Cancer cells have a bias toward survival, often becoming heavily reliant on certain protein pathways to sustain themselves. Scientists are finding ways to turn that survival instinct into a liability — by making the cells even more dependent on those pathways, then choking the pathways off.
It’s an approach that has now yielded a promising combination drug therapy for T-cell prolymphocytic leukemia (T-PLL), a rare, aggressive hematologic cancer. In a recent study in the journal Blood, Dana-Farber researchers analyzed blood samples from two dozen patients with T-PLL and found that pairing the targeted drugs ruxolitinib and venetoclax caused T-PLL cells to die in the laboratory. When they tested the combination in two patients with advanced T-PLL, the results were encouraging: one patient experienced a deep remission, and the other, whose cancer was rapidly worsening, saw the advance of the disease come to halt.
“T-PLL is an especially challenging cancer to treat. The current treatments, such as chemotherapy and the antibody drug alemtuzumab, aren’t very effective and lead to considerable toxicities,” says Dana-Farber’s Matthew Davids, MD, senior author of the study. “We urgently need to identify the molecular vulnerabilities of T-PLL cells so we can design clinical trials of drugs that target those weaknesses. Our study is one of the first to do that.”
A ‘unique opportunity’
A major obstacle to molecular research in T-PLL is the rarity of the disease. The relatively small number of patients — about 200 adults in the U.S. are diagnosed with it each year — has made it difficult to obtain sufficient tissue samples to study.
For the current study, Charles Herbaux, MD, MSc — a postdoctoral fellow in Davids’ lab — utilized a collection of 20 T-PLL primary samples from patients across France that were banked at his home institution, Lille University School of Medicine. These, combined with four from Dana-Farber, provided “a unique opportunity to study the molecular dependencies of this disease,” Davids remarks.
Researchers already had a clue to one of those vulnerabilities. Studies had shown that the drug venetoclax, which blocks a protein called BCL-2, produced brief responses in some patients with T-PLL. BCL-2 is a survival protein — so-called because it inhibits cells from dying through a natural process known as apoptosis. The temporary effectiveness of venetoclax in patients with T-PLL suggested that the tumor cells were sustained, in part, by BCL-2.
The challenge then became to find a targeted drug that could work synergistically with venetoclax. Researchers analyzed the 24 T-PLL samples using a novel technique called BH3 profiling, which gauges how likely a cell is to undergo apoptosis, and how functionally dependent it is on certain survival proteins. The technique, developed in the laboratory of Dana-Farber’s Anthony Letai, MD, PhD, showed that while many of the cells were indeed dependent on BCL-2, many more were dependent on MCL-1, another survival protein.
“The reliance on MCL-1 suggested why venetoclax alone is not sufficient therapy for T-PLL,” Davids notes. Treating T-PLL cells in the laboratory with drugs that target BCL-2 or MCL-1 produced promising results, but MCL-1-blocking drugs are still early in development, and their range of side effects in patients is not known.
The investigators then tested other drugs that block protein pathways also known to be awry in T-PLL. Inhibiting the JAK/STAT or HDAC pathways — both key targets in the disease — had little effect on their own. But BH3 profiling suggested that targeting the JAK/STAT and BCL-2 pathways simultaneously would be beneficial. That proved correct.
“In laboratory studies, we found that the JAK/STAT inhibitor ruxolitinib seemed to make the tumor cells more BCL-2 dependent. That, in turn, made them more susceptible to venetoclax,” Davids remarks. “This happened even in cells that were MCL-1 dependent. Treatment with ruxolitinib rewired the cells toward dependence on BCL-2.”
The results prompted the treatment of two patients with treatment-resistant T-PLL with the tandem of ruxolitinib and venetoclax. The results — a deep remission in one patient and stabilized disease in the second patient, who had particularly aggressive T-PLL — suggest the potential of this approach. Investigators are exploring opening a clinical trial of the combination for patients with the disease.