Combination therapy research strategy comes full circle

When asked about his approach to treating childhood leukemia, Donald Pinkel, MD, the first medical director (and first employee) of St. Jude, stated, “There were some leukemia cells that were sensitive to one drug, and other cells that were sensitive to another. But if we used all these drugs at once and hit them along different pathways, we could permanently inhibit the development of resistant cells.” This simple approach to treating cancer set in motion the Total Therapy clinical studies, raising the abysmal 4% survival of children with acute lymphoblastic leukemia (ALL) to 94% today in the United States. 

Through 17 iterations, the Total Therapy approach has leveraged drug combination strategies to build on Pinkel’s legacy and improve patient outcomes, modernizing medications to address increasingly difficult-to-treat cases. A common presumption in the field is that these drug combinations are synergistic (when two drugs combined exceed expectations defined by their addition). This belief is commonly used to motivate further discovery studies seeking synergistic combinations. However, synergy in the lab does not always translate to clinical efficacy. Considering this, Christian Meyer, PhD, Department of Pharmacy & Pharmaceutical Sciences, set out to identify common misconceptions surrounding effective combination treatments. 

“I started engaging other researchers and setting up monthly workshop meetings to discuss the state of the drug synergy field,” said Meyer. “The goal was to distill a consensus framework for the challenges facing drug combination discovery with an eye toward marking the 2026 centennial anniversary of the first drug synergy metric called Loewe Additivity.”

A collaboration to find the real activity in drug combinations

As a result of these discussions and a comprehensive analysis of clinically successful and unsuccessful drug combinations, Meyer and his colleagues concluded that the pursuit of synergy was coming at the cost of activity. “What we should care about is whether the combination actually improves patient outcomes, but that’s not how we are analyzing the early stages of the combination discovery pipeline,” Meyer said.

“We tend to look for synergy in the early phases of a screening campaign, often involving testing cancer cells in culture. And if the front-end filter is for synergy, highly effective, nonsynergistic, combinations may be thrown out.”

In a 2026 call-to-action published in Med, first- and co-corresponding author Meyer and his colleagues emphasize a need to recast the objectives of preclinical studies to align them better with clinical outcome, just as Pinkel did in 1967. The researchers distilled their discussions down to three key observations to set researchers up for success in drug combination discovery:

1. Synergy in the lab is not the same as activity in the clinic

Historically, the most effective and safe combinations pair drugs that are already safe and effective on their own. “Many pediatric cancer combinations, such as vincristine, doxorubicin and cyclophosphamide, work because they’re tolerated in patients and target different liabilities in cells, not because of mechanistic synergy,” said co-author Anang Shelat, PhD, Lead Discovery Informatics Center director and Department of Chemical Biology & Therapeutics associate member. “Independent actions protect patients from resistance, give doctors another strategy in play, and provide an extra boost. That’s what we see in leukemia therapies and standard-of-care regimens: Find the niches that survive, find something that hits them, and add it.”

This point is supported by the many synergistic pairings that fail in the clinic because they are simply not effective enough.

2. Patients should come first in preclinical studies

Synergistic combinations frequently cause toxicity in clinical trials. As Meyer noted, this is largely due to on-target, off-tissue effects. “We observed that toxicity is often based on specificity,” he said. “For example, if a combination is synergistic in diverse tumor backgrounds such as leukemia, ovarian cancer and glioblastoma cells that are not connected by a common mutation or driver, then it’s likely going to be a toxic combination, because its mechanism isn’t specific to the disease tissue. This is counter to the commonly held belief that broad synergy is a suitable indication to pursue a combination.”

The drug combinations most likely to succeed clinically will limit toxicity through specificity — working only in a diseased tissue. Further, nonactive single agents, which commonly increase toxicity, should be reduced. If this level of safety is established as a primary goal of preclinical studies, combinations entering clinical trials that are too toxic could be significantly reduced.

3. It’s OK to say ‘antagonism’

An antagonistic drug combination is one where the total activity is less than would be expected by each individual drug. This lack of activity may seem counterproductive, but in some cases, this can be the right approach. This practice has already seen clinical success in the case of leucovorin. High doses of the drug methotrexate, which affects folate metabolism, are often given to high-risk cancer patients. Methotrexate causes toxicity that could become intolerable, but doctors get around this by giving the drug leucovorin, a methotrexate antagonist, 24 hours later.

“Cancer cells are more dependent on the folate pathway than normal cells, so the time lag is used to bring everything to the brink before pulling back with the rescue antagonist,” Shelat explained. “Leucovorin rescue is a mainstay in pediatric cancer.”

Still, despite examples such as this, investigations into antagonistic pairs are perceived with an air of skepticism. The researchers stress that drug combination discovery could benefit from a more agnostic approach to synergy and antagonism.

“The word ‘antagonism’ is used in a negative connotation, but mathematically defined, there is nothing inherently ‘good’ about a synergistic drug over an antagonistic drug or vice versa,” Meyer said. “It’s an accident of linguistics that the word ‘synergy’ is positive, and the word ‘antagonism’ is negative. But there may be so many useful antagonistic drug combinations yet to be discovered.” 

“The type of interaction present in a drug combination, whether it is additive, synergistic or antagonistic, should guide subsequent preclinical studies rather than be used as a hard filter to select which combinations to pursue further,” Shelat added.

Back to basics for the next era of drug combination discovery

While the siren song of “synergy” in preclinical studies is widespread, Meyer, Shelat and their colleagues are hopeful that the field will shift toward prioritizing efficacy and tolerability in patients as the only guiding light.

“There is no institution on earth that better exemplifies this idea than St. Jude, founded on the Total Therapy approach,” Meyer said. “It was never about designing a synergistic drug combination; instead, by targeting the different heterogeneous compartments in different tumor types, the tumor could be eliminated using drug combinations.” Just as Pinkel began with the idea of designing drug combinations with patients in mind from the outset, so too are St. Jude researchers carrying that vision forward today.