal state sounds like the work of Houdini: seemingly impossible. But like Houdini’s daring feats, tumor reversion—when malignant cells regain control of their growth and simply stop behaving like cancer cells—is a very real thing.
Now, researchers at NewYork-Presbyterian/Columbia University Medical Center have launched the first multicenter clinical trial of a compound that has been shown to induce tumor reversion in the laboratory.
Scientists first observed the phenomenon at the beginning of the 20th century, but it is very rare, occurring at an estimated rate of one in 100,000. In cancer, normal cells become malignant when genetic mutations disable normal growth and survival control mechanisms, causing cells to multiply at an unreasonable pace. In tumor reversion, additional mutations or other genetic changes can occur that cause the cells to regain control of their growth.
In the 1960s and 1970s, Columbia University scientist Robert Pollack and his graduate student Scott Powers, and others, worked to isolate and characterize these cancer revertant cells in hopes of learning how they regain control of the cell’s growth infrastructure—and gaining further insight into the mechanisms of cancer.
The experimental tools that were available at the time made the search difficult, and cancer researchers largely moved away from studying tumor revertants. But in the intervening years, a small group of researchers, including Adam Telerman and Robert Amson of Ecole Normal Superiéure, Paris, France, continued exploring the mechanics of this mysterious process by focusing on the molecular mechanisms that control tumor reversion.
And in an article published last year in Nature Reviews Cancer, Dr. Pollack, a biology professor at Columbia University, and Dr. Powers, now a cancer biologist at Cold Spring Harbor Laboratory and Stony Brook University, argued that tumor reversion therapy may help us evade one of cancer treatment’s thorniest problems: resistance.
Current cancer patients can avail themselves of treatments such as chemotherapy, radiation therapy, and targeted therapy, which attacks specific pro-cancer cellular mechanisms. Although they work differently, each of these treatments is designed to kill as many cancer cells as possible. Even immunotherapy, which temporarily releases the immune system’s built-in brake system, puts cancer cells squarely in the bull’s eye. The theory is that launching an all-out attack against cancer cells—as exhorted by the National Cancer Institute’s War on Cancer in 1971—may prevent the cancer from progressing and metastasizing, or spreading, throughout the body.
But according to Pollack, this line of attack is flawed. “Not only does this approach presume that each drug offers the solution for cancer, but it also neglects some pretty fundamental aspects of evolution that we often refuse to acknowledge,” says Pollack, who left his lab in 1994 to focus on teaching and writing. “It presumes that the developers of new cancer treatments have the answer, when their goal should be to sit back a bit and listen to what the cells are telling us.”
What Pollack means is that no matter how many cancer cells are killed, evolution is usually one step ahead. (Pollack, who is currently Director of theUniversity Seminars program and of Columbia’s Research Cluster on Science and Subjectivity, has a knack for putting science into a macro perspective.) Several well-known experiments—and real-life patient experiences—have shown that even if many cancer cells succumb to treatment, others may carry a pre-existing mutation that allows them to evade treatment altogether. In the 1940s, scientists Max Delbrück and Salvador Luria demonstrated that these mutations occur unpredictably and unintentionally. Later, in the 1950s, the scientific team of Joshua and Esther Lederberg also showed that such ‘resistance’ mutations occur in the absence of exposure to an anti-cancer drug—before treatment has begun.
“In cancer treatment, there is a good chance that some of the cancer cells will already contain genes that render them resistant to therapy. If enough of these resistant cells survive, the cancer comes back,” says Powers. Then it’s back to the drawing board.
But though it was possible to select for tumor revertants in the 1960s and 1970s, says Powers, it was very difficult to study the genetic underpinnings of this phenomenon. That’s because the mutations that cause a tumor cell to escape malignancy are rare. Before the advent of whole exome sequencing (which sequences all of the genes expressed by the genome in cells), researchers lacked the tools to identify the elusive mutations that caused tumor cells to revert back to normal.