Blazing a TRAIL in acute myeloid leukemia treatment

Acute myeloid leukemia (AML) is the most common form of leukemia in adults and second-most common in children. Despite its prevalence, treatments for AML have remained the same for much of the past 40 years. AML is a cancer which affects myeloid cells, the precursors for red and white blood cells and platelets. When these cells are prevented from maturing, they rapidly accumulate, leading to a quick onset of AML symptoms, namely hemorrhaging and a heightened risk of infection.

The rapid development and unpredictability of AML, which has at least eight different subtypes based on the cell type from which the leukemia developed, means it is complicated to treat. Traditional therapeutics involve anthracycline-based chemotherapies such as doxorubicin in combination with cytarabine-based chemotherapies. These drugs insert themselves into DNA, halting all function of gene expression — like derailing a train by placing a block of wood onto the tracks.

While the five-year survival for patients with pediatric AML is approximately 70%, overall survival decreases with age, around 30% for adults and below 10% for adults over 65. This is compounded by poor prognoses in patients with relapsed disease and the significant cardiotoxicity of chemotherapies such as doxorubicin, which limit their long-term therapeutic use.

Scientists at St. Jude are looking to increase the therapeutic options for AML patients by studying the leading candidates for novel therapeutics in AML. Led by John Schuetz, PhD, Department of Pharmacy and Pharmaceutical Sciences, researchers are optimizing the next generation of drugs that harness natural cell-death pathways.

Harnessing cell-death pathways to treat AML

A recent advance to standard AML treatment incorporated venetoclax. Venetoclax binds to the B-cell lymphoma-2 (BCL-2) protein, blocking its ability to protect against apoptosis (cell death). However, venetoclax alone shows low efficacy, meaning it must be combined with other chemotherapies to elicit a positive effect. Research on the optimal combination approaches for venetoclax is ongoing, and new drugs are entering the market, such as the tyrosine kinase 3 inhibitor quizartinib. The armamentaria of drugs available to treat AML remains concerningly small, considering the diversity of drug responses among the AML subtypes.

There is growing interest in utilizing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to treat AML. TRAIL is a protein that selectively induces apoptosis in cancer cells when activated by binding to specific cell-death receptors while sparing normal cells. TRAIL–activating drugs have yet to reach their full clinical potential; however, one such drug that has shown promise is ONC201.

ONC201 demonstrated good safety and efficacy through phase 2 clinical trials — warranting a deeper understanding of the mechanism by which it works. These studies revealed that while ONC201 activates TRAIL, the drug also activates a mitochondrial protein involved in cell death called ClpP. This dual activation shows that ONC201 has a multi-pronged attack on cancer cells.

Learning from these studies, researchers theorized that by leveraging ONC201’s chemical scaffold, called an imipridone, they could design even more effective AML treatments. Published in Cancer Research, Schuetz and his team collaborated with Wayne State University School of Medicine researchers to mechanistically investigate one stand-out member of these next-generation imipridone-based drugs, ONC213.

Almost identical, nothing alike

While ONC201 and ONC213 are almost identical, to the researcher’s surprise, they functioned differently. “If you look at the two structures, there are one or two small differences between ONC201 and ONC213,” Schuetz said, “But how they function to kill AML is completely different.”

ONC201 kills cancer cells in multiple distinct ways. However, despite its TRAIL–targeting origins, ONC213 does not activate TRAIL, and although it does activate ClpP in cell-free systems, the subsequent cell-death pathway initiated was very different from the one induced by ONC201.

“We showed that in vitro, ONC213 activates ClpP, but in AML cells, you don’t see any of the hallmark reductions in mitochondrial enzymes that ONC201 produces,” said Schuetz.

The researchers showed that the mechanism of action for ONC213 runs through a protein called alpha-ketoglutarate dehydrogenase (α-KGDH). α-KGDH plays a vital role in the citric acid cycle, which releases the energy stored in nutrients.

“We took cells treated with ONC213, isolated mitochondria and looked at the catalytic activity of α-KGDH. Within a few hours, there was rapid suppression of activity,” said Schuetz. “We also did comparisons with ONC201 and found that ONC201 did not suppress α-KGDH.”

α-KGDH represents promising new AML target

But how does the citric acid cycle influence cancer cell survival? Gene expression analysis reveals that suppression of α-KGDH triggers a unique mitochondrial stress response cascade that has devastating effects in AML cells. Unlike normal myeloid cells, which primarily gain energy from glycolysis, AML cancer cells often shift energy metabolism to α-KGDH for a continued energy supply. Like flipping a breaker, ONC213 cuts AML progenitor cells off from this energy supply, leading to a mitochondrial stress response and, eventually, cell death. Notably, the drug even showed efficacy in cells from a patient with relapsed disease.

The results are promising, but drugs based on imipridone are still in their developmental infancy for AML treatment. One major hurdle for ONC213 is that it also reduces MCL-1 levels, which has been tied to cardiotoxicity and, recently, mitochondrial metabolism. Still, uncovering α-KGDH as a potential AML target is an exciting breakthrough.

Schuetz is hot on the trail to understand this link better. “While α-KGDH is important, we think there are some other things going on in the cells, too. We’re doing some metabolic CRISPR screens and some mass spectrometry thermal shift experiments to identify other targets,” he said.

Through research efforts like these, scientists can tease apart the mechanism behind potential therapeutics — revealing novel druggable pathways. By building upon these efforts to learn more about the weaknesses of AML, researchers will chip away at poor outcomes and develop the next generation of therapies for this disease.