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Boston — A team of Dana-Farber Cancer Institute investigators discovered that a subset of myeloid and lymphoid leukemias depend on a molecular complex called PI3Kgamma for survival. The study provides both mechanistic and preclinical evidence supporting the rapid initiation of clinical trials for patients with acute myeloid leukemia (AML) to test an existing medicine that inhibits the complex, called eganelisib, both alone and in combination with the most used AML chemotherapy, cytarabine. The study was published in Nature.
“Given what we’ve observed, we can move very quickly to take these medicines, which appear to be safe and well tolerated, to patients with AML,” says principal investigator Andrew Lane, MD, PhD, a clinician-scientist in the Adult Leukemia Program at Dana-Farber. “We are planning clinical trials to start hopefullywithin the next year.”
Treatment for AML has advanced in the last decade, but most patients ultimately relapse after treatment. Therapies that target AML-related mutations have provided options for subsets of patients, though the cancer eventually evolves to evade the therapy.
The Dana-Farber team took a different approach to searching for therapeutic targets. Rather than focusing on mutations, first author Qingyu Luo, MD, PhD, a research fellow in Lane’s lab, used genome wide CRISPR interference to search for genes that AML cells rely on to grow.
He found a promising hit. A subset of leukemia cells relied on a gene called PI3KR5 to survive. That gene produces an important portion of the PI3Kgamma complex.
This hit was attractive in part because the PI3Kgamma complex had been studied before, though not in AML. In addition, a medicine already existed to inhibit it. This drug, eganelisib, has been tested in trials for certain solid tumors to enhance cancer immunotherapy.
What Luo and Lane had found, however, was a completely different mechanism of action in which the drug might work directly on leukemia cells to stop their growth.
To validate this hypothesis, the team treated animal models harboring patient-derived leukemia xenografts with eganelisib. They found that the leukemia xenografts predicted to be highly dependent on PI3Kgamma shrank, and the animal models survived longer when treated with eganelisib.
Looking at The Cancer Genome Atlas Data (TCGA), the team found that patients with AML predicted to be sensitive to eganelisib don’t do as well in terms of survival on existing therapies compared to those with negative biomarkers. This finding suggests that this patient group, which can be identified by high levels of PI3KR5 expression, has a need for new medicines and could potentially benefit from treatment with eganelisib.
“This is a drug that is ready to be tested in patients with AML,” says Lane. “It’s already been used in clinical trials for many patients with solid tumors.”
Luo, who initiated this research to improve existing therapies for AML, also treated animal models of leukemia with cytarabine alone and with eganelisib plus cytarabine. The team found that those treated with a combination of eganelisib and cytarabine survived longer than those treated with cytarabine alone, regardless of the leukemia’s sensitivity to PI3Kgamma inhibition alone.
The observations suggested that the two medicines worked synergistically. Luo investigated and found that PI3Kgamma, when inhibited, also results in the suppression of a leukemia cell metabolic process called oxidative phosphorylation (OXPHOS). Leukemia cells depend on OXPHOS for energy, and suppression of OXPHOS can result in their demise.
Luo also discovered that leukemia cells that survive standard treatment with cytarabine tend to be more dependent on PI3Kgamma than they were prior to treatment. These surviving leukemia cells — which are the cause of AML relapse — could be vulnerable to combination therapy with eganelisib and cytarabine.
“We want synergy, where two drugs mesh with each other,” says Luo. “Through inhibition of PI3Kgamma, eganelisib has this downstream effect of suppressing an energy pathway important in AML relapse.”
The team is now focused on designing clinical trials for patients.
“This study provides the scientific rationale for a clinical application and also helps us understand where the discoveries apply to the needs of our patients,” says Lane. “Dana-Farber is one of the unique places where you can go from molecular biology in the lab to testing in models based on patient samples and then to rapidly initiating a clinical trial on the basis of this science.”