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.
Outsmarting Cancer by Following Nature’s Lead
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 the University 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.
Without the right tools, by the 1990s, many cancer researchers turned their attention toward the discovery of oncogenes—genes that, when mutated, interfere with normal cellular processes and trigger malignant behavior. These discoveries led to the development of targeted therapies, which halt cancer progression by disrupting the cascade of events set into motion by these oncogenes. This targeted approach promised to yield a more effective solution with fewer side effects than conventional cytotoxic treatments, which kill tumor and healthy cells. But shortly after they were adopted in the clinic, many of these targeted therapies unleashed an unexpectedly powerful, fast-moving wave of resistance.
“The problem is that cancer is smarter than drugs that target specific pathways,” says Mark Frattini, MD, PhD, associate professor of medicine and experimental therapeutics at Columbia University Medical Center and director of research for the Hematologic Malignancies Section, an oncologist at NewYork-Presbyterian/Columbia and an expert in blood cancers. “They will often find another pathway to get past that point, and that’s when relapse occurs.”
In recent years, the problem that once dogged tumor reversion research—a lack of tools for identifying the rare mutations—has been solved, largely through the efforts of Telerman and Amson. With this in mind, Pollack and Powers suggest that resistance might be avoided, or at least defanged, by identifying these rare mutations and learning how they work.
Teaming Up to Test Revertant-Specific Therapy
To test tumor reversion in the clinic, two major issues needed to be resolved: finding a drug that would facilitate reversion and designing a clinical trial to test the therapy in patients with relapsed or chemotherapy-resistant cancer.
A few years ago, Telerman and Amson noticed that people with several types of cancer, including cancer of the colon, lung, and melanoma, had high levels of a protein called TCTP. Experiments revealed that TCTP inhibits apoptosis—programmed cellular suicide that occurs in normal cells but not in malignant cells, allowing them to survive. Later, they found that patients with an aggressive blood cancer known as acute myeloid leukemia (AML) and high levels of TCTP tended to have poor outcomes.
Chemotherapy is ineffective for about 30 percent of AML patients, and at least 50 percent of those who achieve remission eventually relapse. Mutations in the tumor suppressor gene, p53, which normally regulates the cell cycle and triggers apoptosis in the face of cellular DNA damage, were also associated with poor outcomes. The researchers theorized that they could improve AML treatment outcomes by finding a way to modify these two genes to reduce TCTP and restore normal p53 function.
Using a cellular screening approach, Telerman and Amson looked for a known drug that could decrease TCTP levels. Their most promising candidate was sertraline (Zoloft), a commonly prescribed antidepressant that belongs to a class of medications called selective serotonin reuptake inhibitors (SSRIs). Lab studies revealed that sertraline binds to TCTP, preventing it from activating another protein, MDM2, which, in turn, inactivates and subsequently destroys the p53 tumor suppressor protein. Preclinical studies of sertraline in solid tumors, including colon, cancer, and breast cancer, showed that inhibiting the expression of TCTP increased the number of revertant cells by 30 percent. Additional experiments revealed that sertraline was the only SSRI on the market with this unique ability. But without testing it in the clinic, there was no way to know whether this approach would work in patients who had failed initial treatment.
As it would happen, Frattini was introduced to Telerman and Amson via one of his long-time mentors, Judy Karp, MD, an international expert in acute leukemia, both clinically and scientifically, at Johns Hopkins Medical Center in Baltimore. Karp had collaborated with Telerman and Amson to test sertraline in combination with standard chemotherapy (cytarabine) in primary patient samples of AML. After seeing the positive results, Karp brought the three groups together. Frattini jumped at the chance to test the combination therapy in patients with relapsed AML, with Karp, Telerman, and Amson as collaborators.
With funding secured from the Leukemia and Lymphoma Society, Frattini has launched a small Phase I, dose-escalating trial of sertraline in combination with cytarabine, a chemotherapy agent commonly used to treat AML, at Columbia. The primary goal is to test safety at different dosage levels of sertraline, but a secondary aim is to determine if sertraline can help restore normal p53 function. “We are expecting that at higher doses of sertraline, given after the first administration of chemotherapy during the critical [DNA] synthesis phase of the cell cycle, will allow the tumor suppressor to do its job, triggering cell death among the malignant cells and resensitizing remaining cells to chemotherapy,” says Frattini.
So far, the Columbia site is currently accruing patients. Johns Hopkins will enroll additional patients, pending their IRB approval. Frattini’s team, which leads a tissue repository for blood cancers, will process samples from both institutions. Frattini’s and Telerman’s labs will perform the correlative studies.
Two Campuses, One Idea
Learning about the clinical trial taking place at Columbia’s campus on 168th Street has been deeply satisfying for Pollack, who recently met Frattini for the first time. “Imagine how I feel, hearing about this clinical trial 40 years after my initial work to learn from tumor revertants. I am getting used to the idea that reverting to normal is finally in play as a potential treatment for cancer, right here in our own university.”
Pollack’s excitement stems from the inevitable connecting of the dots, beginning with his own work in the lab to the elegant studies of Telerman and Amson and finally moving ahead to the current sertraline clinical trial. It is a fitting scene for a former researcher who wants us to admit that while we may not have an elegant and ultimate solution for cancer, we may finally get to see what happens when we work with evolution, not against it.
